title: Dysregulation of FHL1 spliceforms due to an indel mutation produces an Emery-Dreifuss muscular dystrophy plus phenotype.
abstract: 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.
authors: Department of Women's and Children's Health, Dunedin School of Medicine, Dunedin, New Zealand.
authors: Heather R
authors: HR
authors: Tiffin
authors: Zandra A
authors: ZA
authors: Jenkins
authors: Mary J
authors: MJ
authors: Gray
authors: Sophia R
authors: SR
authors: Cameron-Christie
authors: Jennifer
authors: J
authors: Eaton
authors: Salim
authors: S
authors: Aftimos
authors: David
authors: D
authors: Markie
authors: Stephen P
authors: SP
authors: Robertson
mesh_terms: D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D060588:LIM Domain Proteins / Q000235:genetics*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics
chemical_list: C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; D020928:Mitogen-Activated Protein Kinases