Four and a half LIM protein 1 gene mutations cause four distinct human myopathies: A comprehensive review of the clinical, histological and pathological features

Cowling, Belinda S.; Cottle, Denny L; Wilding, Brendan; D’Arcy, Colleen; Mitchell, Christina A.; Mcgrath, Meagan Jane

doi:10.1016/j.nmd.2011.01.001

Cited by 70 publications

(78 citation statements)

References 95 publications

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“…The insertion of a large aliphatic hydrophobic isoleucine between the rigid aromatic Phe127 and the hydrophilic Thr128 possibly disrupts the protein conformation by causing alteration of the orientation and spatial relationship between the tandem zincfingers. 9,22,23 Although menadione-NBT staining was not performed in any of our patients and we cannot formally rule out the presence of RB, the clinical phenotype of our patients was not consistent with a diagnosis of RBM. In agreement with this finding, mutations affecting the LIM2 domain were reported also in three EDMD patients without RB, 17 suggesting that the different type of mutations observed in these patients (small or large in-frame or out-of-frame deletions/insertions) might be responsible for the possible absence of RB in these patients.…”

Section: Discussionmentioning

confidence: 65%

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: Discussionmentioning

confidence: 65%

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

et al. 2011

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“…Many clinical symptoms of RBM overlap with those of SPM and XMPMA, including severely affected males and variable penetrance in females, spinal rigidity, scapular winging, contractures and cardiac involvement (Cowling et al, 2011). Benign cases of RBM have a very low prevalence of reducing bodies, between 0.2 and 0.5% of biopsied muscle fibres (Tomé and Fardeau, 1975;Oh et al, 1983), and inclusion prevalence varies between muscle fascicles (Schreckenbach et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…FHL1 three-amino-acid deletions identified in RSS and RBM accumulate in vitro FHL1 mutations might affect conserved zinc-ion-binding residues that are crucial for the integrity of the LIM domain or the mutations might occur outside the LIM domain. This is proposed to dictate both disease severity and/or the expression level of mutant FHL1 protein (reviewed in Cowling et al, 2011). SPM and XMPMA FHL1 mutations show reduced FHL1 expression, do not affect LIM 2 zinc-binding residues and are milder compared with RBM.…”

Section: Spm and Xmpma Fhl1 Mutants Accumulate In Vitro And Form Redumentioning

confidence: 99%

“…1). RBM generally exhibits dominant inheritance with progressive muscle loss, rigid spine, scapular winging and contractures, and, in some cases, severe infantile and childhood onset with rapid progression and cardiac/respiratory failure (reviewed in Cowling et al, 2011). RBM is distinguished by the presence of intracellular protein aggregates called 'reducing bodies' in affected muscle, which stain positively with Menadione-NBT (M-NBT).…”

Section: Introductionmentioning

confidence: 99%

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FHL1 mutations that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation

Wilding

Mcgrath

Bonne

et al. 2014

Journal of Cell Science

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FHL1 mutations cause several clinically heterogeneous myopathies, including reducing body myopathy (RBM), scapuloperoneal myopathy (SPM) and X-linked myopathy with postural muscle atrophy (XMPMA). The molecular mechanisms underlying the pathogenesis of FHL1 myopathies are unknown. Protein aggregates, designated 'reducing bodies', that contain mutant FHL1 are detected in RBM muscle but not in several other FHL1 myopathies. Here, RBM, SPM and XMPMA FHL1 mutants were expressed in C2C12 cells and showed equivalent protein expression to wild-type FHL1. These mutants formed aggregates that were positive for the reducing body stain Menadione-NBT, analogous to RBM muscle aggregates. However, hypertrophic cardiomyopathy (HCM) and Emery-Dreifuss muscular dystrophy (EDMD) FHL1 mutants generally exhibited reduced expression. Wild-type FHL1 promotes myoblast differentiation; however, RBM, SPM and XMPMA mutations impaired differentiation, consistent with a loss of normal FHL1 function. Furthermore, SPM and XMPMA FHL1 mutants retarded myotube formation relative to vector control, consistent with a dominant-negative or toxic function. Mutant FHL1 myotube formation was partially rescued by expression of a constitutively active FHL1-binding partner, NFATc1. This is the first study to show that FHL1 mutations identified in several clinically distinct myopathies lead to similar protein aggregation and impair myotube formation, suggesting a common pathogenic mechanism despite heterogeneous clinical features.

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“…[1][2][3] Mutations in FHL1 have been associated with diverse chronic myopathies. 4 These include late-onset X-linked scapulo-axio-peroneal myopathy with bent spine syndrome, 5 reducing body myopathy, 6,7 X-linked dominant scapuloperoneal muscular dystrophy, 8 rigid spine syndrome, 9 and contractures and cardiomyopathy mimicking Emery-Dreifuss muscular dystrophy. 10,11 Most FHL1 mutations appear in the second or fourth LIM domains with a single mutation in the third LIM domain.…”

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confidence: 99%

Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy

Selcen

Bromberg

Chin³

et al. 2011

Neurology

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Objective: Some pathologic features of the FHL1 myopathies and the myofibrillar myopathies (MFMs) overlap; we therefore searched for mutations in FHL1 in our cohort of 50 patients with genetically undiagnosed MFM. Methods:Mutations in FHL1 were identified by direct sequencing. Polymorphisms were excluded by using allele-specific PCR in 200 control subjects. Structural changes in muscle were analyzed by histochemistry, immunocytochemistry, and electron microscopy. Results:We detected 2 novel and 1 previously identified missense mutation in 5 patients. Patients 1-4 presented before age 30, display menadione-nitro blue tetrazolium-positive reducing bodies, and harbor mutations in the FHL1 LIM2 domain. Patient 5 presented at age 75 and has no reducing bodies, and his mutation is not in a LIM domain. The clinical features include progressive muscle weakness, hypertrophied muscles, rigid spine, and joint contractures, and 1 patient also has peripheral neuropathy. High-resolution electron microscopy reveals the reducing bodies composed of 13-nm tubulofilaments initially emanating from Z-disks. At a more advanced stage, abundant reducing bodies appear in the cytoplasm and nuclei with concomitant myofibrillar disintegration, accumulation of cytoplasmic degradation products, and aggregation of endoplasmic reticulum and sarcotubular profiles. The four-and-a-half LIM domain protein 1 (FHL1), encoded by FHL1, is located on Xq26.3. It is highly expressed in skeletal and cardiac muscle and less abundantly in brain, placenta, lung, liver, kidney, pancreas, and testis.1-3 Mutations in FHL1 have been associated with diverse chronic myopathies. 4 These include late-onset X-linked scapulo-axio-peroneal myopathy with bent spine syndrome, 5 reducing body myopathy, 6,7 X-linked dominant scapuloperoneal muscular dystrophy, 8 rigid spine syndrome, 9 and contractures and cardiomyopathy mimicking Emery-Dreifuss muscular dystrophy. 10,11 Most FHL1 mutations appear in the second or fourth LIM domains with a single mutation in the third LIM domain.Myofibrillar myopathies (MFMs) arise from primary degeneration of the muscle fibers and represent a morphologically distinct but genetically heterogeneous subset of muscular dystrophies. The unifying histologic findings are early disintegration of the Z-disk followed by myofibrillar disintegration, aggregation of degraded filaments into pleomorphic granular or hyaline inclusions, and ectopic expression of multiple Z-disk-related and other proteins in the affected muscle fibers.12-14 Although some pathologic features of the FHL1 muscular dystrophies and the MFMs overlap, reducing bodies have been detected only in FHL1 dystrophies. 7,15 We here report 2 novel

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Four and a half LIM protein 1 gene mutations cause four distinct human myopathies: A comprehensive review of the clinical, histological and pathological features

Cited by 70 publications

References 95 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

FHL1 mutations that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation

Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy

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