The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3050, Australia.
Cell Death Dis. 2021 Apr 1;12(4):345. doi: 10.1038/s41419-021-03636-5.
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.
青年发病型糖尿病（MODY）是一种常染色体显性疾病，存在不完全外显率。在一个有多个世代糖尿病和几个早发糖尿病兄弟姐妹的家庭中，我们发现了先前报道的 P33T PDX1 破坏性突变。有趣的是，这种替代也存在于一个健康的兄弟姐妹中。相比之下，在糖尿病家族成员中仅发现了第二个非常罕见的坏死性凋亡末端效应物 MLKL 的杂合性破坏性突变。坏死性凋亡的异常细胞死亡是炎症性疾病的一个原因，并且已广泛涉及人类病理学，但尚未归因于糖尿病的功能。在这里，我们报告在糖尿病患者中观察到的 MLKL 取代，G316D，导致其上游激活剂 RIPK3 激酶的磷酸化减少，并且在两种不同的 MLKL 人细胞系中没有重新组成坏死性凋亡的能力。这种 MLKL 突变可能作为 P33T PDX1 突变的修饰因子，并表明坏死性凋亡受损在糖尿病中的潜在作用。我们的发现强调了在揭示 MODY 的不完全外显率方面进行家族研究的重要性，并进一步支持了调节性坏死性凋亡在人类疾病中的参与。
