An X-Linked Myopathy with Postural Muscle Atrophy and Generalized Hypertrophy, Termed XMPMA, Is Caused by Mutations in FHL1

Windpassinger, Christian; Schöser, Benedikt; Straub, Volker; Hochmeister, Sonja; Noor, Abdul; Lohberger, Birgit; Farra, Natalie; Petek, Erwin; Schwarzbraun, Thomas; Ofner, Lisa; Löscher, Wolfgang N.; Wagner, Klaus; Lochmüller, Hanns; Vincent, John B.; Quasthoff, Stefan

doi:10.1016/j.ajhg.2007.09.004

Cited by 148 publications

(146 citation statements)

References 27 publications

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“…Table 1). This family has previously been British families with FHL1 founder mutation A Sarkozy et al reported as the 'UK family' in the original report by Windpassinger et al 9 Patient F1/18 showed first symptoms in his late 30s when he started noticing shoulder, proximal arm and hip muscle weakness. Weakness progressed over time and caused difficulties in walking, with myalgia in calves and thighs.…”

Section: Phenotypic Presentationmentioning

confidence: 89%

“…12,13,16 RBM may also be seen as a condition within a larger phenotypic spectrum of protein aggregate myopathies, such as the myofibrillar myopathies. 18 Here, we report three British families with X-linked muscle diseases, one being part of our original report, 9 presenting with partly heterogeneous phenotypes but sharing the p.Phe127_Tyr128insIle mutation in the FHL1 gene and a common Xq26 haplotype.…”

Section: Introductionmentioning

confidence: 87%

“…FHL1 mutation screening was performed using primers, amplification conditions and a protocol previously reported. 9 For haplotype analysis of the FHL1 locus, the following markers were selected and analysed as previously described: DXS8009, AFMa288xd5, AFM205wd2, AFMb340zd9, DXS8074, DXS8033, DXS8094, DXS1041 and DXS1227. 9 …”

Section: Genetic Analysismentioning

confidence: 99%

“…9 This change gives rise to the insertion of an additional isoleucine within the second LIM domain (p.Phe127_Thr128insIle). The mutation was present in all the tested male family members and in a heterozygous state in two affected females of family F2.…”

Section: Molecular Analysismentioning

confidence: 99%

“…8 We first described FHL1 gene mutations in families presenting with an X-linked myopathy with postural muscle atrophy and generalized hypertrophy (XMPMA). 9 Concurrently, FHL1 gene mutations have been detected in X-linked dominant scapuloperoneal myopathy, 10,11 and subsequently in a wide spectrum of partly overlapping conditions, such as reducing body myopathy (RBM), [12][13][14] rigid spine syndrome, 15 Emery-Dreifuss muscular dystrophy (EDMD), 16 and in a single family with contractures, rigid spine, and cardiomyopathy. 17 It has been suggested to classify FHL1-related disorders into two main groups, the 'reducing body (RB) subgroup' including RBM, X-linked dominant scapuloperoneal myopathy and rigid spine syndrome, all characterized by RB at histological examination, and a second subgroup, including the XMPMA and EDMD patients, characterized by later onset and absence of RB.…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene

et al. 2011

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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.

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Section: Phenotypic Presentationmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 87%

Section: Genetic Analysismentioning

confidence: 99%

Section: Molecular Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene

et al. 2011

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Molecular Genetics of Emery–Dreifuss Muscular Dystrophy

Morris

Sewry

Wehnert

2010

Encyclopedia of Life Sciences

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Emery–Dreifuss muscular dystrophy (EDMD) is a rare neuromuscular disorder typically characterised by early contractures, slowly progressive muscular wasting, and life‐threatening heart conduction disturbances, which can develop into a cardiomyopathy. Some severe neonatal cases have also been identified. There is a wide intrafamilial and interfamilial clinical variability. Genetically, X‐linked recessive ( EMD1 and EDMD6 ), autosomal dominant ( EMD2 , EDMD4 and EDMD5 ) and autosomal recessive (EMD3) forms can be distinguished. By molecular genetic methods, EDMD can be associated with mutations in the STA (emerin gene symbol), LMNA (lamin A/C gene symbol), SYNE (nesprin gene symbol) 1 , SYNE2 and Four and a Half LIM Domain 1 ( FHL1 ) genes. Female carriers of the X‐linked forms may manifest with cardiac symptoms but heterozygous carriers of the autosomal forms do not show symptoms. Only approximately 46% of unrelated EDMD patients have a mutation in known genes pointing to further genetic heterogeneity in EDMD. The molecular pathogenesis is unresolved, but there is evidence for gene expression changes via altered nuclear signalling and for reduced resistance of muscles to physical damage during contraction. Key Concepts: Emery–Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder recognised clinically by three features: early contractures, a characteristic pattern of muscle wasting and cardiac conduction defects. EDMD was originally described as an X‐linked disorder, later found to be caused by mutations in the STA gene encoding a nuclear membrane protein, emerin. Molecular genetic analysis allows precise subtyping of EDMD into X‐linked forms ( STA and FHL1 associated), autosomal dominant forms ( LMNA , SYNE1/SYNE2 associated) and an autosomal recessive form ( LMNA associated). Wide clinical variability of EDMD and clinical overlap with other clinical entities frequently require consideration of patients not completely fulfilling the EDMD diagnostic criteria for molecular genetic differentiation in STA , LMNA , SYNE1/SYNE2 and FHL1 . Digenic pathogenesis has been observed including LMNA / STA , LMNA / DES and SYNE1/SYNE2 . In most cases, EDMD mutations affect proteins located in the nuclear membrane where they interact with each other. Many patients do not have mutations in genes identified so far, so further genes are expected to be involved in the pathogenesis of EDMD.

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Molecular Genetics ofEmery–Dreifuss Muscular Dystrophy

Meinke

2018

Encyclopedia of Life Sciences

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Emery–Dreifuss muscular dystrophy (EDMD) is a rare neuromuscular disorder typically characterised by early contractures, slowly progressive muscular wasting and life‐threatening heart conduction disturbances, which can develop into a cardiomyopathy. There is a wide intrafamilial and interfamilial clinical variability. Genetically, X‐linked recessive, autosomal dominant and autosomal recessive forms can be distinguished. Female carriers of the X‐linked forms may manifest with cardiac symptoms. By molecular genetic methods, EDMD can be associated with mutations in several genes encoding nuclear envelope proteins. These proteins are lamin A, emerin, FHL1, nesprins and SUN proteins. Still only approximately half of unrelated patients diagnosed with EDMD have a mutation in known genes pointing to further genetic heterogeneity in EDMD. The molecular pathogenesis is not fully resolved, but there are effects on signalling, mechanical stability and gene expression. Key Concepts Emery–Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder recognised clinically by three features: early contractures, a characteristic pattern of muscle wasting and cardiac conduction defects. EDMD was originally described as an X‐linked disorder, later found to be caused by mutations in the EMD gene encoding a nuclear membrane protein, emerin. Molecular genetic analysis allows precise subtyping of EDMD into X‐linked forms ( EMD and FHL1 associated), autosomal dominant forms ( LMNA , SYNE1 / SYNE2 associated) and autosomal recessive forms ( LMNA and SUN1 associated). Wide clinical variability of EDMD and clinical overlap with other clinical entities frequently require consideration of patients not completely fulfilling the EDMD diagnostic criteria for molecular genetic differentiation in EMD , LMNA , SYNE1/SYNE2 , SUN1 and FHL1 . Digenic pathogenesis has been observed including LMNA / EMD , LMNA / DES , SYNE1/SYNE2 , LMNA / SUN1 , LMNA / SUN2 and EMD / SUN1 . In all cases, EDMD mutations affect proteins located at the nuclear envelope where they interact with each other. Many patients do not have mutations in genes identified so far, so further genes are expected to be involved in the pathogenesis of EDMD.

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An X-Linked Myopathy with Postural Muscle Atrophy and Generalized Hypertrophy, Termed XMPMA, Is Caused by Mutations in FHL1

Cited by 148 publications

References 27 publications

Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene

Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene

Molecular Genetics of Emery–Dreifuss Muscular Dystrophy

Molecular Genetics ofEmery–Dreifuss Muscular Dystrophy

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