Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans

Berry, Vanita; Gregory‐Evans, Cheryl Y.; Emmett, Warren; Waseem, Naushin; Raby, Jacob; Prescott, Quincy; Moore, Anthony T.; Bhattacharya, Siladitya

doi:10.1038/ejhg.2013.52

Cited by 55 publications

(36 citation statements)

References 19 publications

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“…While autosomal dominant WFS1 mutations have been associated with non-syndromic low-frequency sensorineural hearing loss, congenital hearing impairment, diabetes mellitus and/or optic atrophy, and congenital nuclear cataract (22,23,24,25), common heterozygous variants of WFS1 have been reported either in type 2 diabetes mellitus in populations of European and African American descent (26,27,28), or with an increased frequency of psychiatric disorders including endogenous depression, alteration of short-term memory, anxiety, and suicide attempts (29), suggesting the role of WFS1 in determining incomplete phenotypes.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

Perrotta

Iorgi

Ragione

et al. 2015

European Journal of Endocrinology

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Objective: Idiopathic early-onset central diabetes insipidus (CDI) might be due to mutations of arginine vasopressinneurophysin II (AVP-NPII (AVP)) or wolframin (WFS1) genes. Design and methods: Sequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia. Results: Two patients carried a mutation in the AVP gene: a heterozygous G-to-T transition at nucleotide position 322 of exon 2 (c.322GOT) resulting in a stop codon at position 108 (p.Glu108X), and a novel deletion from nucleotide 52 to 54 (c.52_54delTCC) producing a deletion of a serine at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene localized on different alleles. The first change was A-to-G transition at nucleotide 997 in exon 8 (c.997AOG), resulting in a valine residue at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392_2393insACG causing the addition of an aspartate residue at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While similar WFS1 protein levels were detected in fibroblasts from healthy subjects and from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed in the patient fibroblasts as well as in patients with Wolfram syndrome. Conclusions: Early-onset CDI is associated with de novo mutations of the AVP gene and with hereditary WFS1 gene changes. These findings have valuable implications for management and genetic counseling.

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Section: European Journal Of Endocrinologymentioning

confidence: 99%

Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

Perrotta

Iorgi

Ragione

et al. 2015

European Journal of Endocrinology

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“…Although cataracts have been reported in some patients with Wolfram syndrome, they are not a consistent feature of the disease and are not congenital. Interestingly, isolated congenital nuclear cataracts have been previously reported in one family with a heterozygous WFS1 mutation (13) (Fig. 1), highlighting the importance of WFS1 in function and/or development of the eye lens.…”

Section: Discussionmentioning

confidence: 85%

“…Additional dominantly acting WFS1 mutations have been previously reported to cause autosomal dominant forms of both optic atrophy and hearing loss (10–12), low-frequency hearing loss (8,9), congenital cataracts (13), and isolated adult-onset diabetes (7). In these patients, the dominant phenotype is less severe than typically seen in classic recessive Wolfram syndrome (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Dominant ER Stress–Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts

et al. 2017

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Neonatal diabetes is frequently part of a complex syndrome with extrapancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There are still patients with neonatal diabetes who have novel genetic syndromes. We performed exome sequencing in a patient and his unrelated, unaffected parents to identify the genetic etiology of a syndrome characterized by neonatal diabetes, sensorineural deafness, and congenital cataracts. Further testing was performed in 311 patients with diabetes diagnosed before 1 year of age in whom all known genetic causes had been excluded. We identified 5 patients, including the initial case, with three heterozygous missense mutations in WFS1 (4/5 confirmed de novo). They had diabetes diagnosed before 12 months (2 before 6 months) (5/5), sensorineural deafness diagnosed soon after birth (5/5), congenital cataracts (4/5), and hypotonia (4/5). In vitro studies showed that these WFS1 mutations are functionally different from the known recessive Wolfram syndrome–causing mutations, as they tend to aggregate and induce robust endoplasmic reticulum stress. Our results establish specific dominant WFS1 mutations as a cause of a novel syndrome including neonatal/infancy-onset diabetes, congenital cataracts, and sensorineural deafness. This syndrome has a discrete pathophysiology and differs genetically and clinically from recessive Wolfram syndrome.

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“…However, further genetic tests are required to determine the carrier status. It is important to consider that heterozygous variants in WFS1 can cause Wolfram-like syndrome (section 2.3), and autosomal dominant cataracts, 26 so patients must be examined to exclude any manifestations. This must be undertaken following genetic counselling and arguably when the patient can make their own decision.…”

Section: Can a Genetic Test In The Index Patient Save Genetic Or Othementioning

confidence: 99%

Clinical utility gene card for: Wolfram syndrome

et al. 2016

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Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans

Cited by 55 publications

References 19 publications

Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

Dominant ER Stress–Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts

Clinical utility gene card for: Wolfram syndrome

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