Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Four Japanese families with familial hyperproinsulinemia exhibited a shared alteration at Arg65 of proinsulin, implicating this residue as a mutational hotspot (PMID:7859596). Affected individuals demonstrated elevated proinsulin-to-insulin ratios and abnormal insulin release profiles consistent with impaired B–C junction cleavage. Segregation across each kindred supports an autosomal dominant inheritance pattern with co-segregation of the Arg65 locus and biochemical phenotype. While the precise nucleotide change remains to be defined, functional assays revealed defective proinsulin processing in affected subjects (PMID:7859596). No conflicting reports have been documented for INS in hyperproinsulinemia. Key take-home: INS Arg65 variants cause a cleavage defect leading to hyperproinsulinemia and should be considered in diagnostic sequencing of familial cases.
Gene–Disease AssociationLimitedFour unrelated probands in independent families with INS Arg65 involvement ([PMID:7859596]) Genetic EvidenceLimitedFour families with segregation of elevated proinsulin and an Arg65 locus without precise molecular characterisation ([PMID:7859596]) Functional EvidenceLimitedIn vitro insulin release assays demonstrated impaired proinsulin processing in affected individuals ([PMID:7859596]) |