, Volume 14, Issue 2, pp 113–121 | Cite as

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

  • Heather R. Tiffin
  • Zandra A. Jenkins
  • Mary J. Gray
  • Sophia R. Cameron-Christie
  • Jennifer Eaton
  • Salim Aftimos
  • David Markie
  • Stephen P. RobertsonEmail author
Original Article


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.


EDMD FHL1 Noonan syndrome RAS-MAPK signalling 



The authors thank the family for their participation in this research. This work was funded by Curekids New Zealand.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Heather R. Tiffin
    • 1
  • Zandra A. Jenkins
    • 1
  • Mary J. Gray
    • 1
  • Sophia R. Cameron-Christie
    • 1
  • Jennifer Eaton
    • 2
  • Salim Aftimos
    • 2
  • David Markie
    • 3
  • Stephen P. Robertson
    • 1
    Email author
  1. 1.Department of Women’s and Children’s HealthDunedin School of MedicineDunedinNew Zealand
  2. 2.Genetic Services New ZealandAuckland City HospitalAucklandNew Zealand
  3. 3.Department of PathologyDunedin School of MedicineDunedinNew Zealand

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