Dominant ER stress-inducing WFS1 mutations underlie a genetic syndrome of neonatal/infancy-onset diabetes, congenital sensorineural deafness, and congenital cataracts
dc.contributor.author | De Franco, Elisa | |
dc.contributor.author | Flanagan, Sarah E. | |
dc.contributor.author | Yagi, Takuya | |
dc.contributor.author | Abreu, Damien | |
dc.contributor.author | Mahadevan, Jana | |
dc.contributor.author | Johnson, Matthew B. | |
dc.contributor.author | Jones, Garan | |
dc.contributor.author | Acosta, Fernanda | |
dc.contributor.author | Mulaudzi, M.C. (Mphelekedzeni) | |
dc.contributor.author | Lek, Ngee | |
dc.contributor.author | Oh, Vera | |
dc.contributor.author | Petz, Oliver | |
dc.contributor.author | Caswell, Richard | |
dc.contributor.author | Ellard, Sian | |
dc.contributor.author | Urano, Fumihiko | |
dc.contributor.author | Hattersley, Andrew T. | |
dc.date.accessioned | 2018-01-17T06:56:05Z | |
dc.date.available | 2018-01-17T06:56:05Z | |
dc.date.issued | 2017-07 | |
dc.description.abstract | Neonatal 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.department | Paediatrics and Child Health | en_ZA |
dc.description.librarian | hj2018 | en_ZA |
dc.description.sponsorship | ATH 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.uri | http://diabetes.diabetesjournals.org/ | en_ZA |
dc.identifier.citation | De 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.issn | 0012-1797 (print) | |
dc.identifier.issn | 1939-327X (online) | |
dc.identifier.other | 10.2337/db16-1296 | |
dc.identifier.uri | http://hdl.handle.net/2263/63576 | |
dc.language.iso | en | en_ZA |
dc.publisher | American Diabetes Association Inc. | en_ZA |
dc.rights | © 2017 by the American Diabetes Association | en_ZA |
dc.subject | Congenital cataracts | en_ZA |
dc.subject | Congenital sensorineural deafness | en_ZA |
dc.subject | Infancy-onset diabetes | en_ZA |
dc.subject | Neonatal diabetes | en_ZA |
dc.subject | ER stress–inducing WFS1 mutations | en_ZA |
dc.title | Dominant ER stress-inducing WFS1 mutations underlie a genetic syndrome of neonatal/infancy-onset diabetes, congenital sensorineural deafness, and congenital cataracts | en_ZA |
dc.type | Postprint Article | en_ZA |