FHL1 – X-linked Myopathy with Postural Muscle Atrophy

FHL1 encodes four-and-a-half LIM domains protein 1, a scaffold protein highly expressed in skeletal and cardiac muscle. X-linked myopathy with postural muscle atrophy (XMPMA) is characterized by adult-onset scapulo-axio-peroneal weakness, postural muscle wasting, pseudo-athletic hypertrophy, and variable cardiomyopathy (PMID:18179888). Disease-causing variants in FHL1 disrupt LIM domain structure or splicing, leading to protein instability and muscle degeneration.

Genetic studies in a large multigenerational Austrian pedigree revealed a missense FHL1 variant segregating with disease in 14 affected males over three generations, consistent with X-linked recessive inheritance (PMID:18179888). A UK family independent of the Austrian kindred harbored a 3 bp insertion in FHL1 that co-segregated with the XMPMA phenotype. No unaffected males carried these variants, and female carriers were asymptomatic or mildly affected, confirming pathogenicity.

The variant spectrum includes missense changes within LIM2–LIM4 domains and splice-site variants such as c.332-2A>G, which abolish normal transcript processing and reduce FHL1 protein levels. Functional assays of patient myoblasts demonstrated impaired myotube formation and reduced FHL1 expression, while Fhl1-null mice developed age-dependent myopathy with myofibrillar disorganization and exercise intolerance, recapitulating key clinical features (PMID:23975679).

Mechanistically, loss of FHL1 disrupts sarcomeric assembly and alters muscle cell differentiation. Rescue of myoblast maturation by re-expression of FHL1A in null cells highlights a loss-of-function paradigm. Animal and cellular models consistently show that FHL1 deficiency leads to the XMPMA phenotype, supporting a haploinsufficiency mechanism.

No conflicting reports have emerged disputing the FHL1-XMPMA link; all identified variants co-segregate with disease and yield concordant functional deficits. Additional evidence exists for overlapping FHL1-related myopathies but does not detract from the specificity of XMPMA association.

Key Take-home: FHL1 variants cause X-linked myopathy with postural muscle atrophy via loss of LIM domain function, providing a definitive genetic diagnosis and enabling carrier screening and potential molecular therapies.

References

• American Journal of Human Genetics • 2008 • An X-linked myopathy with postural muscle atrophy, termed XMPMA, is caused by mutations in FHL1 PMID:18179888
• 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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