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Hypertrophic cardiomyopathy (HCM) is characterised by unexplained left ventricular hypertrophy and preserved or increased ejection fraction in the absence of secondary causes. While sarcomeric gene mutations predominate, recent evidence implicates signalling proteins in HCM pathogenesis. In 401 Indian HCM patients and 3 521 controls, exome and targeted sequencing identified a recurrent heterozygous missense variant in RPS6KB1 (c.139G>T (p.Gly47Trp)) in two unrelated families (PMID:34916228).
A replication study in the UK Biobank cardiomyopathy cohort (n = 190) uncovered two additional heterozygous missense variants (p.Gln49Lys and p.Tyr62His) absent from matched controls (n = 16 479) and population databases. An independent Arab HCM patient carried p.Pro445Ser, reinforcing allelic heterogeneity. All variants were absent in regional controls and gnomAD, supporting their rarity and potential pathogenicity.
Family studies demonstrated autosomal dominant inheritance with co-segregation of p.Gly47Trp in two pedigrees (affected_relatives = 2). A total of five unrelated probands across three cohorts harbour heterozygous RPS6KB1 variants, providing moderate genetic evidence. These missense changes cluster in the kinase domain, suggesting a conserved mechanism.
Functional assays in cellular models showed that mutant S6K1 proteins exhibit constitutive activation, hyperphosphorylating downstream targets rpS6 and ERK1/2 compared with wild type. This gain-of-function effect aligns with aberrant mTOR signalling known to drive cardiomyocyte hypertrophy.
Mechanistically, enhanced S6K1 kinase activity likely promotes maladaptive cardiac growth through increased protein synthesis and MAPK pathway activation. No conflicting reports have been documented to date, and the functional data concordantly support a pathogenic role.
Early detection of RPS6KB1 variant carriers enables family screening, risk stratification and tailored management for HCM. Inclusion of RPS6KB1 in HCM gene panels may improve diagnostic yield and guide preventive strategies.
Key Take-home: Rare heterozygous gain-of-function missense variants in RPS6KB1 cause autosomal dominant hypertrophic cardiomyopathy via enhanced kinase activity and downstream pathway hyperphosphorylation.
Gene–Disease AssociationModerateFive probands in three unrelated cohorts; segregation in two families; concordant gain-of-function functional data Genetic EvidenceModerateFive probands with heterozygous missense variants; segregation in two pedigrees; absence in controls Functional EvidenceModerateCellular models show gain-of-function with hyperphosphorylation of rpS6 and ERK1/2 |