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A recent study of patients with early-onset diabetes and suggestive family histories identified seven APPL1 variants in autosomal dominant MODY14, including five novel alleles: four missense (p.Asp632Tyr, p.Arg633His, p.Arg532Gln, p.Ile642Met) and one intronic (c.1153-16A>T), in addition to the two previously reported truncating and missense mutations (PMID:38464380). All variants cluster within the phosphotyrosine-binding domain of APPL1, but segregation data remain limited.
In vitro functional assays demonstrated that c.1894G>T (p.Asp632Tyr) and c.1595G>A (p.Arg532Gln) markedly reduce APPL1 mRNA and protein expression and impair insulin receptor signaling in patient-derived models, supporting a loss-of-function mechanism (PMID:38464380). Taken together, the current evidence supports a Limited clinical validity classification for the APPL1–Maturity-onset diabetes of the young type 14 association. Key take-home: APPL1 phosphotyrosine-binding domain variants warrant consideration in genetic testing for early-onset autosomal dominant diabetes.
Gene–Disease AssociationLimitedSeven APPL1 variants identified in a single study with limited segregation data and initial functional studies ([PMID:38464380]) Genetic EvidenceLimitedFive novel missense and one intronic APPL1 variants in fewer than ten probands, familial segregation unquantified ([PMID:38464380]) Functional EvidenceModerateIn vitro assays showed that c.1595G>A (p.Arg532Gln) and c.1894G>T (p.Asp632Tyr) reduce APPL1 mRNA and protein levels, supporting a loss-of-function mechanism ([PMID:38464380]) |