Dominant ER stress-inducing WFS1 mutations underlie a genetic syndrome of neonatal/infancy-onset diabetes, congenital sensorineural deafness, and congenital cataracts

dc.contributor.authorDe Franco, Elisa
dc.contributor.authorFlanagan, Sarah E.
dc.contributor.authorYagi, Takuya
dc.contributor.authorAbreu, Damien
dc.contributor.authorMahadevan, Jana
dc.contributor.authorJohnson, Matthew B.
dc.contributor.authorJones, Garan
dc.contributor.authorAcosta, Fernanda
dc.contributor.authorMulaudzi, M.C. (Mphelekedzeni)
dc.contributor.authorLek, Ngee
dc.contributor.authorOh, Vera
dc.contributor.authorPetz, Oliver
dc.contributor.authorCaswell, Richard
dc.contributor.authorEllard, Sian
dc.contributor.authorUrano, Fumihiko
dc.contributor.authorHattersley, Andrew T.
dc.date.accessioned2018-01-17T06:56:05Z
dc.date.available2018-01-17T06:56:05Z
dc.date.issued2017-07
dc.description.abstractNeonatal diabetes is frequently part of a complex syndrome with extra-pancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There remain 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 aetiology 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 3 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 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.en_ZA
dc.description.departmentPaediatrics and Child Healthen_ZA
dc.description.librarianhj2018en_ZA
dc.description.sponsorshipATH and SE are the recipients of a Wellcome Trust Senior Investigator award and ATH is employed as a core member of staff within the NIHR funded Exeter Clinical Research Facility. EDF is a Naomi Berrie Fellow in Diabetes Research. SEF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number: 105636/Z/14/Z). This work was partly supported by grants from National Institutes of Health (DK020579 and UL1 TR000448) to FU.en_ZA
dc.description.urihttp://diabetes.diabetesjournals.org/en_ZA
dc.identifier.citationDe Franco E., Flanagan S.E., Yagi T. et al. 2017, 'Dominant ER stress-inducing WFS1 mutations underlie a genetic syndrome of neonatal/infancy-onset diabetes, congenital sensorineural deafness, and congenital cataracts', Diabetes, vol. 66, no. 7, pp. 2044-2053.en_ZA
dc.identifier.issn0012-1797 (print)
dc.identifier.issn1939-327X (online)
dc.identifier.other10.2337/db16-1296
dc.identifier.urihttp://hdl.handle.net/2263/63576
dc.language.isoenen_ZA
dc.publisherAmerican Diabetes Association Inc.en_ZA
dc.rights© 2017 by the American Diabetes Associationen_ZA
dc.subjectCongenital cataractsen_ZA
dc.subjectCongenital sensorineural deafnessen_ZA
dc.subjectInfancy-onset diabetesen_ZA
dc.subjectNeonatal diabetesen_ZA
dc.subjectER stress–inducing WFS1 mutationsen_ZA
dc.titleDominant ER stress-inducing WFS1 mutations underlie a genetic syndrome of neonatal/infancy-onset diabetes, congenital sensorineural deafness, and congenital cataractsen_ZA
dc.typePostprint Articleen_ZA

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