We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Dominant ER Stress-Inducing Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts.
- Authors
De Franco, Elisa; Flanagan, Sarah E.; Takuya Yagi; Abreu, Damien; Mahadevan, Jana; Johnson, Matthew B.; Jones, Garan; Acosta, Fernanda; Mulaudzi, Mphele; Ngee Lek; Oh, Vera; Petz, Oliver; Caswell, Richard; Ellard, Sian; Fumihiko Urano; Hattersley, Andrew T.; Yagi, Takuya; Lek, Ngee; Urano, Fumihiko
- Abstract
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.
- Subjects
NEONATAL diseases; DIABETES in children; PEDIATRIC endocrinology; ENDOPLASMIC reticulum; ORGANELLES; CATARACT; SENSORINEURAL hearing loss; DIABETES; IMMUNOBLOTTING; MEMBRANE proteins; MUSCLE hypotonia; GENETIC mutation; RESEARCH funding; SYNDROMES; PHENOTYPES; GENETIC carriers; WOLFRAM syndrome; IN vitro studies
- Publication
Diabetes, 2017, Vol 66, Issue 7, p2044
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db16-1296