A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes
Publication Year 2021-04-01, Volume 12, Issue #4, Page 345
Journal Title
Cell Death & Disease
Maturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL(-/-) human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY's incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.
WEHI Research Division(s)
PubMed ID
Open Access at Publisher's Site
NHMRC Grants
NHMRC/1172929 NHMRC/1058190
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Creation Date: 2021-04-28 08:15:49
Last Modified: 2021-05-06 08:45:40
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