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Download fileLoss of MANF Causes Childhood Onset Syndromic Diabetes due to Increased Endoplasmic Reticulum Stress
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posted on 2021-01-26, 23:31 authored by Hossam Montaser, Kashyap A Patel, Diego Balboa, Hazem Ibrahim, Väinö Lithovius, Anna Näätänen, Vikash Chandra, Korcan Demir, Sezer Acar, Tawfeg Ben-Omran, Kevin Colclough, Jonathan M. Locke, Matthew Wakeling, Maria Lindahl, Andrew Hattersley, Jonna Saarimäki-Vire, Timo OtonkoskiMANF
is an endoplasmic reticulum resident protein that plays a crucial role in attenuating
ER stress responses. Although MANF is indispensable for the survival and
function of mouse beta cells, its precise role in human beta cell development
and function is unknown. Herein, we show that lack of MANF in humans results in
diabetes due to increased ER stress leading to impaired beta 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 beta 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 beta cells in vitro. Upon implantation to
immunocompromised mice, the MANF knockout grafts presented elevated ER stress
and functional failure, particularly in diabetic recipients. 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 beta cell function and demonstrate the crucial role of MANF in
this process.