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Updated: Nov 10, 2025
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes
Joanne M Hildebrand1,2, Bernice Lo3, Sara Tomei3
1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
Abstract:
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.
Insights
A rare MLKL gene mutation, G316D, was found in diabetic family members, suggesting impaired necroptosis contributes to Maturity-onset diabetes of the young (MODY) by modifying a known PDX1 mutation.
Area of Science:
- Genetics
- Molecular Biology
- Cellular Biology
Background:
- Maturity-onset diabetes of the young (MODY) is an autosomal dominant condition with incomplete penetrance.
- The P33T PDX1 mutation is a known cause of MODY.
- Necroptosis, a form of programmed cell death, is implicated in inflammatory diseases but its role in diabetes is unclear.
Purpose of the Study:
- To investigate the genetic factors contributing to incomplete penetrance in a family with MODY.
- To explore the potential role of necroptosis in the pathogenesis of diabetes.
Main Methods:
- Genetic sequencing to identify mutations in affected and unaffected family members.
- Functional assays using MLKL-/- human cell lines to assess the impact of the MLKL G316D mutation on necroptosis.
- Analysis of MLKL phosphorylation by RIPK3 kinase.
Main Results:
- A known P33T PDX1 mutation was identified in both diabetic and healthy individuals.
- A novel, rare heterozygous MLKL mutation (G316D) was exclusively found in diabetic family members.
- The MLKL G316D mutation impairs necroptosis by reducing phosphorylation and eliminating the capacity to induce cell death.
Conclusions:
- The MLKL G316D mutation may act as a genetic modifier, influencing the penetrance of the PDX1 mutation in MODY.
- Impaired necroptosis, due to MLKL mutations, is implicated as a potential factor in diabetes development.
- Family studies are crucial for understanding the complex genetic basis of MODY and incomplete penetrance.
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