YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

Area of Science:

• Genetics
• Endocrinology
• Neuroscience

Background:

• Neonatal diabetes results from single-gene mutations affecting pancreatic beta cell function or number.
• Investigating rare diabetes subtypes illuminates crucial beta cell biological processes.

Purpose of the Study:

• To identify the genetic cause of a rare neonatal diabetes syndrome presenting with microcephaly and epilepsy.
• To elucidate the functional role of the YIPF5 gene in pancreatic beta cells and neuronal development.

Main Methods:

• Genetic analysis of five families to identify causative mutations.
• Utilized three human beta cell models: YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout/knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells.
• Assessed the impact of YIPF5 loss-of-function on ER-Golgi trafficking, proinsulin processing, ER stress, and beta cell apoptosis.

Main Results:

• Identified homozygous YIPF5 mutations in six patients with neonatal diabetes, microcephaly, and epilepsy.
• YIPF5 loss-of-function in beta cells caused proinsulin retention in the ER, ER stress, and subsequent beta cell failure.
• YIPF5 deficiency increased beta cell sensitivity to ER stress-induced apoptosis.

Conclusions:

• Recessive YIPF5 mutations cause a congenital syndrome characterized by microcephaly, epilepsy, and neonatal/early-onset diabetes.
• YIPF5 plays a critical role in both pancreatic beta cell function and neuronal development.
• This study is the first to link mutations in ER-to-Golgi trafficking genes to diabetes.