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Publication
Sex-biased islet ß cell dysfunction is caused by the MODY MAFA S64F variant by
inducing premature aging and senescence in males.
Authors Walker EM, Cha J, Tong X, Guo M, Liu JH, Yu S, Iacovazzo D, Mauvais-Jarvis F,
Flanagan SE, Korbonits M, Stafford J, Jacobson DA, Stein R
Submitted By Submitted Externally on 3/9/2022
Status Published
Journal Cell reports
Year 2021
Date Published 10/1/2021
Volume : Pages 37 : 109813
PubMed Reference 34644565
Abstract A heterozygous missense mutation of the islet ß cell-enriched MAFA transcription
factor (p.Ser64Phe [S64F]) is found in patients with adult-onset ß cell
dysfunction (diabetes or insulinomatosis), with men more prone to diabetes than
women. This mutation engenders increased stability to the unstable MAFA protein.
Here, we develop a S64F MafA mouse model to determine how ß cell function is
affected and find sex-dependent phenotypes. Heterozygous mutant males
(MafAS64F/+) display impaired glucose tolerance, while females are slightly
hypoglycemic with improved blood glucose clearance. Only MafAS64F/+ males show
transiently higher MafA protein levels preceding glucose intolerance and
sex-dependent changes to genes involved in Ca2+ signaling, DNA damage, aging,
and senescence. MAFAS64F production in male human ß cells also accelerate
cellular senescence and increase senescence-associated secretory proteins
compared to cells expressing MAFAWT. These results implicate a conserved
mechanism of accelerated islet aging and senescence in promoting diabetes in
MAFAS64F carriers in a sex-biased manner.




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