Publications by authors named "Moien Kanaan"

40 Publications

Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis.

Front Cell Dev Biol 2021 20;9:671210. Epub 2021 May 20.

Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.

Bone homeostasis is a complex, multi-step process, which is based primarily on a tightly orchestrated interplay between bone formation and bone resorption that is executed by osteoblasts and osteoclasts (OCLs), respectively. The essential physiological balance between these cells is maintained and controlled at multiple levels, ranging from regulated gene expression to endocrine signals, yet the underlying cellular and molecular mechanisms are still poorly understood. One approach for deciphering the mechanisms that regulate bone homeostasis is the characterization of relevant pathological states in which this balance is disturbed. In this article we describe one such "error of nature," namely the development of acute recessive osteopetrosis (ARO) in humans that is caused by mutations in sorting nexin 10 (SNX10) that affect OCL functioning. We hypothesize here that, by virtue of its specific roles in vesicular trafficking, SNX10 serves as a key selective regulator of the composition of diverse membrane compartments in OCLs, thereby affecting critical processes in the sequence of events that link the plasma membrane with formation of the ruffled border and with extracellular acidification. As a result, SNX10 determines multiple features of these cells either directly or, as in regulation of cell-cell fusion, indirectly. This hypothesis is further supported by the similarities between the cellular defects observed in OCLs form various models of ARO, induced by mutations in SNX10 and in other genes, which suggest that mutations in the known ARO-associated genes act by disrupting the same plasma membrane-to-ruffled border axis, albeit to different degrees. In this article, we describe the population genetics and spread of the original arginine-to-glutamine mutation at position 51 (R51Q) in SNX10 in the Palestinian community. We further review recent studies, conducted in animal and cellular model systems, that highlight the essential roles of SNX10 in critical membrane functions in OCLs, and discuss possible future research directions that are needed for challenging or substantiating our hypothesis.
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http://dx.doi.org/10.3389/fcell.2021.671210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173195PMC
May 2021

An SNX10-dependent mechanism downregulates fusion between mature osteoclasts.

J Cell Sci 2021 05 11;134(9). Epub 2021 May 11.

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.

Homozygosity for the R51Q mutation in sorting nexin 10 (SNX10) inactivates osteoclasts (OCLs) and induces autosomal recessive osteopetrosis in humans and in mice. We show here that the fusion of wild-type murine monocytes to form OCLs is highly regulated, and that its extent is limited by blocking fusion between mature OCLs. In contrast, monocytes from homozygous R51Q SNX10 mice fuse uncontrollably, forming giant dysfunctional OCLs that can become 10- to 100-fold larger than their wild-type counterparts. Furthermore, mutant OCLs display reduced endocytotic activity, suggesting that their deregulated fusion is due to alterations in membrane homeostasis caused by loss of SNX10 function. This is supported by the finding that the R51Q SNX10 protein is unstable and exhibits altered lipid-binding properties, and is consistent with a key role for SNX10 in vesicular trafficking. We propose that OCL size and functionality are regulated by a cell-autonomous SNX10-dependent mechanism that downregulates fusion between mature OCLs. The R51Q mutation abolishes this regulatory activity, leading to excessive fusion, loss of bone resorption capacity and, consequently, to an osteopetrotic phenotype in vivo. This article has an associated First Person interview with the joint first authors of the paper.
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http://dx.doi.org/10.1242/jcs.254979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182410PMC
May 2021

Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1.

Clin Genet 2020 10 24;98(4):353-364. Epub 2020 Aug 24.

Community Genetics Department, Public Health Services, Ministry of Health, Ramat Gan, Israel.

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results show that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.
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http://dx.doi.org/10.1111/cge.13817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045518PMC
October 2020

Helicase-inactivating mutation yields Fanconi anemia with microcephaly and other congenital abnormalities.

Cold Spring Harb Mol Case Stud 2020 10 7;6(5). Epub 2020 Oct 7.

Molecular Genetics Laboratory, Istishari Arab Hospital, Ramallah, Palestine.

Fanconi anemia is a genetically and phenotypically heterogeneous disorder characterized by congenital anomalies, bone marrow failure, cancer, and sensitivity of chromosomes to DNA cross-linking agents. One of the 22 genes responsible for Fanconi anemia is , in which biallelic truncating mutations lead to Fanconi anemia group J and monoallelic truncating mutations predispose to certain cancers. However, of the more than 1000 reported missense mutations in , very few have been functionally characterized. We evaluated the functional consequence of BRIP1 p.R848H (c.2543G > A), which was homozygous in two cousins with low birth weight, microcephaly, upper limb abnormalities, and imperforate anus and for whom chromosome breakage analysis of patient cells revealed increased mitomycin C sensitivity. BRIP1 p.R848H alters a highly conserved residue in the catalytic DNA helicase domain. We show that BRIP1 p.R848H leads to a defect in helicase activity. Heterozygosity at this missense has been reported in multiple cancer patients but, in the absence of functional studies, classified as of unknown significance. Our results support that this mutation is pathogenic for Fanconi anemia in homozygotes and for increased cancer susceptibility in heterozygous carriers.
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http://dx.doi.org/10.1101/mcs.a005652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552932PMC
October 2020

Genomic analysis of inherited hearing loss in the Palestinian population.

Proc Natl Acad Sci U S A 2020 08 3;117(33):20070-20076. Epub 2020 Aug 3.

Department of Biology, Bethlehem University, Bethlehem 72372, Palestine.

The genetic characterization of a common phenotype for an entire population reveals both the causes of that phenotype for that place and the power of family-based, population-wide genomic analysis for gene and mutation discovery. We characterized the genetics of hearing loss throughout the Palestinian population, enrolling 2,198 participants from 491 families from all parts of the West Bank and Gaza. In Palestinian families with no prior history of hearing loss, we estimate that 56% of hearing loss is genetic and 44% is not genetic. For the great majority (87%) of families with inherited hearing loss, panel-based genomic DNA sequencing, followed by segregation analysis of large kindreds and transcriptional analysis of participant RNA, enabled identification of the causal genes and mutations, including at distant noncoding sites. Genetic heterogeneity of hearing loss was striking with respect to both genes and alleles: The 337 solved families harbored 143 different mutations in 48 different genes. For one in four solved families, a transcription-altering mutation was the responsible allele. Many of these mutations were cryptic, either exonic alterations of splice enhancers or silencers or deeply intronic events. Experimentally calibrated in silico analysis of transcriptional effects yielded inferences of high confidence for effects on splicing even of mutations in genes not expressed in accessible tissue. Most (58%) of all hearing loss in the population was attributable to consanguinity. Given the ongoing decline in consanguineous marriage, inherited hearing loss will likely be much rarer in the next generation.
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http://dx.doi.org/10.1073/pnas.2009628117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443947PMC
August 2020

Massive osteopetrosis caused by non-functional osteoclasts in R51Q SNX10 mutant mice.

Bone 2020 07 8;136:115360. Epub 2020 Apr 8.

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

The R51Q mutation in sorting nexin 10 (SNX10) was shown to cause a lethal genetic disease in humans, namely autosomal recessive osteopetrosis (ARO). We describe here the first R51Q SNX10 knock-in mouse model and show that mice homozygous for this mutation exhibit massive, early-onset, and widespread osteopetrosis. The mutant mice exhibit multiple additional characteristics of the corresponding human disease, including stunted growth, failure to thrive, missing or impacted teeth, occasional osteomyelitis, and a significantly-reduced lifespan. Osteopetrosis in this model is the result of osteoclast inactivity that, in turn, is caused by absence of ruffled borders in the mutant osteoclasts and by their inability to secrete protons. These results confirm that the R51Q mutation in SNX10 is a causative factor in ARO and provide a model system for studying this rare disease.
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http://dx.doi.org/10.1016/j.bone.2020.115360DOI Listing
July 2020

Inclusion of hemimegalencephaly into the phenotypic spectrum of NPRL3 pathogenic variants in familial focal epilepsy with variable foci.

Epilepsia 2019 06 21;60(6):e67-e73. Epub 2019 May 21.

Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.

Despite tremendous progress through next generation sequencing technologies, familial focal epilepsies are insufficiently understood. We sought to identify the genetic basis in multiplex Palestinian families with familial focal epilepsy with variable foci (FFEVF). Family I with 10 affected individuals and Family II with five affected individuals underwent detailed phenotyping over three generations. The phenotypic spectrum of the two families varied from nonlesional focal epilepsy including nocturnal frontal lobe epilepsy to severe structural epilepsy due to hemimegalencephaly. Whole-exome sequencing and single nucleotide polymorphism array analysis revealed pathogenic variants in NPRL3 in each family, a partial ~38-kb deletion encompassing eight exons (exons 8-15) and the 3'-untranslated region of the NPRL3 gene in Family I, and a de novo nonsense variant c.1063C>T, p.Gln355* in Family II. Furthermore, we identified a truncating variant in the PDCD10 gene in addition to the NPRL3 variant in a patient with focal epilepsy from Family I. The individual also had developmental delay and multiple cerebral cavernomas, possibly demonstrating a digenic contribution to the individual's phenotype. Our results implicate the association of NPRL3 with hemimegalencephaly, expanding the phenotypic spectrum of NPRL3 in FFEVF and underlining that partial deletions are part of the genotypic spectrum of NPRL3 variants.
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http://dx.doi.org/10.1111/epi.15665DOI Listing
June 2019

The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies.

Acta Ophthalmol 2019 Sep 29;97(6):e877-e886. Epub 2019 Mar 29.

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Purpose: To identify the accurate clinical diagnosis of rare syndromic inherited retinal diseases (IRDs) based on the combination of clinical and genetic analyses.

Methods: Four unrelated families with various autosomal recessive syndromic inherited retinal diseases were genetically investigated using whole-exome sequencing (WES).

Results: Two affected subjects in family MOL0760 presented with a distinctive combination of short stature, developmental delay, congenital mental retardation, microcephaly, facial dysmorphism and retinitis pigmentosa (RP). Subjects were clinically diagnosed with suspected Kabuki syndrome. WES revealed a homozygous nonsense mutation (c.5492dup, p.Asn1831Lysfs*8) in VPS13B that is known to cause Cohen syndrome. The index case of family MOL1514 presented with both RP and liver dysfunction, suspected initially to be related. WES identified a homozygous frameshift mutation (c.1787_1788del, p.His596Argfs*47) in AGBL5, associated with nonsyndromic RP. The MOL1592 family included three affected subjects with crystalline retinopathy, skin ichthyosis, short stature and congenital adrenal hypoplasia, and were found to harbour a homozygous nonsense mutation (c.682C>T, p.Arg228Cys) in ALDH3A2, reported to cause Sjögren-Larsson syndrome (SLS). In the fourth family, SJ002, two siblings presented with hypotony, psychomotor delay, dysmorphic facial features, pathologic myopia, progressive external ophthalmoplegia and diffuse retinal atrophy. Probands were suspected to have atypical Kearns-Sayre syndrome, but were diagnosed with combined oxidative phosphorylation deficiency-20 due to a novel suspected missense variant (c.1691C>T, p.Ala564Val) in VARS2.

Conclusion: Our findings emphasize the important complement of WES and thorough clinical investigation in establishing precise clinical diagnosis. This approach constitutes the basis for personalized medicine in rare IRDs.
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http://dx.doi.org/10.1111/aos.14095DOI Listing
September 2019

The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures.

J Neurol 2017 Jul 15;264(7):1421-1425. Epub 2017 Jun 15.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Mutations or structural genomic alterations of the X-chromosomal gene ARHGEF9 have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of ARHGEF9 by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2-3 years and intellectual disability. Three developed afebrile seizures between age 7-17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel ARHGEF9 variant (c.967G>A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in ARHGEF9 may be more common than previously assumed in patients with intellectual disability and mild epilepsy.
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http://dx.doi.org/10.1007/s00415-017-8539-3DOI Listing
July 2017

Broadening the phenotype of DFNB28: Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment.

Hear Res 2017 04 12;347:56-62. Epub 2017 Jan 12.

Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype.
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http://dx.doi.org/10.1016/j.heares.2016.12.017DOI Listing
April 2017

Loss of function of PCDH12 underlies recessive microcephaly mimicking intrauterine infection.

Neurology 2016 05 29;86(21):2016-24. Epub 2016 Apr 29.

From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.

Objective: To identify the genetic basis of a recessive syndrome characterized by prenatal hyperechogenic brain foci, congenital microcephaly, hypothalamic midbrain dysplasia, epilepsy, and profound global developmental disability.

Methods: Identification of the responsible gene by whole exome sequencing and homozygosity mapping.

Results: Ten patients from 4 consanguineous Palestinian families manifested in utero with hyperechogenic brain foci, microcephaly, and intrauterine growth retardation. Postnatally, patients had progressive severe microcephaly, neonatal seizures, and virtually no developmental milestones. Brain imaging revealed dysplastic elongated masses in the midbrain-hypothalamus-optic tract area. Whole exome sequencing of one affected child revealed only PCDH12 c.2515C>T, p.R839X, to be homozygous in the proband and to cosegregate with the condition in her family. The allele frequency of PCDH12 p.R839X is <0.00001 worldwide. Genotyping PCDH12 p.R839X in 3 other families with affected children yielded perfect cosegregation with the phenotype (probability by chance is 2.0 × 10(-12)). Homozygosity mapping revealed that PCDH12 p.R839X lies in the largest homozygous region (11.7 MB) shared by all affected patients. The mutation reduces transcript expression by 84% (p < 2.4 × 10(-13)). PCDH12 is a vascular endothelial protocadherin that promotes cellular adhesion. Endothelial adhesion disruptions due to mutations in OCLN or JAM3 also cause congenital microcephaly, intracranial calcifications, and profound psychomotor disability.

Conclusions: Loss of function of PCDH12 leads to recessive congenital microcephaly with profound developmental disability. The phenotype resembles Aicardi-Goutières syndrome and in utero infections. In cases with similar manifestations but no evidence of infection, our results suggest consideration of an additional, albeit rare, cause of congenital microcephaly.
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http://dx.doi.org/10.1212/WNL.0000000000002704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887125PMC
May 2016

Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families.

Eur J Hum Genet 2016 10 6;24(10):1430-5. Epub 2016 Apr 6.

Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.

Tooth development is controlled by the same processes that regulate formation of other ectodermal structures. Mutations in the genes underlying these processes may cause ectodermal dysplasia, including severe absence of primary or permanent teeth. Four consanguineous Palestinian families presented with oligodontia and hair and skin features of ectodermal dysplasia. Appearance of ectodermal dysplasia was consistent with autosomal recessive inheritance. Exome sequencing followed by genotyping of 56 informative relatives in the 4 families suggests that the phenotype is due to homozygosity for KREMEN1 p.F209S (c.626 T>C) on chromosome 22 at g.29,521,399 (hg19). The variant occurs in the highly conserved extracellular WSC domain of KREMEN1, which is known to be a high affinity receptor of Dickkopf-1, a component of the Dickkopf-Kremen-LRP6 complex, and a potent regulator of Wnt signaling. The Wnt signaling pathway is critical to development of ectodermal structures. Mutations in WNT10A, LRP6, EDA, and other genes in this pathway lead to tooth agenesis with or without other ectodermal anomalies. Our results implicate KREMEN1 for the first time in a human disorder and provide additional details on the role of the Wnt signaling in ectodermal and dental development.
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http://dx.doi.org/10.1038/ejhg.2016.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027678PMC
October 2016

The GPSM2/LGN GoLoco motifs are essential for hearing.

Mamm Genome 2016 Feb 11;27(1-2):29-46. Epub 2015 Dec 11.

Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel.

The planar cell polarity (PCP) pathway is responsible for polarizing and orienting cochlear hair cells during development through movement of a primary cilium, the kinocilium. GPSM2/LGN, a mitotic spindle-orienting protein associated with deafness in humans, is a PCP effector involved in kinocilium migration. Here, we link human and mouse truncating mutations in the GPSM2/LGN gene, both leading to hearing loss. The human variant, p.(Trp326*), was identified by targeted genomic enrichment of genes associated with deafness, followed by massively parallel sequencing. Lgn (ΔC) mice, with a targeted deletion truncating the C-terminal GoLoco motifs, are profoundly deaf and show misorientation of the hair bundle and severe malformations in stereocilia shape that deteriorates over time. Full-length protein levels are greatly reduced in mutant mice, with upregulated mRNA levels. The truncated Lgn (ΔC) allele is translated in vitro, suggesting that mutant mice may have partially functioning Lgn. Gαi and aPKC, known to function in the same pathway as Lgn, are dependent on Lgn for proper localization. The polarization of core PCP proteins is not affected in Lgn mutants; however, Lgn and Gαi are misoriented in a PCP mutant, supporting the role of Lgn as a PCP effector. The kinocilium, previously shown to be dependent on Lgn for robust localization, is essential for proper localization of Lgn, as well as Gαi and aPKC, suggesting that cilium function plays a role in positioning of apical proteins. Taken together, our data provide a mechanism for the loss of hearing found in human patients with GPSM2/LGN variants.
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http://dx.doi.org/10.1007/s00335-015-9614-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913375PMC
February 2016

A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis.

J Clin Invest 2015 Nov 20;125(11):4295-304. Epub 2015 Oct 20.

Ovarian development and maintenance are poorly understood; however, diseases that affect these processes can offer insights into the underlying mechanisms. XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries, with subsequent lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism. Here, we report an extended consanguineous family of Palestinian origin, in which 4 females exhibited XX-GD. Using homozygosity mapping and whole-exome sequencing, we identified a recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A, p.D447N). This mutation segregated with the XX-GD phenotype and was not present in available databases or in 150 healthy ethnically matched controls. NUP107 is a component of the nuclear pore complex, and the NUP107-associated protein SEH1 is required for oogenesis in Drosophila. In Drosophila, Nup107 knockdown in somatic gonadal cells resulted in female sterility, whereas males were fully fertile. Transgenic rescue of Drosophila females bearing the Nup107D364N mutation, which corresponds to the human NUP107 (p.D447N), resulted in almost complete sterility, with a marked reduction in progeny, morphologically aberrant eggshells, and disintegrating egg chambers, indicating defective oogenesis. These results indicate a pivotal role for NUP107 in ovarian development and suggest that nucleoporin defects may play a role in milder and more common conditions such as premature ovarian failure.
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http://dx.doi.org/10.1172/JCI83553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639971PMC
November 2015

Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress.

J Med Genet 2015 Sep 12;52(9):636-41. Epub 2015 Jun 12.

Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Background: Familial glucocorticoid deficiency (FGD) reflects specific failure of adrenocortical glucocorticoid production in response to adrenocorticotropic hormone (ACTH). Most cases are caused by mutations encoding ACTH-receptor components (MC2R, MRAP) or the general steroidogenesis protein (StAR). Recently, nicotinamide nucleotide transhydrogenase (NNT) mutations were found to cause FGD through a postulated mechanism resulting from decreased detoxification of reactive oxygen species (ROS) in adrenocortical cells.

Methods And Results: In a consanguineous Palestinian family with combined mineralocorticoid and glucocorticoid deficiency, whole-exome sequencing revealed a novel homozygous NNT_c.598 G>A, p.G200S, mutation. Another affected, unrelated Palestinian child was also homozygous for NNT_p.G200S. Haplotype analysis showed this mutation is ancestral; carrier frequency in ethnically matched controls is 1/200. Assessment of patient fibroblasts for ROS production, ATP content and mitochondrial morphology showed that biallelic NNT mutations result in increased levels of ROS, lower ATP content and morphological mitochondrial defects.

Conclusions: This report of a novel NNT mutation, p.G200S, expands the phenotype of NNT mutations to include mineralocorticoid deficiency. We provide the first patient-based evidence that NNT mutations can cause oxidative stress and both phenotypic and functional mitochondrial defects. These results directly demonstrate the importance of NNT to mitochondrial function in the setting of adrenocortical insufficiency.
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http://dx.doi.org/10.1136/jmedgenet-2015-103078DOI Listing
September 2015

RBM28, a protein deficient in ANE syndrome, regulates hair follicle growth via miR-203 and p63.

Exp Dermatol 2015 Aug 26;24(8):618-22. Epub 2015 May 26.

Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Alopecia-neurological defects-endocrinopathy (ANE) syndrome is a rare inherited hair disorder, which was shown to result from decreased expression of the RNA-binding motif protein 28 (RBM28). In this study, we attempted to delineate the role of RBM28 in hair biology. First, we sought to obtain evidence for the direct involvement of RBM28 in hair growth. When RBM28 was downregulated in human hair follicle (HF) organ cultures, we observed catagen induction and HF growth arrest, indicating that RBM28 is necessary for normal hair growth. We also aimed at identifying molecular targets of RBM28. Given that an RBM28 homologue was recently found to regulate miRNA biogenesis in C. elegans and given the known pivotal importance of miRNAs for proper hair follicle development, we studied global miRNA expression profile in cells knocked down for RBM28. This analysis revealed that RBM28 controls the expression of miR-203. miR-203 was found to regulate in turn TP63, encoding the transcription factor p63, which is critical for hair morphogenesis. In conclusion, RBM28 contributes to HF growth regulation through modulation of miR-203 and p63 activity.
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http://dx.doi.org/10.1111/exd.12737DOI Listing
August 2015

Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure.

J Med Genet 2015 Jun 14;52(6):391-9. Epub 2015 Apr 14.

Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Background: Primary gonadal failure is characterised by primary amenorrhoea or early menopause in females, and oligospermia or azoospermia in males. Variants of the minichromosome maintenance complex component 8 gene (MCM8) have recently been shown to be significantly associated with women's menopausal age in genome-wide association studies. Furthermore, MCM8-knockout mice are sterile. The objective of this study was to elucidate the genetic aetiology of gonadal failure in two consanguineous families presenting as primary amenorrhoea in the females and as small testes and azoospermia in a male.

Methods And Results: Using whole exome sequencing, we identified two novel homozygous mutations in the MCM8 gene: a splice (c.1954-1G>A) and a frameshift (c.1469-1470insTA). In each consanguineous family the mutation segregated with the disease and both mutations were absent in 100 ethnically matched controls. The splice mutation led to lack of the wild-type transcript and three different aberrant transcripts predicted to result in either truncated or significantly shorter proteins. Quantitative analysis of the aberrantly spliced transcripts showed a significant decrease in total MCM8 message in affected homozygotes for the mutation, and an intermediate decrease in heterozygous family members. Chromosomal breakage following exposure to mitomcyin C was significantly increased in cells from homozygous individuals for c.1954-1G>A, as well as c.1469-1470insTA.

Conclusions: MCM8, a component of the pre-replication complex, is crucial for gonadal development and maintenance in humans-both males and females. These findings provide new insights into the genetic disorders of infertility and premature menopause in women.
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http://dx.doi.org/10.1136/jmedgenet-2014-102921DOI Listing
June 2015

Novel myosin mutations for hereditary hearing loss revealed by targeted genomic capture and massively parallel sequencing.

Eur J Hum Genet 2014 Jun 9;22(6):768-75. Epub 2013 Oct 9.

Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Hereditary hearing loss is genetically heterogeneous, with a large number of genes and mutations contributing to this sensory, often monogenic, disease. This number, as well as large size, precludes comprehensive genetic diagnosis of all known deafness genes. A combination of targeted genomic capture and massively parallel sequencing (MPS), also referred to as next-generation sequencing, was applied to determine the deafness-causing genes in hearing-impaired individuals from Israeli Jewish and Palestinian Arab families. Among the mutations detected, we identified nine novel mutations in the genes encoding myosin VI, myosin VIIA and myosin XVA, doubling the number of myosin mutations in the Middle East. Myosin VI mutations were identified in this population for the first time. Modeling of the mutations provided predicted mechanisms for the damage they inflict in the molecular motors, leading to impaired function and thus deafness. The myosin mutations span all regions of these molecular motors, leading to a wide range of hearing phenotypes, reinforcing the key role of this family of proteins in auditory function. This study demonstrates that multiple mutations responsible for hearing loss can be identified in a relatively straightforward manner by targeted-gene MPS technology and concludes that this is the optimal genetic diagnostic approach for identification of mutations responsible for hearing loss.
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http://dx.doi.org/10.1038/ejhg.2013.232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023209PMC
June 2014

Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss.

Am J Hum Genet 2012 11;91(5):872-82

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Hereditary hearing loss is characterized by a high degree of genetic heterogeneity. Here we present OTOGL mutations, a homozygous one base pair deletion (c.1430 delT) causing a frameshift (p.Val477Glufs(∗)25) in a large consanguineous family and two compound heterozygous mutations, c.547C>T (p.Arg183(∗)) and c.5238+5G>A, in a nonconsanguineous family with moderate nonsyndromic sensorineural hearing loss. OTOGL maps to the DFNB84 locus at 12q21.31 and encodes otogelin-like, which has structural similarities to the epithelial-secreted mucin protein family. We demonstrate that Otogl is expressed in the inner ear of vertebrates with a transcription level that is high in embryonic, lower in neonatal, and much lower in adult stages. Otogelin-like is localized to the acellular membranes of the cochlea and the vestibular system and to a variety of inner ear cells located underneath these membranes. Knocking down of otogl with morpholinos in zebrafish leads to sensorineural hearing loss and anatomical changes in the inner ear, supporting that otogelin-like is essential for normal inner ear function. We propose that OTOGL mutations affect the production and/or function of acellular structures of the inner ear, which ultimately leads to sensorineural hearing loss.
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http://dx.doi.org/10.1016/j.ajhg.2012.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487139PMC
November 2012

Genomic advances for gene discovery in hereditary hearing loss.

J Basic Clin Physiol Pharmacol 2012 Sep 7;23(3):93-7. Epub 2012 Sep 7.

Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel.

High-throughput sequencing is changing the face of genetic diagnosis and counseling. While in the past, it would take on average 1 to 5 years to identify a mutation leading to deafness, today, the genetic basis for deafness can be determined within months in a child or adult with inherited hearing loss. Obstacles and challenges still remain, but the field is changing at a dramatic rate, making gene discovery a much easier and more efficient task than in the past.
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http://dx.doi.org/10.1515/jbcpp-2012-0033DOI Listing
September 2012

GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome.

Am J Hum Genet 2012 Jun 10;90(6):1088-93. Epub 2012 May 10.

Department of Pediatrics, University of Washington, Seattle Children's Hospital, 98105, USA.

Autosomal-recessive inheritance, severe to profound sensorineural hearing loss, and partial agenesis of the corpus callosum are hallmarks of the clinically well-established Chudley-McCullough syndrome (CMS). Although not always reported in the literature, frontal polymicrogyria and gray matter heterotopia are uniformly present, whereas cerebellar dysplasia, ventriculomegaly, and arachnoid cysts are nearly invariant. Despite these striking brain malformations, individuals with CMS generally do not present with significant neurodevelopmental abnormalities, except for hearing loss. Homozygosity mapping and whole-exome sequencing of DNA from affected individuals in eight families (including the family in the first report of CMS) revealed four molecular variations (two single-base deletions, a nonsense mutation, and a canonical splice-site mutation) in the G protein-signaling modulator 2 gene, GPSM2, that underlie CMS. Mutations in GPSM2 have been previously identified in people with profound congenital nonsyndromic hearing loss (NSHL). Subsequent brain imaging of these individuals revealed frontal polymicrogyria, abnormal corpus callosum, and gray matter heterotopia, consistent with a CMS diagnosis, but no ventriculomegaly. The gene product, GPSM2, is required for orienting the mitotic spindle during cell division in multiple tissues, suggesting that the sensorineural hearing loss and characteristic brain malformations of CMS are due to defects in asymmetric cell divisions during development.
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http://dx.doi.org/10.1016/j.ajhg.2012.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370271PMC
June 2012

Functional characterization of pendrin mutations found in the Israeli and Palestinian populations.

Cell Physiol Biochem 2011 18;28(3):477-84. Epub 2011 Nov 18.

Institute of Pharmacology and Toxicology, Paracelsus Medical University, Salzburg, Austria.

Background: Pendrin is a transport protein exchanging chloride for other anions, such as iodide in the thyroid gland or bicarbonate in the inner ear. Mutations in the SLC26A4 gene encoding for pendrin are responsible for both syndromic (Pendred syndrome) and non-syndromic (non-syndromic enlarged vestibular aqueduct, EVA) hearing loss. Besides clinical and radiological assessments, molecular and functional studies are essential for the correct diagnosis of Pendred syndrome and non-syndromic EVA. While a broad spectrum of mutations found in the Caucasian population has been functionally characterized, little is known about mutations specifically occurring in the populations of the Middle East. Here we show the characterization of the ion transport activity of three pendrin mutations previously found in deaf patients with EVA in the Israeli Jewish and Palestinian Arab populations, i.e. V239D, G334V X335 and I487Y FSX39.

Methods: Wild type and mutated pendrin allelic variants were functionally characterized in a heterologous over-expression system. The Cl(-)/I(-) and Cl(-)/OH(-) exchange activities were assessed by fluorometric methods suitable for measuring iodide fluxes and the intracellular pH.

Results: Both the Cl(-)/I(-) and the Cl(-)/OH(-) exchange activities of pendrin V239D, G334V X335 and I487Y FSX39 were significantly reduced with respect to the wild type, with V239D displaying a residual iodide transport.

Conclusion: Functional assays confirmed the diagnosis of non-syndromic EVA due to SLC26A4 mutations performed by radiological and molecular tests in deaf patients belonging to the Israeli Jewish and Palestinian Arab populations. The new finding that the V239D mutation displays residual function suggests that the symptoms caused by this mutation could be ameliorated by a pendrin 'activator', if available.
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http://dx.doi.org/10.1159/000335109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709187PMC
March 2012

Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families.

Genome Biol 2011 Sep 14;12(9):R89. Epub 2011 Sep 14.

Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

Background: Identification of genes responsible for medically important traits is a major challenge in human genetics. Due to the genetic heterogeneity of hearing loss, targeted DNA capture and massively parallel sequencing are ideal tools to address this challenge. Our subjects for genome analysis are Israeli Jewish and Palestinian Arab families with hearing loss that varies in mode of inheritance and severity.

Results: A custom 1.46 MB design of cRNA oligonucleotides was constructed containing 246 genes responsible for either human or mouse deafness. Paired-end libraries were prepared from 11 probands and bar-coded multiplexed samples were sequenced to high depth of coverage. Rare single base pair and indel variants were identified by filtering sequence reads against polymorphisms in dbSNP132 and the 1000 Genomes Project. We identified deleterious mutations in CDH23, MYO15A, TECTA, TMC1, and WFS1. Critical mutations of the probands co-segregated with hearing loss. Screening of additional families in a relevant population was performed. TMC1 p.S647P proved to be a founder allele, contributing to 34% of genetic hearing loss in the Moroccan Jewish population.

Conclusions: Critical mutations were identified in 6 of the 11 original probands and their families, leading to the identification of causative alleles in 20 additional probands and their families. The integration of genomic analysis into early clinical diagnosis of hearing loss will enable prediction of related phenotypes and enhance rehabilitation. Characterization of the proteins encoded by these genes will enable an understanding of the biological mechanisms involved in hearing loss.
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http://dx.doi.org/10.1186/gb-2011-12-9-r89DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308052PMC
September 2011

A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.

Mamm Genome 2011 Apr 17;22(3-4):170-7. Epub 2010 Dec 17.

Department of Medicine, University of Washington, Seattle, WA 98195-7720, USA.

The motor protein myosin IIIA is critical for maintenance of normal hearing. Homozygosity and compound heterozygosity for loss-of-function mutations in MYO3A, which encodes myosin IIIA, are responsible for inherited human progressive hearing loss DFNB30. To further evaluate this hearing loss, we constructed a mouse model, Myo3a(KI/KI), that harbors the mutation equivalent to the nonsense allele responsible for the most severe human phenotype. Myo3a(KI/KI) mice were compared to their wild-type littermates. Myosin IIIA, with a unique N-terminal kinase domain and a C-terminal actin-binding domain, localizes to the tips of stereocilia in wild-type mice but is absent in the mutant. The phenotype of the Myo3a(KI/KI) mouse parallels the phenotype of human DFNB30. Hearing loss, as measured by auditory brainstem response, is reduced and progresses significantly with age. Vestibular function is normal. Outer hair cells of Myo3a(KI/KI) mice degenerate with age in a pattern consistent with their progressive hearing loss.
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http://dx.doi.org/10.1007/s00335-010-9310-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023428PMC
April 2011

Collaborative genomics for human health and cooperation in the Mediterranean region.

Nat Genet 2010 Aug;42(8):641-5

Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.

The US government has proposed the development of scientific centers of excellence to solve global challenges. We propose such a center of excellence devoted to the genomic analysis of Mediterranean populations of all creeds. This genomic focus is rooted in the region's demographic history, builds on the area's rapidly developing expertise in human genetics, and will yield scientific discoveries of both local and global significance. The genome sequence data of Mediterranean populations will offer unique insights into human evolution and early human migration. The potent combination of highly consanguineous populations in the Mediterranean's southern and eastern rims and regional medical and scientific expertise could lead to the identification and characterization of many genes responsible for human disease. Such discoveries will enable genetic knowledge to be translated into medical knowledge that will benefit local populations and contribute substantially to the understanding of the genetic bases of human diseases worldwide.
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http://dx.doi.org/10.1038/ng0810-641DOI Listing
August 2010

Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51.

Am J Hum Genet 2010 Jul 17;87(1):101-9. Epub 2010 Jun 17.

Department of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195, USA.

Age-related hearing loss is due to death over time, primarily by apoptosis, of hair cells in the inner ear. Studies of mutant genes responsible for inherited progressive hearing loss have suggested possible mechanisms for hair cell death, but critical connections between these mutations and the causes of progressive hearing loss have been elusive. In an Israeli kindred, dominant, adult-onset, progressive nonsyndromic hearing loss DFNA51 is due to a tandem inverted genomic duplication of 270 kb that includes the entire wild-type gene encoding the tight junction protein TJP2 (ZO-2). In the mammalian inner ear, TJP2 is expressed mainly in tight junctions, and also in the cytoplasm and nuclei. TJP2 expression normally decreases with age from embryonic development to adulthood. In cells of affected family members, TJP2 transcript and protein are overexpressed, leading to decreased phosphorylation of GSK-3beta and to altered expression of genes that regulate apoptosis. These results suggest that TJP2- and GSK-3beta-mediated increased susceptibility to apoptosis of cells of the inner ear is the mechanism for adult-onset hearing loss in this kindred and may serve as one model for age-related hearing loss in the general population.
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http://dx.doi.org/10.1016/j.ajhg.2010.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896780PMC
July 2010

Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82.

Am J Hum Genet 2010 Jul 17;87(1):90-4. Epub 2010 Jun 17.

Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.

Massively parallel sequencing of targeted regions, exomes, and complete genomes has begun to dramatically increase the pace of discovery of genes responsible for human disorders. Here we describe how exome sequencing in conjunction with homozygosity mapping led to rapid identification of the causative allele for nonsyndromic hearing loss DFNB82 in a consanguineous Palestinian family. After filtering out worldwide and population-specific polymorphisms from the whole exome sequence, only a single deleterious mutation remained in the homozygous region linked to DFNB82. The nonsense mutation leads to an early truncation of the G protein signaling modulator GPSM2, a protein that is essential for maintenance of cell polarity and spindle orientation. In the mouse inner ear, GPSM2 is localized to apical surfaces of hair cells and supporting cells and is most highly expressed during embryonic development. Identification of GPSM2 as essential to the development of normal hearing suggests dysregulation of cell polarity as a mechanism underlying hearing loss.
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http://dx.doi.org/10.1016/j.ajhg.2010.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896776PMC
July 2010

Nonsense mutation of the stereociliar membrane protein gene PTPRQ in human hearing loss DFNB84.

J Med Genet 2010 Sep 14;47(9):643-5. Epub 2010 May 14.

Department of Life Sciences, Bethlehem University, Bethlehem, Palestinian National Authority.

Background: Moderate to severe prelingual hearing impairment (DFNB84) was observed in an extended consanguineous Palestinian kindred. All affected relatives shared a 12.5 MB homozygous haplotype on chromosome 12q21 with lod score 4.30. This homozygous region harbours the protein tyrosine phosphatase receptor Q gene PTPRQ, which is known to be essential to hearing in mouse.

Methods: Candidate genes in the 12.5 MB homozygous region were characterized genomically and sequenced in deaf and hearing relatives in the family.

Results: Sequence of PTPRQ in affected individuals in the extended kindred revealed c.1285C-->T, leading to p.Gln429Stop. This nonsense mutation co-segregated with hearing loss in the family and was homozygous in all affected relatives. The mutation did not appear among 288 Palestinian controls (576 chromosomes), all adults with normal hearing. No homozygous mutations in PTPRQ appeared in any of 218 other probands with hearing loss.

Conclusion: Identification of the DFNB84 gene represents the first identification of PTPRQ mutation in human hearing loss.
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http://dx.doi.org/10.1136/jmg.2009.075697DOI Listing
September 2010

A truncating mutation in SERPINB6 is associated with autosomal-recessive nonsyndromic sensorineural hearing loss.

Am J Hum Genet 2010 May 6;86(5):797-804. Epub 2010 May 6.

Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.

More than 270 million people worldwide have hearing loss that affects normal communication. Although astonishing progress has been made in the identification of more than 50 genes for deafness during the past decade, the majority of deafness genes are yet to be identified. In this study, we mapped a previously unknown autosomal-recessive nonsyndromic sensorineural hearing loss locus (DFNB91) to chromosome 6p25 in a consanguineous Turkish family. The degree of hearing loss was moderate to severe in affected individuals. We subsequently identified a nonsense mutation (p.E245X) in SERPINB6, which is located within the linkage interval for DFNB91 and encodes for an intracellular protease inhibitor. The p.E245X mutation cosegregated in the family as a completely penetrant autosomal-recessive trait and was absent in 300 Turkish controls. The mRNA expression of SERPINB6 was reduced and production of protein was absent in the peripheral leukocytes of homozygotes, suggesting that the hearing loss is due to loss of function of SERPINB6. We also demonstrated that SERPINB6 was expressed primarily in the inner ear hair cells. We propose that SERPINB6 plays an important role in the inner ear in the protection against leakage of lysosomal content during stress and that loss of this protection results in cell death and sensorineural hearing loss.
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http://dx.doi.org/10.1016/j.ajhg.2010.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869020PMC
May 2010

Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families.

Eur J Hum Genet 2010 Apr 4;18(4):407-13. Epub 2009 Nov 4.

Department of Life Sciences, Bethlehem University, Bethlehem, Palestine.

In communities with high rates of consanguinity and consequently high prevalence of recessive phenotypes, homozygosity mapping with SNP arrays is an effective approach for gene discovery. In 20 Palestinian kindreds with prelingual nonsyndromic hearing loss, we generated homozygosity profiles reflecting linkage to the phenotype. Family sizes ranged from small nuclear families with two affected children, one unaffected sibling, and parents to multigenerational kindreds with 12 affected relatives. By including unaffected parents and siblings and screening 250 K SNP arrays, even small nuclear families yielded informative profiles. In 14 families, we identified the allele responsible for hearing loss by screening a single candidate gene in the longest homozygous region. Novel alleles included missense, nonsense, and splice site mutations of CDH23, MYO7A, MYO15A, OTOF, PJVK, Pendrin/SLC26A4, TECTA, TMHS, and TMPRSS3, and a large genomic deletion of Otoancorin (OTOA). All point mutations were rare in the Palestinian population (zero carriers in 288 unrelated controls); the carrier frequency of the OTOA genomic deletion was 1%. In six families, we identified five genomic regions likely to harbor novel genes for human hearing loss on chromosomes 1p13.3 (DFNB82), 9p23-p21.2/p13.3-q21.13 (DFNB83), 12q14.3-q21.2 (DFNB84; two families), 14q23.1-q31.1, and 17p12-q11.2 (DFNB85).
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http://dx.doi.org/10.1038/ejhg.2009.190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987250PMC
April 2010
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