Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts.
Elisa De FrancoSarah E FlanaganTakuya YagiDamien AbreuJana MahadevanMatthew B JohnsonGaran JonesFernanda AcostaMphele MulaudziNgee LekVera OhOliver PetzRichard CaswellSian EllardFumihiko UranoAndrew T HattersleyPublished in: Diabetes (2017)
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.
Keyphrases
- type diabetes
- cardiovascular disease
- glycemic control
- case report
- hearing loss
- endoplasmic reticulum stress
- genome wide
- intellectual disability
- end stage renal disease
- chronic kidney disease
- copy number
- ejection fraction
- skeletal muscle
- gene expression
- induced apoptosis
- pregnant women
- signaling pathway
- autism spectrum disorder
- transcription factor
- preterm birth
- duchenne muscular dystrophy
- genome wide identification
- gestational age