Dysregulation of FHL1 spliceforms due to an indel mutation produces an Emery-Dreifuss muscular dystrophy plus phenotype

Neurogenetics. 2013 May;14(2):113-21. doi: 10.1007/s10048-013-0359-8. Epub 2013 Mar 2.


Emery-Dreifuss muscular dystrophy (EDMD) is characterised by early-onset joint contractures, progressive muscular weakness and wasting and late-onset cardiac disease. The more common X-linked recessive form of EDMD is caused by mutations in either EMD (encoding emerin) or FHL1 (encoding four and a half LIM domains 1), while mutations in LMNA (encoding lamin A/C), SYNE1 (encoding nesprin-1) and SYNE2 (encoding nesprin-2) lead to autosomal dominant forms of the condition. Here, we identify a three-generation family with an extended EDMD phenotype due to a novel indel mutation in FHL1 that differentially affects the relative expression of the three known transcript isoforms produced from this locus. The additional phenotypic manifestations in this family-proportionate short stature, facial dysmorphism, pulmonary valvular stenosis, thoracic scoliosis, brachydactyly, pectus deformities and genital abnormalities-are reminiscent of phenotypes seen with dysregulated Ras-mitogen-activated protein kinase (RAS-MAPK) signalling [Noonan syndrome (NS) and related disorders]. The misexpression of FHL1 transcripts precipitated by this mutation, together with the role of FHL1 in the regulation of RAS-MAPK signalling, suggests that this mutation confers a complex phenotype through both gain- and loss-of-function mechanisms. This indel mutation in FHL1 broadens the spectrum of FHL1-related disorders and implicates it in the pathogenesis of NS spectrum disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Child
  • Female
  • Humans
  • INDEL Mutation / genetics*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • LIM Domain Proteins / genetics*
  • Male
  • Mitogen-Activated Protein Kinases / genetics
  • Muscle Proteins / genetics*
  • Muscular Dystrophy, Emery-Dreifuss / genetics*
  • Muscular Dystrophy, Emery-Dreifuss / metabolism
  • Muscular Dystrophy, Emery-Dreifuss / pathology
  • Pedigree
  • Phenotype
  • Protein Isoforms / genetics


  • FHL1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • Muscle Proteins
  • Protein Isoforms
  • Mitogen-Activated Protein Kinases