期刊
CELL DEATH & DISEASE
卷 12, 期 4, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-021-03636-5
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资金
- internal Sidra Medicine research funding program
- Australian National Health and Medical Research Council [1058190, 1172929]
- Victorian State Government Operational Infrastructure Support
- Australian Government NHMRC IRIISS [9000653]
- Qatar National Library
- National Health and Medical Research Council of Australia [9000653] Funding Source: NHMRC
The study identified a very rare heterozygous damaging mutation in MLKL, a gene associated with necroptosis, exclusively in diabetic family members, suggesting a potential role of impaired necroptosis in diabetes. On the other hand, a previously reported damaging mutation in PDX1 was found in a healthy sibling in the same family. These findings highlight the importance of family studies in understanding MODY's incomplete penetrance and support the involvement of dysregulated necroptosis in human 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.
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