Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts
Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts
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DOI：
10.2337/db16-1296
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发表时间：
2017-07-01
期刊：
影响因子：
7.7
通讯作者：
Hattersley, Andrew T.
中科院分区：
文献类型：
--
作者：
De Franco, Elisa;Flanagan, Sarah E.;Hattersley, Andrew T.
新生儿糖尿病通常是具有胰外特征的复杂综合征的一部分：迄今为止已鉴定出 18 种导致综合征性新生儿糖尿病的基因。仍有一些新生儿糖尿病患者患有新的遗传综合征。我们对一名患者及其无关、未受影响的父母进行了外显子组测序，以确定以新生儿糖尿病、感音神经性耳聋和先天性白内障为特征的综合征的遗传病因。对 311 名 1 岁前诊断出的糖尿病患者进行了进一步测试，其中所有已知的遗传原因均被排除。我们确定了 5 名患者（包括最初的病例）在 WFS1 中具有 3 个杂合错义突变（4/5 已确认为从头）。他们在 12 个月前诊断出糖尿病（6 个月前诊断出 2 例）（5/5），出生后不久诊断出感音神经性耳聋（5/5），先天性白内障（4/5）和肌张力低下（4/5）。体外研究表明，这些 WFS1 突变在功能上与已知的导致 Wolfram 综合征的隐性突变不同，因为它们倾向于聚集并诱导强大的内质网应激。我们的结果确定特定的显性 WFS1 突变是一种新综合征的原因，包括新生儿/婴儿期发病的糖尿病、先天性白内障和感音神经性耳聋。该综合征具有独立的病理生理学特征，并且在遗传和临床上与隐性沃尔夫勒姆综合征不同。
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.