2026-04-14T07:32:18Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/469282025-12-12T03:58:43Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Montaser, Hossam author Patel, Kashyap A. author Balboa, Diego author Ibrahim, Hazem author Lithovius, Väinö author Näätänen, Anna author Chandra, Vikash author Demir, Korcan author Acar, Sezer author Ben-Omran, Tawfeg author Colclough, Kevin author Locke, Jonathan M author Wakeling, Matthew author Lindahl, Maria author Hattersley, Andrew T. author Saarimäki-Vire, Jonna author Otonkoski, Timo author 2021-03-24T12:52:22Z 2021-03-24T12:52:22Z 2021 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 is indispensable for the survival and function of mouse β-cells, its precise role in human β-cell development and function is unknown. In this study, we show that lack of MANF in humans results in diabetes due to increased ER stress, leading to impaired β-cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the MANF gene. To study the role of MANF in human β-cell development and function, we knocked out the MANF gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of MANF induced mild ER stress and impaired insulin-processing capacity of β-cells in vitro. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in recipients with diabetes. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human β-cell function and demonstrate the crucial role of MANF in this process. Funding: the genetic studies were funded by Wellcome Trust awarded to Kashyp Patel (grant 110082/Z/15/Z). Kashyp Patel is a Wellcome trust Fellow (grant 219606/Z/19/Z). A.T.H. is a Wellcome Trust Senior Investigator (WT098395/Z/12/Z). The experimental studies were funded by the Academy of Findland (grant 297466 and MetaStem Center of Excellence grant 312437), the Sigrid Jusélius Foundation, the Novo Nordisk Foundation and the JDRF (Grant 2-SRA-2018-496-A-B, PI Mart Saarma, co-PI TO) Diabetis Diabetis infantil Sistema nerviós -- Malalties Genètica Proteïnes Estrès Loss of MANF causes childhood-onset syndromic diabetes due to increased endoplasmic reticulum stress