X-linked dominant scapuloperoneal myopathy is due to a mutation in the gene encoding four-and-a-half-LIM protein 1

Am J Hum Genet. 2008 Jan;82(1):208-13. doi: 10.1016/j.ajhg.2007.09.013.


Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder-girdle and peroneal muscles. In a large Italian-American pedigree with dominant SP myopathy (SPM) previously linked to chromosome 12q, we have mapped the disease to Xq26, and, in all of the affected individuals, we identified a missense change (c.365G-->C) in the FHL1 gene encoding four-and-a-half-LIM protein 1 (FHL1). The mutation substitutes a serine for a conserved trypophan at amino acid 122 in the second LIM domain of the protein. Western blot analyses of muscle extracts revealed FHL1 loss that paralleled disease severity. FHL1 and an isoform, FHL1C, are highly expressed in skeletal muscle and may contribute to stability of sarcomeres and sarcolemma, myofibrillary assembly, and transcriptional regulation. This is the first report, to our knowledge, of X-linked dominant SP myopathy and the first human mutation in FHL1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Female
  • Genes, Dominant
  • Genes, X-Linked
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics*
  • LIM Domain Proteins
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Muscle Proteins / chemistry
  • Muscle Proteins / genetics*
  • Muscular Dystrophy, Emery-Dreifuss / genetics*
  • Mutation, Missense*
  • Pedigree
  • Protein Structure, Tertiary


  • FHL1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • Muscle Proteins