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Phenotypic Heterogeneity in British Patients with a Founder Mutation in the FHL1 Gene

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Phenotypic Heterogeneity in British Patients with a Founder Mutation in the FHL1 Gene European Journal of Human Genetics (2011) 19, 1038–1044 & 2011 Macmillan Publishers Limited All rights reserved 1018-4813/11 www.nature.com/ejhg ARTICLE Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene Anna Sarkozy1, Christian Windpassinger2, Judith Hudson1, Charlotte F Dougan3, Bryan Lecky3, David Hilton-Jones4, Michelle Eagle1, Richard Charlton5, Rita Barresi5, Hanns Lochmu¨ller1, Kate Bushby1 and Volker Straub*,1 Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280-amino-acid protein containing four LIM domains and a single zinc-finger domain in the N-terminal region, have been associated with a broad clinical spectrum of X-linked muscle diseases encompassing a variety of different phenotypes. Patients might present with a scapuloperoneal myopathy, a myopathy with postural muscle atrophy and generalized hypertrophy, an Emery–Dreifuss muscular dystrophy, or an early onset myopathy with reducing bodies. It has been proposed that the phenotypic variability is related to the position of the mutation within the FHL1 gene. Here, we report on three British families with a heterogeneous clinical presentation segregating a single FHL1 gene mutation and haplotype, suggesting that this represents a founder mutation. The underlying FHL1 gene mutation was detected by direct sequencing and the founder effect was verified by haplotype analysis of the FHL1 gene locus. A 3-bp insertion mutation (p.Phe127_Thr128insIle) within the second LIM domain of the FHL1 gene was identified in all available affected family members of the three families. Haplotype analysis of the FHL1 region on Xq26 revealed that the families shared a common haplotype. The p.Phe127_Thr128insIle mutation in the FHL1 gene therefore appears to be a British founder mutation and FHL1 gene screening, in particular of exon 6, should therefore be indicated in British patients with a broad phenotypic spectrum of X-linked muscle diseases. European Journal of Human Genetics (2011) 19, 1038–1044; doi:10.1038/ejhg.2011.84; published online 1 June 2011 Keywords: FHL1; myopathy; founder mutation; British INTRODUCTION ‘reducing body (RB) subgroup’ including RBM, X-linked dominant The human four-and-a-half LIM domain 1 (FHL1) gene, located on scapuloperoneal myopathy and rigid spine syndrome, all characterized Xq26.3, encodes for a 32-kDa protein with four and a half tandem repeat by RB at histological examination, and a second subgroup, including LIM domains. LIM domains are cysteine-rich, tandem zinc-finger protein the XMPMA and EDMD patients, characterized by later onset and interaction motifs first recognized in the three homeodomain transcrip- absence of RB.12,13,16 RBM may also be seen as a condition within a tion factors Lin-11, Isl-1 and Mac-3.1–5 FHL1 has at least three isoforms, larger phenotypic spectrum of protein aggregate myopathies, such as a full-length protein (FHL1A) and two additional variants referred to as the myofibrillar myopathies.18 FHL1B and C, differing in their primary structure, expression pattern, Here, we report three British families with X-linked muscle diseases, binding partners and subcellular localizations.6,7 All isoforms are highly one being part of our original report,9 presenting with partly hetero- expressed in skeletal muscle and to a lesser extent also in heart muscle geneous phenotypes but sharing the p.Phe127_Tyr128insIle mutation (leftandrightventricle).8 FHL1 localizes to the sarcomere and the in the FHL1 gene and a common Xq26 haplotype. sarcolemmaandisbelievedtoparticipateinmusclegrowthand differentiation as well as in sarcomere assembly.8 SUBJECTS AND METHODS We first described FHL1 gene mutations in families presenting with Clinical assessment an X-linked myopathy with postural muscle atrophy and generalized Three families were included in the study. Their case histories were reviewed and seven patients were interviewed and examined. Their age ranged between hypertrophy (XMPMA).9 Concurrently, FHL1 gene mutations have 27 and 55 years at the time of the study. Respiratory function was assessed been detected in X-linked dominant scapuloperoneal myopathy,10,11 clinically and spirometrically. In six patients, a formal cardiology assessment and subsequently in a wide spectrum of partly overlapping conditions, was also performed. Clinical information for 13 additional now-deceased 12–14 15 such as reducing body myopathy (RBM), rigid spine syndrome, family members was provided by the patients and their families. A muscle 16 Emery–Dreifuss muscular dystrophy (EDMD), and in a single family biopsy was obtained for diagnostic purposes from at least one individual in with contractures, rigid spine, and cardiomyopathy.17 It has been each of the families. All patients included in this study provided appropriate suggested to classify FHL1-related disorders into two main groups, the consent for the investigations reported. 1Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK; 2Institute of Human Genetics, Medical University of Graz, Graz, Austria; 3The Walton Centre for Neurology and Neurosurgery, Liverpool, UK; 4Department of Clinical Neurology, West Wing, John Radcliffe Hospital, Oxford, UK; 5Muscle Immunoanalysis Unit, Newcastle upon Tyne Hospitals Trust, Newcastle upon Tyne, UK *Correspondence: Professor V Straub, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, NE13BZ,UK. Tel: +44 191 241 8762; Fax: +44 191 241 8770; E-mail: [email protected] Received 21 January 2011; revised 6 April 2011; accepted 14 April 2011; published online 1 June 2011 British families with FHL1 founder mutation ASarkozyet al 1039 Muscle biopsy conditions and a protocol previously reported.9 For haplotype analysis of the Skeletal muscle biopsies were assessed by routine histochemistry and immuno- FHL1 locus, the following markers were selected and analysed as previously analysis. Optimised immunohistochemical and multiplex western blot analysis described: DXS8009, AFMa288xd5, AFM205wd2, AFMb340zd9, DXS8074, were performed as previously described.19,20 In addition, antibodies against DXS8033, DXS8094, DXS1041 and DXS1227.9 myotilin (Novocastra, Newcastle upon Tyne, UK) and desmin (in-house DY14/ 5H2) were also used. At the time of the present study, muscle tissues and RESULTS sections were not available for histological re-evaluation and menadione–NBT staining, and for FHL1 protein immunoanalysis. Phenotypic presentation Main clinical features of the three families are summarized in Table 1. Genetic analysis Genomic DNA was extracted from blood samples using standard procedures. Family 1. Four male individuals in three consecutive generations FHL1 mutation screening was performed using primers, amplification were affected (Figure 1a, Table 1). This family has previously been Table 1 Clinical features of affected members from the three British families segregating the p.Phe127_Thr138insIle mutation in the FHL1 gene Age at onset Presenting Last seen CK level Lung function Patient Sex (years) symptoms (in years) Muscle status and major clinical findings Contractures (IU/l) FVC values F1/5 M 40s Walking N.A. Wheelchair bound from early 50s. Died at age 52. N.A. N.A. Reported to be difficulties affected F1/16 M N.A. Walking N.A. Died at early 50s. N.A. N.A. Reported to be difficulties affected F1/18 M 38 Walking 55 Progressive proximal UL and LL weakness, symmetric scapular winging. Neck 553 2.43 l (in sitting) difficulties Wheelchair bound since the age of 50 years. 2.11 l (in lying) F1/23 M 35 UL/LL 39 Athletic habitus. Mild waddling gait. Mild proximal LL and neck weakness. Neck, TA 1300 4.57 l (in sitting) weakness 4.17 l (in lying) F2/10 F Late Walking N.A. Progressive motor difficulties. Died at 82 for anorexia and old age. N.A. N.A. N.A. adulthood difficulties F2/13 F Late Walking N.A. Progressive motor difficulties, incapacitated in later life. Died at N.A. N.A. N.A. adulthood difficulties 79 years of peritonitis F2/18 M N.A. N.A. N.A. Died at the age of 50 years of dyspnoea due to ‘progressive hypertrophic N.A. N.A. Reported to be muscular paralysis’ affected F2/21 F N.A. N.A. N.A. Wheelchair bound in later life. Died at 88 years due to congestive heart N.A. N.A. N.A. failure and auricular fibrillation F2/26 M N.A. N.A. N.A. Reported to be affected. Died at 62 years of age of gastric ulcer N.A. N.A. N.A. F2/35 M N.A. N.A. N.A. Wheelchair bound since early 40s. Cardiac involvement. Died at 44 years N.A. N.A. N.A. of age due to ‘muscular dystrophy’ F2/42 F Late Walking Late 90s Weak ankles and instability in her hip. Died at 96 years of No N.A. Normal adulthood difficulties age of colon cancer. F2/46 F Early 40s Mild UL/LL 65 Shoulder girdle weakness. Mild neck and pelvic girdle weakness. No 277 Normal weakness Lumbar hyperlordosis. F2/47 M 22 Walking 27 Shoulder girdle and proximal UL weakness. Scapular winging. Mild N.A. 1779 2.3 l (in sitting difficulties pelvic girdle and distal LL weakness, pectoralis wasting. at 35 years) Lumbar hyperlordosis. Cardiac function? F2/49 M Late Proximal 32 Rapidly progressing UL/LL weakness. Scapular winging. Wheelchair Neck 1423 2.73 l (in sitting teens UL/LL bound from 31 years of age. Eye closure weakness. weakness at 32 years) weakness 0.9 l (in sitting at 38 years) F2/55 M 29 Never able 34 Shoulder girdle, proximal UL and pelvic girdle weakness. Asymmetric Neck, elbow 2163 Normal to run. scapular winging. Calf hypertrophy. Lumbar hyperlordosis. Wrists, TAs Proximal weakness F3/9 M N.A. N.A. N.A. Reported to have walking difficulties N.A. N.A. N.A. F3/13 M N.A. N.A. N.A. Reported to have walking difficulties N.A. N.A. N.A. F3/16 M N.A. N.A.
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