FHL1 – Emery-Dreifuss Muscular Dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is a rare X-linked recessive myopathy characterized by early-onset joint contractures, progressive muscle wasting, and cardiac involvement, including conduction defects and arrhythmias. FHL1 encodes four and a half LIM domains protein 1, highly expressed in skeletal and cardiac muscle, and plays critical roles in sarcomere assembly and nuclear envelope integrity. Pathogenic variants in FHL1 define EDMD type 6 (EDMD6), distinct from EMD- and LMNA-related forms. Early genetic diagnosis guides management, surveillance for cardiomyopathy, and sudden death risk stratification.

Genetic evidence for FHL1 in EDMD arises from a cohort of seven unrelated families and one isolated case, identifying seven unique FHL1 mutations including missense and frameshift alleles in distal exons [PMID:19716112]. Inheritance is X-linked recessive, with hemizygous males fully penetrant and heterozygous females variably affected. Eleven male probands carrying FHL1 variants (five truncating, two cysteine-altering missense) presented with the classic triad, and co-segregation was observed across six informative families [PMID:19716112].

The variant spectrum encompasses missense substitutions targeting conserved LIM domains (e.g., c.592C>T (p.Gln198Ter)), loss-of-function indels, splice-site changes, and termination codon losses. A recurrent nonsense mutation c.592C>T (p.Gln198Ter) was reported in a family with EDMD features and left ventricular hypertrophy [PMID:23500067]. These alleles disrupt all three FHL1 isoforms, consistent with a loss-of-protein function mechanism and dominant-negative aggregation in select cases.

Functional studies demonstrate severely reduced FHL1 protein levels in patient myoblasts and biopsies, delayed myotube formation, and pathological cytoplasmic inclusions (“reducing bodies”) in recessive variants. FHL1-null mice develop age-dependent myopathy with myofibrillar disorganization, impaired oxidative capacity, and decreased exercise tolerance, recapitulating human EDMD6 [PMID:23975679]. These models confirm that FHL1 haploinsufficiency leads to skeletal muscle and cardiac pathology.

Mechanistically, FHL1 interacts with nuclear envelope proteins, including lamin A/C and emerin, and its loss perturbs sarcomere stability and intracellular signaling. Gain-of-function missense variants also form toxic aggregates, suggesting a dual pathogenic paradigm dependent on variant class. No significant conflicting reports have emerged, supporting a definitive gene–disease relationship.

Key Take-home: FHL1 analysis should be included in genetic testing panels for X-linked EDMD, enabling early intervention for contractures and cardiomyopathy surveillance, and informing family counseling.

References

• American Journal of Human Genetics • 2009 • Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy. PMID:19716112
• Human Molecular Genetics • 2014 • Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice. PMID:23975679

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