BLK – Maturity-Onset Diabetes of the Young

BLK heterozygous variants have been reported in autosomal dominant maturity-onset diabetes of the young (MODY). Initial linkage and sequencing in six unlinked MODY families identified five rare BLK variants that segregated with diabetes in three families, including the c.211G>A (p.Ala71Thr) missense substitution, and functional assays showed impaired insulin synthesis and secretion in beta-cell lines ([PMID:19667185]). Subsequent case reports confirmed c.211G>A (p.Ala71Thr) in a three-generation pedigree (proband, father, son) with early-onset diabetes ([PMID:39754319]). In total, five probands across three families and segregation in approximately five affected relatives support a limited variant spectrum (missense only) without evidence for recurrent or founder alleles. Population-level analyses do not demonstrate enrichment of BLK variants in diabetes cases ([PMID:36208030]).

Functional in vitro studies demonstrate that p.Ala71Thr reduces BLK protein half-life, diminishes kinase activity, and abolishes its enhancing effect on glucose-stimulated insulin secretion ([PMID:19667185]; [PMID:23224494]). No animal models, rescue experiments, or broader expression studies have been reported. The pathogenic mechanism appears to be loss of function, but absence of replication in large cohorts and limited segregation hinder confirmation. Therefore, the BLK–MODY association is classified as Limited. Additional large pedigrees and in vivo functional studies are required before clinical implementation.

Key Take-home: BLK variants may underlie MODY in rare familial cases, but current evidence is insufficient for routine genetic diagnosis.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2009 • Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. PMID:19667185
• Diabetologia • 2013 • Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes. PMID:23224494
• Human Molecular Genetics • 2022 • Statistical evidence to identify penetrant MODY genes in a large population-based cohort. PMID:36208030

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