RT Journal Article
SR Electronic
T1 Male-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant inducing premature aging and senescence
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.29.177527
DO 10.1101/2020.06.29.177527
A1 Emily M. Walker
A1 Xin Tong
A1 Jeeyeon Cha
A1 Min Guo
A1 Jin-Hua Liu
A1 Sophia Yu
A1 Donato Iacovazzo
A1 Franck Mauvais-Jarvis
A1 Sarah E. Flanagan
A1 Márta Korbonits
A1 John Stafford
A1 David Jacobson
A1 Roland Stein
YR 2020
UL http://biorxiv.org/content/early/2020/06/29/2020.06.29.177527.abstract
AB A heterozygous missense variant in the islet β-cell-enriched MAFA (Ser(S)64Phe(F)) transcription factor was identified in humans who developed either diabetes or insulinomatosis, with males more prone to diabetes. This mutation engenders increased stability to the normally unstable MAFA protein. To obtain insight into how this impacts β cell function, we developed a mouse model expressing S64F MafA and found sex-dependent phenotypes, with heterozygous mutant males displaying impaired glucose tolerance while females were slightly hypoglycemic and had improved blood glucose clearance. Only heterozygous males showed higher MafA protein levels, which preceded the onset of glucose intolerance and sex dependent variations in expression of genes involved in aging, DNA damage, calcium signaling, and senescence. Changes in islet calcium handling and signs of aging and senescence processes were validated in male animals. Together, these results implicate accelerated islet aging and senescence in promoting diabetes in male human S64F MAFA carriers.Competing Interest StatementThe authors have declared no competing interest.