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YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
- Source :
- Journal of Clinical Investigation. December, 2020, Vol. 130 Issue 12, p6338, 16 p.
- Publication Year :
- 2020
-
Abstract
- Neonatal diabetes is caused by single gene mutations reducing pancreatic [beta] cell number or impairing [beta] cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in [beta] cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human [beta] cell models (YIPF5 silencing in EndoC-[beta]H1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects [beta] cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and p cell failure. Partial YIPF5 silencing in EndoC-[beta]H1 cells and a patient mutation in stem cells increased the [beta] cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in [beta] cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.<br />Introduction Neonatal diabetes mellitus develops before 6 months of age and is caused by reduced pancreatic [beta] cell number (reduced formation/increased destruction) or impaired [beta] cell function. Previous studies have [...]
- Subjects :
- Pediatric research
Diabetes mellitus -- Genetic aspects -- Causes of -- Development and progression
Microcephaly -- Genetic aspects -- Causes of -- Development and progression
Stress (Physiology) -- Genetic aspects -- Health aspects
Neonatal diseases -- Genetic aspects -- Causes of -- Development and progression
Endoplasmic reticulum -- Physiological aspects -- Health aspects
Health care industry
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 12
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.644418758
- Full Text :
- https://doi.org/10.1172/JCH41455