FHL1 – Reducing Body Myopathy

FHL1 encodes the four-and-a-half LIM domain 1 protein, mutations in which underlie X-linked reducing body myopathy (RBM), a rare progressive myopathy characterized by intracytoplasmic reducing bodies and early respiratory involvement. RBM presents with progressive limb-girdle and axial muscle weakness, spinal rigidity, scoliosis, joint contractures, elevated creatine kinase, and respiratory insufficiency across male hemizygotes and variably affected female carriers. Diagnosis relies on histochemical identification of menadione-NBT–positive reducing bodies in muscle biopsy and confirmation by FHL1 sequencing.

Genetic evidence supports an X-linked recessive inheritance, with hemizygous males typically severely affected and heterozygous females exhibiting variable penetrance due to X-inactivation. Familial and sporadic RBM cases total over 24 probands across at least nine unrelated families, with mutations exclusively clustering in the second LIM (LIM2) domain of FHL1. A recurrent missense change, c.448T>C (p.Cys150Arg), has been identified in six related members of a German pedigree (three clinically affected) and in additional unrelated cases ([PMID:20571991]; [PMID:31803991]).

Segregation analyses demonstrate co-segregation of LIM2-domain FHL1 variants with disease in multiple families, including six affected relatives carrying c.448T>C (p.Cys150Arg) and four familial cases with de novo mutations in the zinc-coordinating residue His123 ([PMID:20571991]; [PMID:19181672]). Case series and cohort studies have identified at least 27 distinct pathogenic variants—predominantly missense alterations of conserved cysteines and histidines—confirming allelic heterogeneity and a mutational hotspot in LIM2.

Functional studies corroborate pathogenicity via a dominant-negative aggregate mechanism. Laser microdissection coupled with mass spectrometry pinpointed FHL1 as the major component of reducing bodies in patient biopsies, and mutant FHL1 expression in COS-7 and C2C12 cells induces menadione-NBT–positive inclusions trapping wild-type FHL1 ([PMID:18274675]). Fhl1-null mice develop age-dependent progressive myopathy with myofibrillar disorganization and impaired muscle function, supporting loss of function as a contributory mechanism ([PMID:23975679]).

Collectively, the abundant genetic and experimental data satisfy ClinGen criteria for a definitive gene–disease relationship. No conflicting reports have disputed FHL1’s causality in RBM. Ongoing studies suggest additional deep-intronic and copy-number variants may expand the mutational spectrum beyond coding sequence changes.

Key Take-home: FHL1 sequencing should be incorporated in diagnostic panels for X-linked myopathies with reducing bodies, rigid spine features, and early respiratory compromise to enable accurate genetic counseling and anticipate multisystem involvement.

References

• Neuropediatrics • 2010 • Familial reducing body myopathy with cytoplasmic bodies and rigid spine revisited: identification of a second LIM domain mutation in FHL1. PMID:20571991
• Brain • 2009 • Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1. PMID:19181672
• The Journal of Clinical Investigation • 2008 • Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy. PMID:18274675
• 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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