Loss of MANF causes childhood-onset syndromic diabetes due to increased endoplasmic reticulum stress

Montaser, Hossam; Patel, Kashyap A.; Balboa, Diego; Ibrahim, Hazem; Lithovius, Väinö; Näätänen, Anna; Chandra, Vikash; Demir, Korcan; Acar, Sezer; Ben-Omran, Tawfeg; Colclough, Kevin; Locke, Jonathan M; Wakeling, Matthew; Lindahl, Maria; Hattersley, Andrew T.; Saarimäki-Vire, Jonna; Otonkoski, Timo

Loss of MANF causes childhood-onset syndromic diabetes due to increased endoplasmic reticulum stress

Mostra el registre complet Registre parcial de l'ítem

dc.contributor.author Montaser, Hossam
dc.contributor.author Patel, Kashyap A.
dc.contributor.author Balboa, Diego
dc.contributor.author Ibrahim, Hazem
dc.contributor.author Lithovius, Väinö
dc.contributor.author Näätänen, Anna
dc.contributor.author Chandra, Vikash
dc.contributor.author Demir, Korcan
dc.contributor.author Acar, Sezer
dc.contributor.author Ben-Omran, Tawfeg
dc.contributor.author Colclough, Kevin
dc.contributor.author Locke, Jonathan M
dc.contributor.author Wakeling, Matthew
dc.contributor.author Lindahl, Maria
dc.contributor.author Hattersley, Andrew T.
dc.contributor.author Saarimäki-Vire, Jonna
dc.contributor.author Otonkoski, Timo
dc.date.accessioned 2021-03-24T12:52:22Z
dc.date.available 2021-03-24T12:52:22Z
dc.date.issued 2021
dc.description.abstract 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.
dc.description.sponsorship 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)
dc.format.mimetype application/pdf
dc.identifier.citation Montaser H, Patel KA, Balboa D, Ibrahim H, Lithovius V, Näätänen A et al. Loss of MANF causes childhood-onset syndromic diabetes due to increased endoplasmic reticulum stress. Diabetes. 2021 Apr;70(4):1006-1018. DOI: 10.2337/db20-1174
dc.identifier.doi http://dx.doi.org/10.2337/db20-1174
dc.identifier.issn 0012-1797
dc.identifier.uri http://hdl.handle.net/10230/46928
dc.language.iso eng
dc.publisher American Diabetes Association
dc.relation.ispartof Diabetes. 2021 Apr;70(4):1006-18
dc.rights © American Diabetes Association. This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.subject.other Diabetis
dc.subject.other Diabetis infantil
dc.subject.other Sistema nerviós -- Malalties
dc.subject.other Genètica
dc.subject.other Proteïnes
dc.subject.other Estrès
dc.title Loss of MANF causes childhood-onset syndromic diabetes due to increased endoplasmic reticulum stress
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/acceptedVersion

Col·leccions

Articles (Center for Genomic Regulation (CRG))