Publications by authors named "Helge Boman"

30 Publications

  • Page 1 of 1

Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis.

Am J Hum Genet 2017 02 12;100(2):323-333. Epub 2017 Jan 12.

INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.

Nephronophthisis (NPH), an autosomal-recessive tubulointerstitial nephritis, is the most common cause of hereditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as a ciliopathy. We identified mutations in a candidate gene in eight individuals from five families presenting late-onset NPH with massive renal fibrosis. This gene encodes MAPKBP1, a poorly characterized scaffolding protein for JNK signaling. Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects, indicating that MAPKBP1 may represent a new family of NPHP not involved in cilia-associated functions. Instead, MAPKBP1 is recruited to mitotic spindle poles (MSPs) during the early phases of mitosis where it colocalizes with its paralog WDR62, which plays a key role at MSP. Detected mutations compromise recruitment of MAPKBP1 to the MSP and/or its interaction with JNK2 or WDR62. Additionally, we show increased DNA damage response signaling in fibroblasts from affected individuals and upon knockdown of Mapkbp1 in murine cell lines, a phenotype previously associated with NPH. In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH.
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http://dx.doi.org/10.1016/j.ajhg.2016.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294754PMC
February 2017

GBA2 Mutations Cause a Marinesco-Sjögren-Like Syndrome: Genetic and Biochemical Studies.

PLoS One 2017 4;12(1):e0169309. Epub 2017 Jan 4.

Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: With the advent new sequencing technologies, we now have the tools to understand the phenotypic diversity and the common occurrence of phenocopies. We used these techniques to investigate two Norwegian families with an autosomal recessive cerebellar ataxia with cataracts and mental retardation.

Methods And Results: Single nucleotide polymorphism (SNP) chip analysis followed by Exome sequencing identified a 2 bp homozygous deletion in GBA2 in both families, c.1528_1529del [p.Met510Valfs*17]. Furthermore, we report the biochemical characterization of GBA2 in these patients. Our studies show that a reduced activity of GBA2 is sufficient to elevate the levels of glucosylceramide to similar levels as seen in Gaucher disease. Furthermore, leucocytes seem to be the proper enzyme source for in vitro analysis of GBA2 activity.

Conclusions: We report GBA2 mutations causing a Marinesco-Sjögren-like syndrome in two Norwegian families. One of the families was originally diagnosed with Marinesco-Sjögren syndrome based on an autosomal recessive cerebellar ataxia with cataracts and mental retardation. Our findings highlight the phenotypic variability associated with GBA2 mutations, and suggest that patients with Marinesco-Sjögren-like syndromes should be tested for mutations in this gene.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169309PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215700PMC
August 2017

Novel variant: altered respiratory and circadian rhythm, anesthetic sensitivity.

Ann Clin Transl Neurol 2016 11 11;3(11):876-883. Epub 2016 Oct 11.

Center for Medical Genetics and Molecular Medicine Haukeland University Hospital Bergen Norway.

The sodium leak channel, a Na-permeable, nonselective cation channel, is widely expressed in the nervous system, contributing a basal Na-leak conductance and regulating neuronal excitability. A 3-year-old girl, heterozygous for a de novo missense mutation in (c.956C>T; p.Ala319Val) predicted to be deleterious, presented from birth with: stimulus-induced, episodic contractures of the limbs and face with associated respiratory distress; distal arthrogryposis; severe axial hypotonia; and severe global developmental delay (CLIFAHDD syndrome). In infancy, she manifested a reversed sleep-wake rhythm, nocturnal life-threatening respiratory rhythm disturbances with central apnea. Sevoflurane sensitivity caused respiratory depression and cardiac arrest.
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http://dx.doi.org/10.1002/acn3.362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099533PMC
November 2016

Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration.

EMBO Mol Med 2016 Mar;8(3):176-90

Department of Neurology, Haukeland University Hospital, Bergen, Norway Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway

Mitochondrial dysfunction and altered proteostasis are central features of neurodegenerative diseases. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests oligopeptides, including the mitochondrial targeting sequences that are cleaved from proteins imported across the inner mitochondrial membrane and the mitochondrial fraction of amyloid beta (Aβ). We identified two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) associated with an autosomal recessive, slowly progressive syndrome characterised by mental retardation, spinocerebellar ataxia, cognitive decline and psychosis. The pathogenicity of the mutation was tested in vitro, in mutant fibroblasts and skeletal muscle, and in a yeast model. A Pitrm1(+/-) heterozygous mouse showed progressive ataxia associated with brain degenerative lesions, including accumulation of Aβ-positive amyloid deposits. Our results show that PITRM1 is responsible for significant Aβ degradation and that impairment of its activity results in Aβ accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration.
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http://dx.doi.org/10.15252/emmm.201505894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772954PMC
March 2016

High myopia-excavated optic disc anomaly associated with a frameshift mutation in the MYC-binding protein 2 gene (MYCBP2).

Am J Ophthalmol 2015 May 26;159(5):973-9.e2. Epub 2015 Jan 26.

Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway. Electronic address:

Purpose: To investigate the ocular and neurologic manifestations, and to identify the causative mutation in a family with an excavated optic disc anomaly, high myopia, enlarged axial lengths, and abnormal visual evoked response (VER).

Design: Prospective observational case series with whole exome sequencing.

Methods: Institutional study of 8 family members from 3 generations. Clinical examination included visual field examination, optical coherence tomography, axial length measurement, audiometry, visual evoked response (VER), orbital and cerebral magnetic resonance imaging (MRI), and renal ultrasound. DNA was analyzed by whole exome sequencing and Sanger sequencing. Main outcome measures were clinical and radiological findings, and DNA sequence data.

Results: Three affected family members, a father and his 2 daughters, were examined. The parents and siblings of the father were healthy. Affected individuals presented with excavated optic discs, high myopia (-1.00 to -16.00 diopters), and increased axial lengths. Reduced visual acuity (0.05-0.8) and decreased sensitivity on visual field examination were observed. VER revealed prolonged latency times. Affected eyes appeared ovoid on MRI and the father had thin optic nerves. Exome sequencing revealed that the father was heterozygous for a de novo 5 bp deletion in MYCBP2, c.5906_5910del; p.Glu1969Valfs*26. The same mutation was found in his 2 affected daughters, but not in his parents or siblings, or in public databases.

Conclusion: We describe a distinct excavated optic disc anomaly associated with high myopia and increased axial length. The condition appears to follow an autosomal dominant pattern and segregate with a deletion in MYCBP2. We suggest naming this entity high myopia-excavated optic disc anomaly.
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http://dx.doi.org/10.1016/j.ajo.2015.01.021DOI Listing
May 2015

Unusual Stüve-Wiedemann syndrome with complete maternal chromosome 5 isodisomy.

Ann Clin Transl Neurol 2014 Nov 24;1(11):926-32. Epub 2014 Oct 24.

Department of Clinical Science, University of Bergen Bergen, Norway ; Center of Medical Genetics and Molecular Medicine, Haukeland University Hospital Bergen, Norway.

A woman was isozygous for a novel mutation in the leukemia inhibitory factor receptor gene (LIFR) (c.2170C>G; p.Pro724Ala) which disrupts LIFR downstream signaling and results in Stüve-Wiedemann syndrome (STWS). She inherited two identical chromosomes 5 from her mother, heterozygous for the LIFR mutation. The presentation was typical for STWS, except there was no long bone dysplasia. Prominent cold-induced sweating and heat intolerance lead to an initial diagnosis of cold-induced sweating syndrome, excluded by exome sequencing. Skin biopsies provide the first human evidence of failed postnatal cholinergic differentiation of sympathetic neurons innervating sweat glands in cold-induced sweating, and of a neuropathy.
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http://dx.doi.org/10.1002/acn3.126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265064PMC
November 2014

STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.

Orphanet J Rare Dis 2014 Sep 26;9:146. Epub 2014 Sep 26.

Background: A subset of hereditary cerebellar ataxias is inherited as autosomal recessive traits (ARCAs). Classification of recessive ataxias due to phenotypic differences in the cerebellum and cerebellar structures is constantly evolving due to new identified disease genes. Recently, reports have linked mutations in genes involved in ubiquitination (RNF216, OTUD4, STUB1) to ARCA with hypogonadism.

Methods And Results: With a combination of homozygozity mapping and exome sequencing, we identified three mutations in STUB1 in two families with ARCA and cognitive impairment; a homozygous missense variant (c.194A > G, p.Asn65Ser) that segregated in three affected siblings, and a missense change (c.82G > A, p.Glu28Lys) which was inherited in trans with a nonsense mutation (c.430A > T, p.Lys144Ter) in another patient. STUB1 encodes CHIP (C-terminus of Heat shock protein 70 - Interacting Protein), a dual function protein with a role in ubiquitination as a co-chaperone with heat shock proteins, and as an E3 ligase. We show that the p.Asn65Ser substitution impairs CHIP's ability to ubiquitinate HSC70 in vitro, despite being able to self-ubiquitinate. These results are consistent with previous studies highlighting this as a critical residue for the interaction between CHIP and its co-chaperones. Furthermore, we show that the levels of CHIP are strongly reduced in vivo in patients' fibroblasts compared to controls.

Conclusions: These results suggest that STUB1 mutations might cause disease by impacting not only the E3 ligase function, but also its protein interaction properties and protein amount. Whether the clinical heterogeneity seen in STUB1 ARCA can be related to the location of the mutations remains to be understood, but interestingly, all siblings with the p.Asn65Ser substitution showed a marked appearance of accelerated aging not previously described in STUB1 related ARCA, none display hormonal aberrations/clinical hypogonadism while some affected family members had diabetes, alopecia, uveitis and ulcerative colitis, further refining the spectrum of STUB1 related disease.
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http://dx.doi.org/10.1186/s13023-014-0146-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181732PMC
September 2014

Novel SACS mutations identified by whole exome sequencing in a norwegian family with autosomal recessive spastic ataxia of Charlevoix-Saguenay.

PLoS One 2013 13;8(6):e66145. Epub 2013 Jun 13.

Department of Neurology, Haukeland University Hospital, Bergen, Norway ; Department of Clinical Medicine, University of Bergen, Bergen, Norway.

We employed whole exome sequencing to investigate three Norwegian siblings with an autosomal recessive spastic ataxia and epilepsy. All patients were compound heterozygous (c.13352T>C, p.Leu4451Pro; c.6890T>G, p.Leu2297Trp) for mutations in the SACS gene establishing the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The clinical features shown by our patients were typical of this disorder with the exception of epilepsy, which is a rare manifestation. This is the first report of ARSACS in Scandinavian patients and our findings expand the genetic and clinical spectrum of this rare disorder. Moreover, we show that exome sequencing is a powerful and cost-effective tool for the diagnosis of genetically heterogeneous disorders such as the hereditary ataxias.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066145PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681964PMC
January 2014

Variants of anterior segment dysgenesis and cerebral involvement in a large family with a novel COL4A1 mutation.

Am J Ophthalmol 2013 May 6;155(5):946-53. Epub 2013 Feb 6.

Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway.

Purpose: To investigate the diverse ocular manifestations and identify the causative mutation in a large family with autosomal dominant anterior segment dysgenesis accompanied in some individuals by cerebral vascular disease.

Design: Retrospective observational case series and laboratory investigation.

Methods: Forty-five family members from 4 generations underwent ophthalmic examination. Molecular genetic investigation included analysis with single nucleotide polymorphism (SNP) markers and DNA sequencing. Whole exome sequencing was performed in 1 individual.

Results: A broad range of ocular manifestations was observed. Typical cases presented with corneal clouding, anterior synechiae, and iris hypoplasia. Posterior embryotoxon, corectopia, and early cataract development were also seen. One obligate carrier and several other family members had minor ocular anomalies, thus confounding the scoring of affected and unaffected individuals. Cerebral hemorrhages had occurred in 4 individuals, in 3 at birth or during the first year of life. Seven patients with corneal clouding were considered "definitely affected" for linkage studies. Haplotype mapping revealed that they shared a 14 cM region in the terminal part of chromosome 13q that included the locus for COL4A1. The affected family members were heterozygous for a novel COL4A1 sequence variant c.4881C>G (p.Asn1627Lys) predicted to be damaging and not found among 185 local blood donors. Exome sequencing showed that this variant was the only one in the candidate region not found in dbSNP.

Conclusion: Among the family members shown to carry the novel COL4A1 mutation, heterogenous presentations of anterior segment dysgenesis was seen. Testing family members for this mutation also made a definite diagnosis possible in patients with a clinical presentation difficult to classify. In families where anterior segment dysgenesis occurs together with cerebral hemorrhages, genetic analysis of COL4A1 should be considered.
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http://dx.doi.org/10.1016/j.ajo.2012.11.028DOI Listing
May 2013

MRI characterisation of adult onset alpha-methylacyl-coA racemase deficiency diagnosed by exome sequencing.

Orphanet J Rare Dis 2013 Jan 3;8. Epub 2013 Jan 3.

Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we report the diagnostic work-up utilizing exome sequencing and the characterization of clinical features and brain MRI in two siblings with a complex, adult-onset phenotype; including peripheral neuropathy, epilepsy, relapsing encephalopathy, bilateral thalamic lesions, type 2 diabetes mellitus, cataract, pigmentary retinopathy and tremor.

Methods: We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions.

Results: A recessive genetic defect was suspected in two siblings of healthy, but consanguineous parents. Homozygosity mapping revealed three shared homozygous regions and exome sequencing, revealed a novel homozygous c.367 G>A [p.Asp123Asn] mutation in the α-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of α-methylacyl-coA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169 μmol/L, normal <1.5 μmol/L). MRI studies showed characteristic degeneration of cerebellar afferents and efferents, including the dentatothalamic tract and thalamic lesions in both patients.

Conclusions: Metabolic diseases presenting late are diagnostically challenging. We show that appropriately applied, homozygosity mapping and exome sequencing can be decisive for establishing diagnoses such as late onset α-methylacyl-coA racemase deficiency, an autosomal recessive peroxisomal disorder with accumulation of pristanic acid. Our study also highlights radiological features that may assist in diagnosis. Early diagnosis is important as patients with this disorder may benefit from restricted dietary phytanic and pristanic acid intake.
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http://dx.doi.org/10.1186/1750-1172-8-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567975PMC
January 2013

Multiple small hyperintense lesions in the subcortical white matter on cranial MR images in two Turkish brothers with cold-induced sweating syndrome caused by a novel missense mutation in the CRLF1 gene.

Brain Dev 2013 Jun 29;35(6):596-601. Epub 2012 Sep 29.

Department of Pediatric Genetics, Cerrahpaşa Medical School, Istanbul University, Istanbul, Turkey.

Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder characterized by excess sweating induced by cold exposure, camptodactyly and kyphoscoliosis. CISS is genetically heterogeneous. Deficiency of the CRLF1 or the CLCF1 gene function results in one of two clinically indistuinguishable disorders called CISS1 and CISS2, respectively. We present two Turkish brothers (22 and 13 years old) who had excess sweating induced by cold exposure, severe dorsal scoliosis, camptodactyly, reduced pain sensitivity and marfanoid habitus. The patients were homozygous and their parents heterozygous for a novel missense mutation c.413C>T (p.Pro138Leu) in CRLF1 gene. The cranial magnetic resonance imaging (MRI) of two patients also showed multiple small hyperintense lesions in the subcortical white matter. Similar MRI finding has also been reported in a Japanese woman with CISS1 and marfanoid habitus. The lesions found in the present cases showed no characteristic features. However, multiple small hyperintense lesions in subcortical white matter on T2 weighted and fluid attenuation inversion recovery (FLAIR) images may support the clinical diagnosis of CISS.
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http://dx.doi.org/10.1016/j.braindev.2012.08.011DOI Listing
June 2013

Familial diarrhea syndrome caused by an activating GUCY2C mutation.

N Engl J Med 2012 Apr 21;366(17):1586-95. Epub 2012 Mar 21.

Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.

Background: Familial diarrhea disorders are, in most cases, severe and caused by recessive mutations. We describe the cause of a novel dominant disease in 32 members of a Norwegian family. The affected members have chronic diarrhea that is of early onset, is relatively mild, and is associated with increased susceptibility to inflammatory bowel disease, small-bowel obstruction, and esophagitis.

Methods: We used linkage analysis, based on arrays with single-nucleotide polymorphisms, to identify a candidate region on chromosome 12 and then sequenced GUCY2C, encoding guanylate cyclase C (GC-C), an intestinal receptor for bacterial heat-stable enterotoxins. We performed exome sequencing of the entire candidate region from three affected family members, to exclude the possibility that mutations in genes other than GUCY2C could cause or contribute to susceptibility to the disease. We carried out functional studies of mutant GC-C using HEK293T cells.

Results: We identified a heterozygous missense mutation (c.2519G→T) in GUCY2C in all affected family members and observed no other rare variants in the exons of genes in the candidate region. Exposure of the mutant receptor to its ligands resulted in markedly increased production of cyclic guanosine monophosphate (cGMP). This may cause hyperactivation of the cystic fibrosis transmembrane regulator (CFTR), leading to increased chloride and water secretion from the enterocytes, and may thus explain the chronic diarrhea in the affected family members.

Conclusions: Increased GC-C signaling disturbs normal bowel function and appears to have a proinflammatory effect, either through increased chloride secretion or additional effects of elevated cellular cGMP. Further investigation of the relevance of genetic variants affecting the GC-C-CFTR pathway to conditions such as Crohn's disease is warranted. (Funded by Helse Vest [Western Norway Regional Health Authority] and the Department of Science and Technology, Government of India.).
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http://dx.doi.org/10.1056/NEJMoa1110132DOI Listing
April 2012

Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19.

Am J Hum Genet 2011 Nov 20;89(5):634-43. Epub 2011 Oct 20.

Department of Ophthalmology, Haukeland University Hospital, N-5021 Bergen, Norway.

A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause.
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http://dx.doi.org/10.1016/j.ajhg.2011.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213394PMC
November 2011

Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism.

Am J Hum Genet 2010 Sep;87(3):410-7

Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a neurodegenerative disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyze 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects.
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http://dx.doi.org/10.1016/j.ajhg.2010.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933347PMC
September 2010

A novel ADAMTSL4 mutation in autosomal recessive ectopia lentis et pupillae.

Invest Ophthalmol Vis Sci 2010 Dec 11;51(12):6369-73. Epub 2010 Aug 11.

Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway.

Purpose: To examine the ocular malformations and identify the molecular genetic basis for autosomal recessive ectopia lentis et pupillae in five Norwegian families.

Methods: Ten affected persons and 11 first-degree relatives of five Norwegian families underwent ophthalmic and general medical examination. Molecular genetic studies included homozygosity mapping with SNP markers, DNA sequencing, and RT-PCR analysis.

Results: Ocular signs in affected persons were increased median corneal thickness and astigmatism, angle malformation with prominent iris processes, displacement of the pupil and lens, lens coloboma, spherophakia, loss of zonular threads, early cataract development, glaucoma, and retinal detachment. No cardiac or metabolic abnormalities known to be associated with ectopia lentis were detected. Affected persons shared a 0.67 cM region of homozygosity on chromosome 1. DNA sequencing revealed a novel mutation in ADAMTSL4, c.767_786del20. This deletion of 20 base pairs (bp) results in a frameshift and an introduction of a stop codon 113 bp downstream, predicting a C-terminal truncation of the ADAMTSL4 protein (p.Gln256ProfsX38). Expression of truncated ADAMTSL4 mRNA was confirmed by RT-PCR analysis. Three of 190 local blood donors were carriers of this mutation.

Conclusions: Ectopia lentis et pupillae is associated with a number of malformations primarily in the anterior segment of the eye. The causative mutation, which is the first to be described in ectopia lentis et pupillae, disrupts the same gene function previously shown to cause isolated ectopia lentis. The mutation is ancient and may, therefore, be spread to a much larger population than the investigated one.
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http://dx.doi.org/10.1167/iovs.10-5597DOI Listing
December 2010

Cold-induced sweating syndrome with neonatal features of Crisponi syndrome: longitudinal observation of a patient homozygous for a CRLF1 mutation.

Am J Med Genet A 2010 Mar;152A(3):764-9

Department of Aging Medicine and Geriatrics, Shinshu University School of Medicine, Matsumoto, Japan.

Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder caused by mutations in CRLF1 (cytokine receptor-like factor 1), characterized by profuse sweating in cold environmental temperature and craniofacial and skeletal features. Mutations in CRLF1 also cause Crisponi syndrome (CS), characterized by neonatal-onset paroxysmal muscular contractions as well as craniofacial and skeletal manifestations and abnormal functions of the autonomic nerve system. To date, it is an unresolved problem whether the two conditions are distinct clinical entities or a single clinical entity with variable expressions or with different presentations depending on the patients' age at diagnosis. We report on a 30-year-old Japanese woman with CISS and homozygous out-of-frame 23-base deletion of CRLF1. In infancy, she did not show paroxysmal muscular contractions, but showed feeding difficulty, hyperthermia, and facial characteristics including thick and arched eyebrows, a short nose with anteverted nostrils, full cheeks, an inverted upper lip, and a small mouth, resembling those observed in CS. Profuse sweating was noticed at 3 years of age. Cold-induced sweating was recognized in her elementary school days. In adolescence to adulthood, she showed a Marfanoid habitus with progressive kyphoscoliosis and craniofacial characteristics including dolichocephaly, a slender face with poor expression, a distinctive nose with hypoplastic nares, malar hypoplasia, prognathism, and a small mouth. This is the first report of detailed longitudinal observation of a patient with CRLF1 abnormalities, compatible with the notion that CISS and CS may be a single clinical entity.
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http://dx.doi.org/10.1002/ajmg.a.33315DOI Listing
March 2010

Identification of a gene for renal-hepatic-pancreatic dysplasia by microarray-based homozygosity mapping.

J Mol Diagn 2010 Jan 10;12(1):125-31. Epub 2009 Dec 10.

Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen, Norway.

We have investigated a family where two siblings had a developmental disorder associated with polycystic dysplastic kidney disease that was incompatible with postnatal survival. Additional features observed were ductal plate malformation in the liver, dysplasia of the pancreas, and (in one individual) complete situs inversus and polymicrogyria of the cingulate gyri. The autopsy findings were compatible with renal-hepatic-pancreatic dysplasia, a condition with unknown genetic cause at the time of autopsy but with similarities to the Meckel-Gruber/Joubert group of recessive ciliopathies. Consanguinity between the parents made it likely that the mutated gene (with known or potential function in cilia) was located within a rather large region of homozygosity in the affected individuals (identical by descent). Using genetic markers (50K single nucleotide polymorphism microarrays), we found a single large homozygous region of 21.16 Mb containing approximately 200 genes on the long arm of chromosome 3. This region contained two known ciliopathy genes: NPHP3 (adolescent nephronophthisis) and IQCB1 (NPHP5), which is associated with Senior-Löken syndrome. In NPHP3, homozygosity for a deletion of the conserved splice acceptor dinucleotide (AG) preceding exon 20 was found. Our finding confirms the recent report that NPHP3-null mutations cause renal-hepatic-pancreatic dysplasia. Also, our case illustrates that genes for rare and genetically heterogeneous recessive conditions may be identified by homozygosity mapping using single nucleotide polymorphism arrays in the routine clinical setting.
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http://dx.doi.org/10.2353/jmoldx.2010.090033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797727PMC
January 2010

Brittle cornea syndrome associated with a missense mutation in the zinc-finger 469 gene.

Invest Ophthalmol Vis Sci 2010 Jan 6;51(1):47-52. Epub 2009 Aug 6.

Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.

Purpose: To investigate the diverse clinical manifestations, identify the causative mutation and explain the association with red hair in a family with brittle cornea syndrome (BCS).

Methods: Eight family members in three generations underwent ophthalmic, dental, and general medical examinations, including radiologic examination of the spine. Bone mineral density (BMD) and serum levels of vitamin D, parathyroid hormone, and biochemical markers for bone turnover were measured. Skin biopsies were examined by light and transmission electron microscopy. Molecular genetic studies included homozygosity mapping with SNP markers, DNA sequencing, and MC1R genotyping.

Results: At 42 and 48 years of age, respectively, both affected individuals were blind due to retinal detachment and secondary glaucoma. They had extremely thin and bulging corneas, velvety skin, chestnut colored hair, scoliosis, reduced BMD, dental anomalies, hearing loss, and minor cardiac defects. The morphologies of the skin biopsies were normal except that in some areas slightly thinner collagen fibrils were seen in one of the affected individuals. Molecular genetic analysis revealed a novel missense mutation of ZNF469, c.10016G>A, that was predicted to affect the fourth of the five zinc finger domains of ZNF469 by changing the first cysteine to a tyrosine (p.Cys3339Tyr). Both affected individuals were homozygous for the common red hair variant R151C at the MC1R locus.

Conclusions: BCS is a disorder that affects a variety of connective tissues. Reduced BMD and atypical dental crown morphology have not been reported previously. The results confirm that BCS is associated with mutations in ZNF469. The association with red hair in some individuals with BCS is likely to occur by chance.
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http://dx.doi.org/10.1167/iovs.09-4251DOI Listing
January 2010

Familial and sporadic porphyria cutanea tarda: characterization and diagnostic strategies.

Clin Chem 2009 Apr 20;55(4):795-803. Epub 2009 Feb 20.

Norwegian Porphyria Centre (NAPOS), Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.

Background: Porphyria cutanea tarda (PCT) occurs in sporadic (sPCT) and familial (fPCT) forms, which are generally clinically indistinguishable and have traditionally been differentiated by erythrocyte uroporphyrinogen decarboxylase (UROD, EC 4.1.1.37) activity. We used UROD gene sequencing as the reference standard in assessing the diagnostic accuracy of UROD activity, evaluating the mutation spectrum of the UROD gene, determining the frequency and disease attributes of PCT and its subtypes in Norway, and developing diagnostic models that use clinical and laboratory characteristics for differentiating fPCT and sPCT.

Methods: All consecutive patients with PCT diagnosed within a 6-year period were used for incidence calculations. UROD activity analysis, UROD gene sequencing, analysis of hemochromatosis mutations, and registration of clinical and laboratory data were carried out for 253 patients.

Results: Fifty-three percent of the patients had disease-relevant mutations, 74% of which were c.578G>C or c.636+1G>C. The UROD activity at the optimal cutoff had a likelihood ratio (LR) of 9.2 for fPCT, whereas a positive family history had an LR of 19. A logistic regression model indicated that low UROD activity, a high uroporphyrin-heptaporphyrin ratio, a young age at diagnosis, male sex, and low alcohol consumption were predictors of fPCT. The incidence of PCT was 1 in 100 000.

Conclusions: Two commonly occurring mutations are responsible for the high frequency of fPCT in Norway. UROD activity has a high diagnostic accuracy for differentiating the 2 PCT types, and a model that takes into account both clinical information and laboratory test results can be used to predict fPCT.
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http://dx.doi.org/10.1373/clinchem.2008.117432DOI Listing
April 2009

Co-occurrence of vitamin D-dependent rickets type 1 and phenylketonuria.

Acta Paediatr 2008 May;97(5):665-7

Department of Pediatrics, Haukeland University Hospital, N-5021 Bergen, Norway.

Unlabelled: Vitamin D-dependent rickets type 1 (VDDR1) was diagnosed in a 15-month-old girl with well-controlled phenylketonuria (PKU). The patient was homozygous for the PAH mutation L249F. The PAH and CYP27B1 genes are both located on the long arm of chromosome 12 and could possibly have been inherited from a common ancestor. The parents were not aware of any ancestral relationship and the patient was compound heterozygous for two different CYP27B1 mutations (R389H and S416X). Her mutations were shown to originate from each of her four grandparents. In Norway, the co-occurrence of PKU and VDDR1 is expected to occur by chance one to two times per billion births.

Conclusion: The extremely rare co-occurrence of VDDR1 and PKU requires careful genetic work-up and close attention to family information, but the combined treatment of the two metabolic disorders may not create special problems.
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http://dx.doi.org/10.1111/j.1651-2227.2008.00722.xDOI Listing
May 2008

Clinical manifestation of a novel PAX6 mutation Arg128Pro.

Arch Ophthalmol 2008 Mar;126(3):428-30

Department of Ophthalmology, Haukeland University Hospital, N-5021 Bergen, Norway.

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http://dx.doi.org/10.1001/archopht.126.3.428DOI Listing
March 2008

A second decorin frame shift mutation in a family with congenital stromal corneal dystrophy.

Am J Ophthalmol 2006 Sep;142(3):520-1

Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway.

Purpose: To identify the genetic defect in a Belgian family with congenital stromal corneal dystrophy.

Design: Case report and result of deoxyribonucleic acid (DNA) analyses.

Methods: DNA sequencing of polymerase chain reaction (PCR) products generated from amplification of exons and adjacent introns of the decorin gene.

Results: The family consisted of a mother and her son, both suffering from congenital stromal corneal dystrophy. In both individuals, a single base pair deletion (c.941delC) in the coding sequence of the decorin gene was demonstrated, predicting a C-terminal truncation of the decorin protein (p.Pro314fsX14).

Conclusion: This is the second family with congenital stromal corneal dystrophy of the cornea in which a frame shift mutation in the decorin gene has been detected. Both in this family and in a previously reported Norwegian family, a decorin protein missing the 33 C-terminal amino acids is predicted. This observation strongly supports a role for decorin in the pathogenesis of this disorder.
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http://dx.doi.org/10.1016/j.ajo.2006.03.064DOI Listing
September 2006

Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary neurotrophic factor receptor, leads to cold-induced sweating syndrome in a patient.

Proc Natl Acad Sci U S A 2006 Jun 16;103(26):10068-73. Epub 2006 Jun 16.

Institut National de la Santé et de la Recherche Médicale U564, F-49033 Angers, France.

Ciliary neurotrophic factor (CNTF) receptor controls a pathway supporting the differentiation and survival of a wide range of neural cell types during development and in adulthood. Cardiotrophin-like cytokine (CLC)-cytokine-like factor 1 (CLF) composite cytokine is a second ligand for the CNTF alpha-component receptor (CNTFRalpha). This composite cytokine is built on the structural model of IL-12, with a complex formed by a four-helix bundle type I cytokine, CLC (also referred to as CLCF1), bound to a soluble receptor subunit, CLF (also known as CRLF1). We have reported mutations in the chaperone soluble receptor CLF, causing cold-induced sweating syndrome (CISS). In this study, we studied the CLC-mutated alleles in a patient suffering from a similar disease. This patient was compound heterozygous for two different CLC mutations. The first allele was inactivated by a stop codon at position 107 (Y107X). In the second allele, a R197L mutation in the CLC-predicted binding site to the CNTFRalpha was detected. Functional analysis of the mutated protein revealed an incapacity for R197L CLC to bind to CNTFRalpha and activate the subsequent signaling events. Structural and docking interaction studies showed that the R197L substitution destabilized the contact site between CLC and CNTFRalpha.
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http://dx.doi.org/10.1073/pnas.0509598103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1502507PMC
June 2006

Lack of meiotic crossovers during oogenesis in an apparent 45,X Ullrich-Turner syndrome patient with three children.

Am J Med Genet A 2006 May;140(10):1092-7

Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.

A woman with apparent 45,X Ullrich-Turner syndrome was ascertained after the birth of three girls, the last being growth retarded due to a del(X)(p22.11) of grand-paternal origin. In this woman no del(X)-chromosome was detectable in blood by FISH or PCR. Fibroblast cultures from four different biopsies of her skin varied from having 45,X only to mosaic 46,X,del(X) to 46,X,del(X) only. In one fibroblast culture, a few cells with two del(X) chromosomes were found, probably remnants of a paternal dicentric X that caused the condition. Her three daughters were born when she was 29, 31, and 39 years old, respectively, indicating that disomy for the distal half of Xp is not required for normal folliculogenesis. When studying the crossover pattern of her daughters' maternal X-chromosomes, it turned out that one daughter had an X that was exclusively grand-maternal, one daughter lacked crossovers on Xq, and one daughter lacked crossovers on Xp. This suggests that univalent X-chromosomes were present in the Ullrich-Turner patient's primordial egg cells, either because there was only a single X-chromosome present (a 45,X primary oocyte), or because the X-chromosome was a partially or completely unpaired in pachytene, indicating a problem with chromosome association and synapsis formation.
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http://dx.doi.org/10.1002/ajmg.a.31204DOI Listing
May 2006

Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene.

Invest Ophthalmol Vis Sci 2005 Feb;46(2):420-6

Section of Ophthalmology, Department of Clinical Medicine, University of Bergen, Norway.

Purpose: To describe the clinical and pathologic characteristics of a family with a congenital stromal dystrophy of the cornea and to identify the genetic basis for this disorder.

Methods: All family members in three generations underwent ophthalmic examination. Stored corneal buttons were examined by transmission electron microscopy. Molecular genetic studies, including a genome-wide scan with microsatellite markers, linkage analysis, and DNA sequencing, were performed.

Results: The dystrophy was inherited in an autosomal dominant pattern and was seen as clouded corneas shortly after birth. No associated systemic abnormalities or congenital diseases were present. After penetrating keratoplasty (PK), the grafts remained completely clear in 56% of the eyes with a mean (range) observation period of 19.5 years (3-36). Transmission electron microscopy of corneal buttons revealed lamellae with normal arrangement of collagen fibrils separated by abnormal fibrillar layers. Genome-wide screening revealed linkage to chromosome 12q22, with a maximum LOD score of 4.68 at D12S351. Subsequent sequencing of candidate genes revealed a frameshift mutation in the DCN gene (c.967delT) that encodes for decorin, predicting a C-terminal truncation of the decorin protein (p.S323fsX5).

Conclusions: The authors hypothesize that truncated decorin binds to collagen in a suboptimal way, disturbing the regularity of corneal collagen fibril formation and thereby causing corneal opacities. To the best of the authors' knowledge, this is the first description of a disorder associated with an inherited alteration in the decorin gene in humans.
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http://dx.doi.org/10.1167/iovs.04-0804DOI Listing
February 2005

Retarded bone growth in thyroid hormone resistance. A clinical study of a large family with a novel thyroid hormone receptor mutation.

Eur J Endocrinol 2004 Apr;150(4):425-30

University of Bergen, Institute for Clinical Medicine and Molecular Medicine, Central Hospital, Children's Department, N-6807 Forde, Norway.

Objective: Thyroid hormone resistance (RTH) is characterised by variable tissue hyporesponsiveness to thyroid hormone. The disorder is usually caused by mutations in the thyroid hormone receptor beta (TR beta). We describe a large family with this disorder. SUBJECTS AND MEASUREMENT: We identified 36 family members with RTH in four generations by screening relatives of patients with the diagnosis. The diagnosis was verified by identification of a mutation in the thyroid hormone receptor beta (TR beta) gene. Symptoms, clinical findings and laboratory tests of 29 affected individuals were compared with those of 16 first-degree relatives.

Results: Bone maturation in children with RTH was delayed. The height was lower both in children and in adults with RTH than in the controls. Children with RTH had lower birth weight than the controls, particularly when the condition was inherited from the father. We did not observe increased prevalence of neuropsychological symptoms associated with RTH in this family. Palpitations and increased pulse rate indicated mild cardiac hyperthyroidism. Direct sequence analysis of the TR beta gene revealed a novel point mutation, a heterozygous transition c.1031G>C in exon 9 theoretically substituting Gly344Ala.

Conclusions: We found evidence of skeletal tissue hypothyroidism that resulted in permanent growth retardation from prenatal to adult life. We found substantial variations in thyroid hormone levels and clinical presentation, but most individuals were without symptoms of thyroid disorder.
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http://dx.doi.org/10.1530/eje.0.1500425DOI Listing
April 2004

Cold-induced sweating syndrome is caused by mutations in the CRLF1 gene.

Am J Hum Genet 2003 Feb 31;72(2):375-83. Epub 2002 Dec 31.

Center for Medical Genetics and Molecular Medicine, University of Bergen, Norway.

In 1978, Sohar et al. described a strikingly peculiar syndrome in two Israeli sisters. These young women responded to environmental temperatures of 18 degrees C-7 degrees C with profuse sweating on large segments on their back and chest. Both had additional abnormalities, including a high-arched palate, nasal voice, depressed nasal bridge, inability to fully extend their elbows, and kyphoscoliosis. We have observed this disorder in two Norwegian brothers. Genome-wide screening in the two families, followed by saturation marker studies and linkage analysis, identified a 1.4-Mb homozygous candidate region on chromosome 19p12. The maximum multipoint LOD score was 4.22. In both families, DNA sequencing of 25 genes within the candidate region identified potentially deleterious CRLF1 sequence variants that were not found in unaffected control individuals. Our findings confirm that the cold-induced sweating syndrome is an autosomal recessive disorder that is probably caused by impaired function of the CRLF1 gene, and they suggest important developmental functions for human CRLF1.
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http://dx.doi.org/10.1086/346120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC379230PMC
February 2003