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Autosomal dominant variants in DNAJC3 have been implicated in familial type 2 diabetes mellitus (Type 2 Diabetes Mellitus). Whole exome sequencing in a Thai pedigree identified NM_006260.5:c.712C>A (p.His238Asn) segregating with diabetes in two unrelated families ([PMID:29767246]). Population screening revealed the variant in 14/1,000 older-onset T2D cases (MAF = 0.007), 2/500 non-diabetic controls (MAF = 0.002) and 3 prediabetic individuals. In silico modeling predicted altered polar contacts within the tetratricopeptide repeat motifs, and patient‐derived cells showed a 32% reduction in mutant protein expression compared to wild-type, consistent with protein instability ([PMID:29767246]). These functional data support a pathogenic mechanism via impaired endoplasmic reticulum stress regulation. While initial segregation and biochemical assays are concordant, additional large‐scale case series and replication are needed to solidify this gene–disease link.
Key Take-home: DNAJC3 c.712C>A (p.His238Asn) is a candidate autosomal dominant T2D variant warranting targeted screening in familial cases.
Gene–Disease AssociationLimitedSegregation of c.712C>A (p.His238Asn) in 2 unrelated pedigrees; no large replication cohorts Genetic EvidenceLimited2 probands across 2 families; absence of extended segregation counts Functional EvidenceModerateProtein modeling and expression assays demonstrate instability of H238N protein leading to ER stress dysregulation |