FHL1 – Hypertrophic Cardiomyopathy

Four-and-a-half LIM domains protein 1 (FHL1) is an X-linked gene encoding a scaffold protein with key roles in sarcomere assembly and biomechanical stress sensing in both cardiac and skeletal muscle. Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction and myocardial disarray, most often due to sarcomeric gene mutations. However, up to 40% of HCM cases lack pathogenic variants in known HCM genes, prompting investigation of alternative loci. Emerging evidence implicates FHL1 as a novel contributor to isolated HCM, expanding the genetic spectrum of this cardiac disorder (MONDO:0005045).

Genetic analyses revealed an X-linked inheritance pattern in a Czech family with three affected males demonstrating nonobstructive HCM and severe diastolic dysfunction; a frameshift variant c.599_600insT (p.Phe200fsTer32) cosegregated with disease among male relatives and was also observed in a heterozygous female with apical HCM ([PMID:24114807]). In a cohort of 121 HCM patients lacking known sarcomeric mutations, three novel FHL1 variants were identified in unrelated probands: c.134delA (p.Lys45SerfsTer?), c.459C>A (p.Cys153Ter) and c.827G>C (p.Cys276Ser), with the latter two associated with isolated HCM (121 patients evaluated PMID:22523091).

The variant spectrum in HCM includes both protein-truncating and missense changes within LIM domains, for example c.827G>C (p.Cys276Ser), which targets a conserved cysteine in LIM4. Most FHL1 mutations reduce protein stability or disrupt domain folding, consistent with loss-of-function and dominant-negative mechanisms.

Functional studies in C2C12 myoblasts and rat-engineered heart tissue (EHT) demonstrated that mutant FHL1 proteins are degraded by the proteasome, leading to reduced FHL1 levels that can be rescued by proteasome inhibition. In EHT constructs, p.Lys45SerfsTer? increased force generation while p.Cys276Ser decreased both contraction amplitude and relaxation kinetics; both activated the fetal hypertrophic gene program, mirroring human HCM phenotypes ([PMID:22523091]).

Mechanistically, FHL1 mutants appear to act as “poison peptides,” impairing sarcomeric integrity and signaling pathways that regulate hypertrophy and diastolic function. Cellular and tissue models confirm concordant functional effects, supporting a pathogenic role of FHL1 variants in HCM.

Key clinical implications include the recommendation to include FHL1 in genetic panels for HCM, particularly in males with negative sarcomeric testing. Identification of FHL1 mutations informs risk stratification, family screening, and may guide targeted surveillance for diastolic dysfunction. Key Take-home: X-linked FHL1 variants represent a novel cause of isolated HCM, warranting inclusion in diagnostic gene panels for comprehensive genetic evaluation.

References

• Human molecular genetics • 2012 • Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy PMID:22523091
• Circulation. Cardiovascular genetics • 2013 • Isolated X-linked hypertrophic cardiomyopathy caused by a novel mutation of the four-and-a-half LIM domain 1 gene PMID:24114807

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