Publications by authors named "Ravikumar Balasubramanian"

36 Publications

Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants.

Genet Med 2021 Jan 13. Epub 2021 Jan 13.

Harvard Reproductive Sciences Center, The Reproductive Endocrine Unit and The Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Purpose: SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders.

Methods: Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population.

Results: Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD.

Conclusion: SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.
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http://dx.doi.org/10.1038/s41436-020-01051-3DOI Listing
January 2021

Hypothalamic Ceramides and the Ovarian Sympathetic System: At the Crossroads of Obesity and Puberty.

Cell Metab 2021 Jan 1;33(1):6-8. Epub 2020 Dec 1.

Harvard MGH Center for Reproductive Medicine and Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:

Childhood obesity has been linked to early puberty in girls but the mechanism(s) by which overnutrition triggers pubertal onset remain unclear. In a recent issue of Cell Metabolism, Heras et al., 2020 implicate a non-canonical central ceramide to ovarian sympathetic innervation pathway as a novel mediator of obesity-induced pubertal acceleration in female rats.
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http://dx.doi.org/10.1016/j.cmet.2020.11.012DOI Listing
January 2021

Evaluating co-created patient-facing materials to increase understanding of genetic test results.

J Genet Couns 2020 Oct 24. Epub 2020 Oct 24.

Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Patients often have difficulty understanding genetic test reports. Technical language and jargon can impede comprehension and limit patients using results to act on findings. One potential way to improve patient understanding of genetic test reports is to provide patient-facing materials. This study aimed to examine understandability and actionability of co-created patient-facing materials for genetic test results in a research context. We combined interprofessional perspectives and patient engagement to co-create patient-facing materials for patients undergoing research genetic testing for congenital hypogonadotropic hypogonadism (Kallmann syndrome). The iterative development process was guided by principles of health literacy and human-centered design (i.e., design thinking). Readability was assessed using eight validated algorithms. Patients and parents evaluated materials using a web-based survey. The gold standard Patient Education Materials Assessment Tool for print materials (PEMAT-P) was employed to measure understandability (content, style, use of numbers, organization, design, use of visual aids) and actionability. PEMAT-P scores >80% were considered high quality. Results were analyzed descriptively and correlations performed to identify relationships between education/health literacy and PEMAT-P ratings. A consensus score of eight algorithms indicated the materials were an 8 -9th grade reading level. Our findings are consistent with the U.S. Department of Health and Human Services 'average difficulty' classification (i.e., 7th-9th grade). In total, 61 patients/parents evaluated the materials. 'Visual Aids' received the lowest mean PEMAT-P rating (89%). All other parameters scored 90%-97%. PEMAT-P scores did not differ according to educational attainment (less than college vs. college or more, p = 0.28). Participants with adequate health literacy were more likely to approve of the 'organization' of information (p < 0.05). Respondents with low health literacy had more favorable views of 'visual aids' (p < 0.01). Involving patients in a co-creation process can produce high-quality patient-facing materials that are easier to understand.
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http://dx.doi.org/10.1002/jgc4.1348DOI Listing
October 2020

TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci.

Hum Mol Genet 2020 Aug;29(14):2435-2450

Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.

Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated GnRH deficiency (IGD). Here, we report 13 families (12 autosomal dominant and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12, and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD, highlight the genetic links between craniofacial patterning and GnRH dysfunction and begin to assemble the functional network that regulates the development of the GnRH axis.
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http://dx.doi.org/10.1093/hmg/ddaa120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608740PMC
August 2020

Pubertal timing predicts adult psychosexuality: Evidence from typically developing adults and adults with isolated GnRH deficiency.

Psychoneuroendocrinology 2020 09 6;119:104733. Epub 2020 Jun 6.

Department of Anthropology, Pennsylvania State University, Carpenter Building, University Park, PA, 16802, USA. Electronic address:

Evidence suggests that psychosexuality in humans is modulated by both organizational effects of prenatal and peripubertal sex steroid hormones, and by activational effects of circulating hormones in adulthood. Experimental work in male rodents indicates that sensitivity to androgen-driven organization of sexual motivation decreases across the pubertal window, such that earlier puberty leads to greater sex-typicality. We test this hypothesis in typically developing men (n = 231) and women (n = 648), and in men (n = 72) and women (n = 32) with isolated GnRH deficiency (IGD), in whom the precise timing of peripubertal hormone exposure can be ascertained via the age at which hormone replacement therapy (HRT) was initiated. Psychosexuality was measured with the Sexual Desire Inventory-2 (SDI-2) and Sociosexual Orientation Inventory-Revised (SOI-R). In both sexes, earlier recalled absolute pubertal timing predicted higher psychosexuality in adulthood, although the magnitude of these associations varied with psychosexuality type and group (i.e., typically developing and IGD). Results were robust when controlling for circulating steroid hormones in typically developing participants. Age of initiation of HRT in men with IGD negatively predicted SOI-R. We discuss the clinical implications of our findings for conditions in which pubertal timing is medically altered.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104733DOI Listing
September 2020

Hypogonadotropic hypogonadism due to variants in : expanding the phenotypic and genotypic spectrum of Martsolf syndrome.

Cold Spring Harb Mol Case Stud 2020 06 12;6(3). Epub 2020 Jun 12.

Harvard Reproductive Endocrine Sciences Center, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Biallelic pathogenic variants in cause Warburg Micro syndrome (WARBM) and Martsolf syndrome (MS), two rare, phenotypically overlapping disorders characterized by congenital cataracts, intellectual disability, and hypogonadism. Although the initial report documented hypergonadotropic hypogonadism (implying a gonadal defect), an adolescent girl with WARBM/MS was subsequently reported to have hypogonadotropic hypogonadism (implying a central defect in either the hypothalamus or anterior pituitary). However, in adult MS, hypogonadotropism has not been convincingly demonstrated. Additionally, the correlation between the pathogenic severity of variants in and the phenotypic severity also remains unclear. Here we present a clinical report of a woman with congenital cataracts, apparent intellectual disability, and pubertal failure who underwent exome sequencing (ES) to determine a precise molecular diagnosis. Reproductive phenotypes reported previously in individuals with MS and the genotypic spectrum of previous variants were also reviewed. The ES identified pathogenic compound heterozygous variants (c.387-2A > G; p.(Arg428Glu)) combined with her phenotypic features, which enabled a unifying molecular diagnosis of MS. Reproductive evaluation confirmed a normosmic idiopathic hypogonadotropic hypogonadism. Review of the allelic spectrum in WARBM/MS suggests that although variants resulting in complete abrogation of RAB3GAP2 protein function cause severe WARBM, variants associated with partially preserved RAB3GAP2 function cause milder MS. This report expands the genotypic and phenotypic spectrum of MS and demonstrates hypogonadotropic hypogonadism as a key pathophysiologic abnormality in MS. Genotype-phenotype associations of previously reported variants indicate that variants that fully abolish RAB3GAP2 function result in WARBM, whereas MS is associated with variants of lesser severity with residual RAB3GAP2 function.
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http://dx.doi.org/10.1101/mcs.a005033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304352PMC
June 2020

Timing of peripubertal steroid exposure predicts visuospatial cognition in men: Evidence from three samples.

Horm Behav 2020 05 18;121:104712. Epub 2020 Feb 18.

Department of Anthropology, Pennsylvania State University, Carpenter Building, University Park, PA 16802, USA. Electronic address:

Experiments in male rodents demonstrate that sensitivity to the organizational effects of steroid hormones decreases across the pubertal window, with earlier androgen exposure leading to greater masculinization of the brain and behavior. Similarly, some research suggests the timing of peripubertal exposure to sex steroids influences aspects of human psychology, including visuospatial cognition. However, prior studies have been limited by small samples and/or imprecise measures of pubertal timing. We conducted 4 studies to clarify whether the timing of peripubertal hormone exposure predicts performance on male-typed tests of spatial cognition in adulthood. In Studies 1 (n = 1095) and 2 (n = 173), we investigated associations between recalled pubertal age and spatial cognition in typically developing men, controlling for current testosterone levels in Study 2. In Study 3 (n = 51), we examined the relationship between spatial performance and the age at which peripubertal hormone replacement therapy was initiated in a sample of men with Isolated GnRH Deficiency. Across Studies 1-3, effect size estimates for the relationship between spatial performance and pubertal timing ranged from. -0.04 and -0.27, and spatial performance was unrelated to salivary testosterone in Study 2. In Study 4, we conducted two meta-analyses of Studies 1-3 and four previously published studies. The first meta-analysis was conducted on correlations between spatial performance and measures of the absolute age of pubertal timing, and the second replaced those correlations with correlations between spatial performance and measures of relative pubertal timing where available. Point estimates for correlations between pubertal timing and spatial cognition were -0.15 and -0.12 (both p < 0.001) in the first and second meta-analyses, respectively. These associations were robust to the exclusion of any individual study. Our results suggest that, for some aspects of neural development, sensitivity to gonadal hormones declines across puberty, with earlier pubertal hormone exposure predicting greater sex-typicality in psychological phenotypes in adulthood. These results shed light on the processes of behavioral and brain organization and have implications for the treatment of IGD and other conditions wherein pubertal timing is pharmacologically manipulated.
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http://dx.doi.org/10.1016/j.yhbeh.2020.104712DOI Listing
May 2020

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

J Clin Endocrinol Metab 2020 05;105(5)

Clinical Research Branch, National Institute of Environmental Health Sciences, Durham, North Carolina.

Context: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.

Objective: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.

Methods: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.

Results: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient.

Conclusions: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.
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http://dx.doi.org/10.1210/clinem/dgaa065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108682PMC
May 2020

Gli3 Regulates Vomeronasal Neurogenesis, Olfactory Ensheathing Cell Formation, and GnRH-1 Neuronal Migration.

J Neurosci 2020 01 25;40(2):311-326. Epub 2019 Nov 25.

Department of Biological Sciences; The RNA Institute, and the Center for Neuroscience Research; University at Albany, State University of New York, Albany, New York 12222, and

During mammalian development, gonadotropin-releasing-hormone-1 neurons (GnRH-1ns) migrate from the developing vomeronasal organ (VNO) into the brain asserting control of pubertal onset and fertility. Recent data suggest that correct development of the olfactory ensheathing cells (OEC) is imperative for normal GnRH-1 neuronal migration. However, the full ensemble of molecular pathways that regulate OEC development remains to be fully deciphered. Loss-of-function of the transcription factor Gli3 is known to disrupt olfactory development, however, if Gli3 plays a role in GnRH-1 neuronal development is unclear. By analyzing Gli3 extra-toe mutants (Gli3), we found that Gli3 loss-of-function compromises the onset of achaete-scute family bHLH transcription factor 1 (Ascl-1) vomeronasal progenitors and the formation of OEC in the nasal mucosa. Surprisingly, GnRH-1 neurogenesis was intact in Gli3 mice but they displayed significant defects in GnRH-1 neuronal migration. In contrast, Ascl-1 mutants showed reduced neurogenesis for both vomeronasal and GnRH-1ns but less severe defects in OEC development. These observations suggest that Gli3 is critical for OEC development in the nasal mucosa and subsequent GnRH-1 neuronal migration. However, the nonoverlapping phenotypes between Ascl-1 and Gli3 mutants indicate that Ascl-1, while crucial for GnRH-1 neurogenesis, is not required for normal OEC development. Because Kallmann syndrome (KS) is characterized by abnormal GnRH-1ns migration, we examined whole-exome sequencing data from KS subjects. We identified and validated a loss-of-function variant in a KS individual. These findings provide new insights into GnRH-1 and OECs development and demonstrate that human mutations contribute to KS etiology. The transcription factor Gli3 is necessary for correct development of the olfactory system. However, if Gli3 plays a role in controlling GnRH-1 neuronal development has not been addressed. We found that Gli3 loss-of-function compromises the onset of Ascl-1 vomeronasal progenitors, formation of olfactory ensheathing cells in the nasal mucosa, and impairs GnRH-1 neuronal migration to the brain. By analyzing Ascl-1 mutants we dissociated the neurogenic defects observed in Gli3 mutants from lack of olfactory ensheathing cells in the nasal mucosa, moreover, we discovered that Ascl-1 is necessary for GnRH-1 ontogeny. Analyzing human whole-exome sequencing data, we identified a loss-of-function variant in a KS individual. Our data suggest that is a candidate gene contributing to KS etiology.
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http://dx.doi.org/10.1523/JNEUROSCI.1977-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948949PMC
January 2020

A Balanced Translocation in Kallmann Syndrome Implicates a Long Noncoding RNA, RMST, as a GnRH Neuronal Regulator.

J Clin Endocrinol Metab 2020 03;105(3)

Harvard Reproductive Endocrine Science Center, Massachusetts General Hospital, Boston.

Context: Kallmann syndrome (KS) is a rare, genetically heterogeneous Mendelian disorder. Structural defects in KS patients have helped define the genetic architecture of gonadotropin-releasing hormone (GnRH) neuronal development in this condition.

Objective: Examine the functional role a novel structural defect affecting a long noncoding RNA (lncRNA), RMST, found in a KS patient.

Design: Whole genome sequencing, induced pluripotent stem cells and derived neural crest cells (NCC) from the KS patient were contrasted with controls.

Setting: The Harvard Reproductive Sciences Center, Massachusetts General Hospital Center for Genomic Medicine, and Singapore Genome Institute.

Patient: A KS patient with a unique translocation, t(7;12)(q22;q24).

Interventions/main Outcome Measure/results: A novel translocation was detected affecting the lncRNA, RMST, on chromosome 12 in the absence of any other KS mutations. Compared with controls, the patient's induced pluripotent stem cells and NCC provided functional information regarding RMST. Whereas RMST expression increased during NCC differentiation in controls, it was substantially reduced in the KS patient's NCC coincident with abrogated NCC morphological development and abnormal expression of several "downstream" genes essential for GnRH ontogeny (SOX2, PAX3, CHD7, TUBB3, and MKRN3). Additionally, an intronic single nucleotide polymorphism in RMST was significantly implicated in a genome-wide association study associated with age of menarche.

Conclusions: A novel deletion in RMST implicates the loss of function of a lncRNA as a unique cause of KS and suggests it plays a critical role in the ontogeny of GnRH neurons and puberty.
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http://dx.doi.org/10.1210/clinem/dgz011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112981PMC
March 2020

Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History.

J Clin Endocrinol Metab 2019 08;104(8):3403-3414

Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Context: After completion of puberty a subset of men experience functional hypogonadotropic hypogonadism (FHH) secondary to excessive exercise or weight loss. This phenomenon is akin to hypothalamic amenorrhea (HA) in women, yet little is known about FHH in men.

Objective: To investigate the neuroendocrine mechanisms, genetics, and natural history underlying FHH.

Design: Retrospective study in an academic medical center.

Participants: Healthy postpubertal men presenting with symptoms of hypogonadism in the setting of excessive exercise (>10 hours/week) or weight loss (>10% of body weight). Healthy age-matched men served as controls.

Interventions: Clinical assessment, biochemical and neuroendocrine profiling, body composition, semen analysis, and genetic evaluation of genes known to cause isolated GnRH deficiency.

Main Outcome Measures: Reproductive hormone levels, endogenous GnRH-induced LH pulse patterns, and rare genetic variants.

Results: Ten men with FHH were compared with 18 age-matched controls. Patients had significantly lower body mass index, testosterone, LH, and mean LH pulse amplitudes yet normal LH pulse frequency, serum FSH, and sperm counts. Some patients exhibited nocturnal, sleep-entrained LH pulses characteristic of early puberty, and one FHH subject showed a completely apulsatile LH secretion. After decreased exercise and weight gain, five men with men had normalized serum testosterone levels, and symptoms resolved. Rare missense variants in NSMF (n = 1) and CHD7 (n = 1) were identified in two men with FHH.

Conclusions: FHH is a rare, reversible form of male GnRH deficiency. LH pulse patterns in male FHH are similar to those observed in women with HA. This study expands the spectrum of GnRH deficiency disorders in men.
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http://dx.doi.org/10.1210/jc.2018-02697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594303PMC
August 2019

Modeling mutant/wild-type interactions to ascertain pathogenicity of PROKR2 missense variants in patients with isolated GnRH deficiency.

Hum Mol Genet 2018 01;27(2):338-350

Harvard Reproductive Sciences Center and The Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

A major challenge in human genetics is the validation of pathogenicity of heterozygous missense variants. This problem is well-illustrated by PROKR2 variants associated with Isolated GnRH Deficiency (IGD). Homozygous, loss of function variants in PROKR2 was initially implicated in autosomal recessive IGD; however, most IGD-associated PROKR2 variants are heterozygous. Moreover, while IGD patient cohorts are enriched for PROKR2 missense variants similar rare variants are also found in normal individuals. To elucidate the pathogenic mechanisms distinguishing IGD-associated PROKR2 variants from rare variants in controls, we assessed 59 variants using three approaches: (i) in silico prediction, (ii) traditional in vitro functional assays across three signaling pathways with mutant-alone transfections, and (iii) modified in vitro assays with mutant and wild-type expression constructs co-transfected to model in vivo heterozygosity. We found that neither in silico analyses nor traditional in vitro assessments of mutants transfected alone could distinguish IGD variants from control variants. However, in vitro co-transfections revealed that 15/34 IGD variants caused loss-of-function (LoF), including 3 novel dominant-negatives, while only 4/25 control variants caused LoF. Surprisingly, 19 IGD-associated variants were benign or exhibited LoF that could be rescued by WT co-transfection. Overall, variants that were LoF in ≥ 2 signaling assays under co-transfection conditions were more likely to be disease-associated than benign or 'rescuable' variants. Our findings suggest that in vitro modeling of WT/Mutant interactions increases the resolution for identifying causal variants, uncovers novel dominant negative mutations, and provides new insights into the pathogenic mechanisms underlying heterozygous PROKR2 variants.
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http://dx.doi.org/10.1093/hmg/ddx404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886255PMC
January 2018

Reproductive endocrine phenotypes relating to CHD7 mutations in humans.

Am J Med Genet C Semin Med Genet 2017 12 20;175(4):507-515. Epub 2017 Nov 20.

Harvard Reproductive Endocrine Sciences Center of Excellence in Translation Research & Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Mutations in the gene CHD7 cause CHARGE syndrome, a rare multi-organ syndromic disorder. Gonadal defects are common in individuals with CHARGE syndrome (seen in ∼60-80% of cases) and represent the letter "G" in the CHARGE syndrome acronym. The gonadal defect in CHARGE syndrome results from congenital deficiency of the hypothalamic hormone Gonadotropin-releasing hormone (GnRH), which manifests clinically as pubertal failure and infertility, and biochemically as hypogonadotropic hypogonadism (low sex steroid hormone levels with inappropriately normal or low gonadotropin levels). In addition to the gonadal endocrine abnormalities, in a small minority of individuals with CHARGE, additional endocrine defects including growth hormone deficiency, multiple pituitary hormone deficits and primary hypothyroidism may also be seen. CHD7 mutations disrupt the targeting of olfactory axons and the migration of GnRH-synthesizing neurons during embryonic development, resulting in congenital idiopathic hypogonadotropic hypogonadism (IHH) and anosmia (or hyposmia), two features that define human Kallmann syndrome. Since Kallmann syndrome is one of the constituent phenotypes within CHARGE, recent studies have investigated the role of CHD7 mutations in individuals with IHH and established that deleterious missense mutations in CHD7 are associated with Kallmann syndrome as well as normosmic form of IHH. These missense mutations affect the ATPase and nucleosome remodeling activities of the CHD7 protein. These observations suggest that CHD7 protein function is critical for the ontogeny of GnRH neurons and neuroendocrine regulation of GnRH secretion.
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http://dx.doi.org/10.1002/ajmg.c.31585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790312PMC
December 2017

Corrigendum: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Nat Genet 2017 05;49(6):969

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http://dx.doi.org/10.1038/ng0617-969cDOI Listing
May 2017

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Nat Genet 2017 Feb 9;49(2):238-248. Epub 2017 Jan 9.

Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.
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http://dx.doi.org/10.1038/ng.3743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473428PMC
February 2017

Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency.

J Clin Endocrinol Metab 2015 Oct 24;100(10):E1378-85. Epub 2015 Jul 24.

Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.

Context: Loss of function (LoF) mutations in more than 20 genes are now known to cause isolated GnRH deficiency (IGD) in humans. Most causal IGD mutations are typically private, ie, limited to a single individual/pedigree. However, somewhat paradoxically, four IGD genes (GNRH1, TAC3, PROKR2, and GNRHR) have been shown to harbor LoF founder mutations that are shared by multiple unrelated individuals. It is not known whether similar founder mutations occur in other IGD genes.

Objective: The objective of the study was to determine whether shared deleterious mutations in IGD-associated genes represent founder alleles.

Setting: This study was an international collaboration among academic medical centers.

Methods: IGD patients with shared mutations, defined as those documented in three or more unrelated probands in 14 IGD-associated genes, were identified from various academic institutions, the Human Gene Mutation Database, and literature reports by other international investigators. Haplotypes of single-nucleotide polymorphisms and short tandem repeats surrounding the mutations were constructed to assess genetic ancestry.

Results: A total of eight founder mutations in five genes, GNRHR (Q106R, R262Q, R139H), TACR3 (W275X), PROKR2 (R85H), FGFR1 (R250Q, G687R), and HS6ST1 (R382W) were identified. Most founder alleles were present at low frequency in the general population. The estimated age of these mutant alleles ranged from 1925 to 5600 years and corresponded to the time of rapid human population expansion.

Conclusions: We have expanded the spectrum of founder alleles associated with IGD to a total of eight founder mutations. In contrast to the approximately 9000-year-old PROKR2 founder allele that may confer a heterozygote advantage, the rest of the founder alleles are relatively more recent in origin, in keeping with the timing of recent human population expansion and any selective heterozygote advantage of these alleles requires further evaluation.
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http://dx.doi.org/10.1210/jc.2015-2262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596034PMC
October 2015

Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome.

J Clin Endocrinol Metab 2015 Mar 5;100(3):E473-7. Epub 2015 Jan 5.

Harvard Reproductive Endocrine Sciences Center (R.B.), The Reproductive Endocrine Unit of the Department of Medicine (R.B.), Massachusetts General Hospital, Boston, Massachusetts 02114; Harvard Medical School (R.B., S.C., P.B.K., C.A., W.-M.C., E.C.E.), Boston, Massachusetts 02115; Department of Neurology (S.C., P.B.K., C.A., W.-M.C., E.C.E.), Kirby Neurobiology Center (S.C., C.A., W.-M.C., E.C.E.), and Department of Ophthalmology (S.E.M., E.C.E.), Boston Children's Hospital, Boston, Massachusetts 02115; and Howard Hughes Medical Institute (S.C., C.A., W.-M.C., E.C.E.), Chevy Chase, Maryland 20815.

Context: A heterozygous de novo c.1228G>A mutation (E410K) in the TUBB3 gene encoding the neuronal-specific β-tubulin isotype 3 (TUBB3) causes the TUBB3 E410K syndrome characterized by congenital fibrosis of the extraocular muscles (CFEOM), facial weakness, intellectual and social disabilities, and Kallmann syndrome (anosmia with hypogonadotropic hypogonadism). All TUBB3 E410K subjects reported to date are sporadic cases.

Objective: This study aimed to report the clinical, genetic, and molecular features of a familial presentation of the TUBB3 E410K syndrome.

Design: Case report of a mother and three affected children with clinical features of the TUBB3 E410K syndrome.

Setting: Academic Medical Center.

Main Outcome Measures: Genetic analysis of the TUBB3 gene and clinical evaluation of endocrine and nonendocrine phenotypes.

Results: A de novo TUBB3 c.1228G>A mutation arose in a female proband who displayed CFEOM, facial weakness, intellectual and social disabilities, and anosmia. However, she underwent normal sexual development at puberty and had three spontaneous pregnancies with subsequent autosomal-dominant inheritance of the mutation by her three boys. All sons displayed nonendocrine features of the TUBB3 E410K syndrome similar to their mother but, in addition, had variable features suggestive of additional endocrine abnormalities.

Conclusions: This first report of an autosomal-dominant inheritance of the TUBB3 c.1228G>A mutation in a family provides new insights into the spectrum and variability of endocrine phenotypes associated with the TUBB3 E410K syndrome. These observations emphasize the need for appropriate clinical evaluation and complicate genetic counseling of patients and families with this syndrome.
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http://dx.doi.org/10.1210/jc.2014-4107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333039PMC
March 2015

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency.

Proc Natl Acad Sci U S A 2014 Dec 3;111(50):17953-8. Epub 2014 Dec 3.

Harvard Reproductive Endocrine Sciences Center & Reproductive Endocrine Unit of the Department of Medicine, and Medicine,

Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.
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http://dx.doi.org/10.1073/pnas.1417438111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273325PMC
December 2014

Signaling role of prokineticin 2 on the estrous cycle of female mice.

PLoS One 2014 14;9(3):e90860. Epub 2014 Mar 14.

Department of Pharmacology, University of California, Irvine, California, United States of America.

The possible signaling role of prokineticin 2 (PK2) and its receptor, prokineticin receptor 2 (PKR2), on female reproduction was investigated. First, the expression of PKR2 and its co-localization with estrogen receptor (ERα) in the hypothalamus was examined. Sexually dimorphic expression of PKR2 in the preoptic area of the hypothalamus was observed. Compared to the male mice, there was more widespread PKR2 expression in the preoptic area of the hypothalamus in the female mice. The likely co-expression of PKR2 and ERα in the preoptic area of the hypothalamus was observed. The estrous cycles in female PK2-null, and PKR2-null heterozygous mice, as well as in PK2-null and PKR2-null compound heterozygous mice were examined. Loss of one copy of PK2 or PKR2 gene caused elongated and irregular estrous cycle in the female mice. The alterations in the estrous cycle were more pronounced in PK2-null and PKR2-null compound heterozygous mice. Consistent with these observations, administration of a small molecule PK2 receptor antagonist led to temporary blocking of estrous cycle at the proestrous phase in female mice. The administration of PKR2 antagonist was found to blunt the circulating LH levels. Taken together, these studies indicate PK2 signaling is required for the maintenance of normal female estrous cycles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090860PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954593PMC
December 2014

Absence of central circadian pacemaker abnormalities in humans with loss of function mutation in prokineticin 2.

J Clin Endocrinol Metab 2014 Mar 1;99(3):E561-6. Epub 2014 Jan 1.

Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine (R.B., J.E.H., A.A.D., N.P., W.F.C.), Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Sleep Medicine (D.A.C., E.B.K., C.A.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and Department of Endocrinology-Hospital São João (D.P.), Department of Experimental Biology-Faculty of Medicine (D.P.), and Institute of Molecular Pathology and Immunology at the University of Porto (IPATIMUP) (D.P.), 4200-319 Porto, Portugal.

Context: Loss of prokineticin 2 (PROK2) signaling in mice disrupts circadian rhythms, but the role of PROK2 signaling in the regulation of circadian rhythms in humans is undetermined.

Objective: The aim of the study was to examine the circadian rhythms of humans with a complete loss-of-function PROK2 mutation using an inpatient constant routine (CR) protocol.

Design And Setting: We conducted a case study in an academic medical center.

Subjects And Methods: Two siblings (one male and one female, ages 67 and 62 y, respectively) with isolated GnRH deficiency (IGD) due to a biallelic loss-of-function PROK2 mutation were studied using an inpatient CR protocol. Historical data from inpatient CR protocols conducted in healthy controls (ages 65-81 y) were used for comparison.

Main Outcome Measures: We measured circadian phase markers (melatonin, cortisol, and core body temperature) and neurobehavioral performance (psychomotor vigilance task [PVT] and subjective alertness scale).

Results: Circadian waveforms of melatonin and cortisol did not differ between the IGD participants with PROK2 mutation and controls. In both IGD participants, neurobehavioral testing with PVT showed disproportionate worsening of PVT lapses and median reaction time in the second half of the CR.

Conclusions: Humans with loss of PROK2 signaling lack abnormalities in circadian phase markers, indicating intact central circadian pacemaker activity in these patients. These results suggest that PROK2 signaling in humans is not required for central circadian pacemaker function. However, impaired PVT in the PROK2-null participants despite preserved endocrine rhythms suggests that PROK2 may transmit circadian timing information to some neurobehavioral neural networks.
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http://dx.doi.org/10.1210/jc.2013-2096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942237PMC
March 2014

Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system.

J Clin Endocrinol Metab 2014 Mar 1;99(3):861-70. Epub 2013 Jan 1.

Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit (V.F.S., Y.-M.C., M.F.L., R.B., L.P., A.D., N.P., F.J.H., J.E.H., K.A.M., P.A.B., S.B.S.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology (Y.-M.C.), Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115; and Department of Endocrinology (R.Q.), Institute for Human Genetics, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne NE1 3BZ, United Kingdom.

Context: A subset of patients diagnosed with idiopathic hypogonadotropic hypogonadism (IHH) later achieves activation of their hypothalamic-pituitary-gonadal axis with normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal.

Objective: The objective of this study was to determine the natural history of reversal and to identify associated phenotypes and genotypes.

Design, Setting, And Subjects: This was a retrospective review of clinical, biochemical, and genetic features of patients with IHH evaluated at an academic medical center.

Main Outcome Measures: History of spontaneous fertility, regular menses, testicular growth, or normalization of serum sex steroids, LH secretory profiles, brain imaging findings, and sequences of 14 genes associated with IHH were reviewed.

Results: Of 308 patients with IHH, 44 underwent reversal. Time-to-event analysis estimated a lifetime incidence of reversal of 22%. There were no differences in the rates of cryptorchidism, micropenis, or partial pubertal development in patients with reversal vs IHH patients without reversal. Fifteen patients with reversal (30%) had Kallmann syndrome (IHH and anosmia); one had undetectable olfactory bulbs on a brain magnetic resonance imaging scan. Subjects with reversal were enriched for mutations affecting neurokinin B signaling compared with a cohort of IHH patients without reversal (10% vs 3%, P = .044), had comparable frequencies of mutations in FGFR1, PROKR2, and GNRHR, and had no mutations in KAL1. Five men did not sustain their reversal and again developed hypogonadotropism.

Conclusions: Reversal of IHH may be more widespread than previously appreciated and occurs across a broad range of genotypes and phenotypes. Enrichment for mutations that disrupt neurokinin B signaling in patients who reversed indicates that, despite the importance of this signaling pathway for normal pubertal timing, its function is dispensable later in life. The occurrence of reversal in a patient with no olfactory bulbs demonstrates that these structures are not essential for normal reproductive function. Patients with IHH require lifelong monitoring for reversal and, if reversal occurs, subsequent relapse also may occur.
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http://dx.doi.org/10.1210/jc.2013-2809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942233PMC
March 2014

Reversal of isolated hypogonadotropic hypogonadism: long-term integrity of hypothalamo-pituitary-testicular axis in two men is dependent on intermittent androgen exposure.

Clin Endocrinol (Oxf) 2014 Sep 30;81(3):473-6. Epub 2013 Oct 30.

Endocrine Unit, Royal Victoria Infirmary, Newcastle-upon-Tyne Hospitals Foundation NHS Trust, Newcastle-upon-Tyne, UK.

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http://dx.doi.org/10.1111/cen.12347DOI Listing
September 2014

Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes.

J Clin Endocrinol Metab 2013 May 26;98(5):E943-53. Epub 2013 Mar 26.

Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Context: The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening.

Objective: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations.

Subjects: Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes.

Main Outcome Measures: Reproductive and nonreproductive phenotypes within each genetic group were measured.

Results: Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors.

Conclusions: Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening.
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http://dx.doi.org/10.1210/jc.2012-4116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644607PMC
May 2013

A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3.

Brain 2013 Feb 31;136(Pt 2):522-35. Epub 2013 Jan 31.

Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, USA.

Missense mutations in TUBB3, the gene that encodes the neuronal-specific protein β-tubulin isotype 3, can cause isolated or syndromic congenital fibrosis of the extraocular muscles, a form of complex congenital strabismus characterized by cranial nerve misguidance. One of the eight TUBB3 mutations reported to cause congenital fibrosis of the extraocular muscles, c.1228G>A results in a TUBB3 E410K amino acid substitution that directly alters a kinesin motor protein binding site. We report the detailed phenotypes of eight unrelated individuals who harbour this de novo mutation, and thus define the 'TUBB3 E410K syndrome'. Individuals harbouring this mutation were previously reported to have congenital fibrosis of the extraocular muscles, facial weakness, developmental delay and possible peripheral neuropathy. We now confirm by electrophysiology that a progressive sensorimotor polyneuropathy does indeed segregate with the mutation, and expand the TUBB3 E410K phenotype to include Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), stereotyped midface hypoplasia, intellectual disabilities and, in some cases, vocal cord paralysis, tracheomalacia and cyclic vomiting. Neuroimaging reveals a thin corpus callosum and anterior commissure, and hypoplastic to absent olfactory sulci, olfactory bulbs and oculomotor and facial nerves, which support underlying abnormalities in axon guidance and maintenance. Thus, the E410K substitution defines a new genetic aetiology for Moebius syndrome, Kallmann syndrome and cyclic vomiting. Moreover, the c.1228G>A mutation was absent in DNA from ∼600 individuals who had either Kallmann syndrome or isolated or syndromic ocular and/or facial dysmotility disorders, but who did not have the combined features of the TUBB3 E410K syndrome, highlighting the specificity of this phenotype-genotype correlation. The definition of the TUBB3 E410K syndrome will allow clinicians to identify affected individuals and predict the mutation based on clinical features alone.
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http://dx.doi.org/10.1093/brain/aws345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572929PMC
February 2013

An ancient founder mutation in PROKR2 impairs human reproduction.

Hum Mol Genet 2012 Oct 5;21(19):4314-24. Epub 2012 Jul 5.

Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston 02114, MA, USA.

Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ~123 kb haplotype whose population frequency is ≤10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.
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http://dx.doi.org/10.1093/hmg/dds264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441126PMC
October 2012

Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications.

J Clin Endocrinol Metab 2012 Jan 9;97(1):E136-44. Epub 2011 Nov 9.

Harvard Reproductive Endocrine Sciences Center, Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Bartlett Hall Extension, 5th Floor, 55 Fruit Street, Boston, Massachusetts 02114, USA.

Context: The olfactory phenotype in patients with idiopathic hypogonadotropic hypogonadism (IHH) ranges from complete anosmia (Kallmann syndrome) to normosmia (normosmic IHH). However, the true prevalence of intermediary olfactory phenotypes (hyposmia) in IHH patients has not yet been assessed, and systematic correlations with anatomical and genetic abnormalities have not been reported.

Objective: The objective of this study was to evaluate olfactory function in a large IHH cohort and correlate these findings with olfactory magnetic resonance imaging (MRI) and underlying genetic etiology.

Design And Setting: We conducted a cross-sectional case-control study at an academic referral center.

Patients: A total of 286 IHH patients (201 males and 85 females) and 2183 healthy historic controls (1011 males and 1172 females) were studied.

Main Outcome Measures: We measured olfactory function using the University of Pennsylvania Smell Identification Test; in 208 subjects, the genetic etiology of IHH was ascertained by DNA sequencing; in a minor subset [39 of 286 subjects (13%)], olfactory structures were determined by MRI.

Results: In the IHH cohort, 31.5% were anosmic, 33.6% were hyposmic, and 34.9% were normosmic. Most hyposmic (seven of 11) subjects with MRI data exhibited olfactory structure abnormalities. Of hyposmic subjects, 39.5% harbored mutations in genes involved in either GnRH neuronal migration or GnRH secretion.

Conclusions: IHH subjects display a broad spectrum of olfactory function, with a significant hyposmic phenotype in nearly one third of subjects. The hyposmic subjects harbor mutations in genes affecting GnRH neuronal migration and its secretion, suggesting a pathophysiological overlap between Kallmann syndrome and normosmic IHH. Accurate olfactory phenotyping in IHH subjects will inform the pathophysiology of this condition and guide genetic testing.
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http://dx.doi.org/10.1210/jc.2011-2041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251934PMC
January 2012

Isolated GnRH deficiency: a disease model serving as a unique prism into the systems biology of the GnRH neuronal network.

Mol Cell Endocrinol 2011 Oct 12;346(1-2):4-12. Epub 2011 Jul 12.

Harvard Reproductive Endocrine Sciences Center & The Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

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http://dx.doi.org/10.1016/j.mce.2011.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226734PMC
October 2011

The puzzles of the prokineticin 2 pathway in human reproduction.

Mol Cell Endocrinol 2011 Oct 1;346(1-2):44-50. Epub 2011 Jun 1.

Harvard Reproductive Endocrine Sciences Center of Excellence, The Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston 02114, USA.

Prokineticin, 1 (PROK1) and prokineticin 2 (PROK2), are two closely related proteins that were identified as the mammalian homologs of their two amphibian homologs, mamba intestinal toxin (MIT-1) and Bv8. MIT-1 was initially identified as a non-toxic constituent in the venom of the black mamba snake (Dendroaspis polylepis) (Joubert and Strydom, 1980) while Bv8 was identified in the skin secretion of the toad, Bombina variegate (Mollay et al., 1999). All three homologs stimulate gastrointestinal motility thus accounting for their family name "prokineticins" (Schweitz et al., 1990, 1999). However, since its initial description, both PROK1 and PROK2 have been found to regulate a dazzling array of biological functions throughout the body. In particular, PROK1 acts as a potent angiogenic mitogen on endocrine vascular epithelium, thus earning its other name, Endocrine gland-vascular endothelial factor (EG-VEGF) (LeCouter et al., 2002). In contrast, the PROK2 signaling pathway is a critical regulator of olfactory bulb morphogenesis and sexual maturation in mammals and this function is the focus of this review.
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http://dx.doi.org/10.1016/j.mce.2011.05.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216477PMC
October 2011

The role of the prokineticin 2 pathway in human reproduction: evidence from the study of human and murine gene mutations.

Endocr Rev 2011 Apr 29;32(2):225-46. Epub 2010 Oct 29.

Harvard Center for Reproductive Endocrine Sciences, Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, 02114, USA.

A widely dispersed network of hypothalamic GnRH neurons controls the reproductive axis in mammals. Genetic investigation of the human disease model of isolated GnRH deficiency has revealed several key genes crucial for GnRH neuronal ontogeny and GnRH secretion. Among these genes, prokineticin 2 (PROK2), and PROK2 receptor (PROKR2) have recently emerged as critical regulators of reproduction in both mice and humans. Both prok2- and prokr2-deficient mice recapitulate the human Kallmann syndrome phenotype. Additionally, PROK2 and PROKR2 mutations are seen in humans with Kallmann syndrome, thus implicating this pathway in GnRH neuronal migration. However, PROK2/PROKR2 mutations are also seen in normosmic GnRH deficiency, suggesting a role for the prokineticin signaling system in GnRH biology that is beyond neuronal migration. This observation is particularly surprising because mature GnRH neurons do not express PROKR2. Moreover, mutations in both PROK2 and PROKR2 are predominantly detected in the heterozygous state with incomplete penetrance or variable expressivity frequently seen within and across pedigrees. In some of these pedigrees, a "second hit" or oligogenicity has been documented. Besides reproduction, a pleiotropic physiological role for PROK2 is now recognized, including regulation of pain perception, circadian rhythms, hematopoiesis, and immune response. Therefore, further detailed clinical studies of patients with PROK2/PROKR2 mutations will help to map the broader biological role of the PROK2/PROKR2 pathway and identify other interacting genes/proteins that mediate its molecular effects in humans.
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http://dx.doi.org/10.1210/er.2010-0007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365793PMC
April 2011