Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)–resident protein that plays a crucial role in attenuating ER stress responses. Although MANF indispensable for the survival and function of mouse ?-cells, its precise human ?-cell development unknown. In this study, we show lack humans results diabetes due to increased stress, leading impaired function. We identified two patients from different families with childhood neurodevelopmental disorder associated homozygous loss-of-function mutations gene. To study function, knocked out gene embryonic stem cells differentiated them into pancreatic endocrine cells. Loss induced mild insulin-processing capacity ?-cells vitro. Upon implantation immunocompromised mice, knockout grafts presented elevated functional failure, particularly recipients diabetes. By describing new form monogenic syndrome caused by disturbed highlight importance adequate regulation proper demonstrate process.