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ABSTRACT: The syntrophins and dystrobrevins are members of the dystrophin-associated protein complex, and are thought to function as modular adaptors for signalling proteins recruited to the sarcolemmal membrane. We have characterised the expression of the syntrophins (alpha-, beta1-, and beta2-) and alpha-dystrobrevin by immunohistochemistry in normal human muscle and in biopsies from 162 patients with myopathies of unknown aetiology (with normal staining for dystrophin and other dystrophin-associated proteins). Unlike mice, beta2-syntrophin is expressed at the sarcolemma in post-natal human skeletal muscle. Deficiency of alpha-dystrobrevin +/- beta2-syntrophin was present in 16/162 (10%) patients, compared to age-matched controls. All patients presented with congenital-onset hypotonia and weakness, although there was variability in clinical severity. Two major clinical patterns emerged: patients with deficiency of beta2-syntrophin and alpha-dystrobrevin presented with severe congenital weakness and died in the first year of life, and two patients with deficiency of alpha-dystrobrevin had congenital muscular dystrophy with complete external ophthalmoplegia. We have sequenced the coding regions of alpha-dystrobrevin and beta2-syntrophin in these patients, and identified a new isoform of dystrobrevin, but have not identified any mutations. This suggests that disease causing mutations occur outside the coding region of these genes, in gene(s) encoding other components of the syntrophin-dystrobrevin subcomplex, or in gene(s) responsible for their post-translational modification and normal localisation.
Neuromuscular Disorders 09/2003; 13(6):456-67. · 2.80 Impact Factor
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ABSTRACT: An important step in the diagnostic evaluation of a patient with recessive limb-girdle muscular dystrophy is the immunohistochemical analysis of the components of the sarcoglycan complex in a muscle biopsy specimen. Even though a primary mutation in any of the four sarcoglycan genes (alpha-, beta-,gamma-, delta-sarcoglycan) may cause secondary deficiencies in all the other sarcoglycan proteins, more specific immunohistochemical patterns have emerged with the potential to guide and abbreviate the necessary molecular genetic investigations. In gamma-sarcoglycan mutations, the pattern consists of absent or prominently reduced gamma-sarcoglycan immunoreactivity in combination with reduced but detectable immunoreactivity for the other components, with preservation of delta-sarcoglycan. In five consecutive patients, this pattern was able to predict primary gamma-sarcoglycan mutations. Five different mutations were found, including a recurrent novel splice mutation, a large deletion of the entire gene and a novel missense mutation (Leu90Ser). The mutation Cys283Tyr, previously restricted to Gypsy populations was found in compound heterozygosity with del521T, common in north Africa. The variety of known and novel mutations found indicates that the immunohistochemical profile of gamma-sarcoglycan mutations is not restricted to a particular mutation or type of mutation, but rather is a general reflection of the effect of gamma-sarcoglycan mutations on the composition of the sarcoglycan complex. Complete immunohistochemical analysis with all available sarcoglycan antibodies, therefore, is a useful tool to guide the molecular genetic investigations that are necessary to arrive at the correct genetic diagnosis in a given case.
Neuromuscular Disorders 04/2002; 12(3):273-80. · 2.80 Impact Factor
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ABSTRACT: Initial reports of patients with laminin alpha2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achieve independent ambulation, markedly raised creatine kinase, and characteristic white matter hypodensity on cerebral magnetic resonance imaging. We report a series of five patients with laminin alpha2 deficiency, only one of whom has this severe classical CMD phenotype, and review published reports to characterise the expanded phenotype of laminin alpha2 deficiency, as illustrated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with laminin alpha2 deficiency, 12% of reported cases have later onset, slowly progressive weakness more accurately designated limb-girdle muscular dystrophy. In addition, the following clinical features are reported with increased frequency: mental retardation (~6%), seizures (~8%), subclinical cardiac involvement (3-35%), and neuronal migration defects (4%). At least 25% of patients achieve independent ambulation. Notably, three patients with laminin alpha2 deficiency were asymptomatic, 10 patients had normal MRI (four with LAMA2 mutations reported), and between 10-20% of cases had maximum recorded creatine kinase of less than 1000 U/l. LAMA2 mutations have been identified in 25% of cases. Sixty eight percent of these have the classical congenital muscular dystrophy, but this figure is likely to be affected by ascertainment bias. We conclude that all dystrophic muscle biopsies, regardless of clinical phenotype, should be studied with antibodies to laminin alpha2. In addition, the use of multiple antibodies to different regions of laminin alpha2 may increase the diagnostic yield and provide some correlation with severity of clinical phenotype.
Journal of Medical Genetics 11/2001; 38(10):649-57. · 6.36 Impact Factor
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Y He, K J Jones,
N Vignier,
G Morgan,
M Chevallay,
A Barois,
B Estournet-Mathiaud,
H Hori,
T Mizuta,
F M Tomé,
K N North,
P Guicheney
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ABSTRACT: The authors report a case of congenital muscular dystrophy with mild nonprogressive muscle weakness, white matter hypodensity, and absence of the laminin alpha2 chain in muscle fibers with two antibodies, but not with four others. They identified mutations in LAMA2, which explain the partial laminin alpha2 deficiency. Analysis of this case and two others allows us to refine the epitopes of two of the commercial antibodies, and illustrate the importance of using antibodies directed against different domains of the protein.
Neurology 11/2001; 57(7):1319-22. · 8.31 Impact Factor
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Clinical Genetics 12/1998; 54(5):443-5. · 3.13 Impact Factor
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ABSTRACT: Abnormalities of dystrophin, the sarcoglycans, and laminin alpha2 are responsible for a subset of the muscular dystrophies. In this study we aim to characterise the nature and frequency of abnormalities of these proteins in an Australian population and to formulate an investigative algorithm to aid in approaching the diagnosis of the muscular dystrophies. To reduce ascertainment bias, biopsies with dystrophic (n=131) and non-dystrophic myopathic (n=71) changes were studied with antibodies to dystrophin, alpha, beta, and gamma sarcoglycan, beta dystroglycan, and laminin alpha2, and results were correlated with clinical phenotype. Abnormalities of dystrophin, the sarcoglycans, or laminin alpha2 were present in 61/131 (47%) dystrophic biopsies and in 0/71 myopathic biopsies, suggesting that immunocytochemical study of dystrophin, the sarcoglycans, and laminin alpha2 may, in general, be restricted to patients with dystrophic biopsies. Two patients with mutations identified in gamma sarcoglycan had abnormal dystrophin (by immunocytochemistry and immunoblot), showing that abnormalities of dystrophin may be a secondary phenomenon. Therefore, biopsies should not be excluded from sarcoglycan analysis on the basis of abnormal dystrophin alone. The diagnostic yield was highest in those with severe, rapidly progressive limb-girdle weakness (92%). Laminin alpha2 deficiency was identified in 5/131 (4%) patients; 215 patients presented after infancy, indicating that abnormalities of laminin alpha2 are not limited to the congenital muscular dystrophy phenotype. Overall patterns of immunocytochemistry and immunoblotting provided a guide to mutation analysis and, on the basis of this study, we have formulated a diagnostic algorithm to guide the investigation of patients with muscular dystrophy.
Journal of Medical Genetics 06/1998; 35(5):379-86. · 6.36 Impact Factor
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Journal of Inherited Metabolic Disease 12/1997; 20(6):833-4. · 3.58 Impact Factor
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ABSTRACT: Recent advances in molecular genetics research have revolutionised our understanding of the childhood muscular dystrophies. The first breakthrough came in 1987 with the identification of the gene for dystrophin, the protein that is abnormal in X-linked Duchenne muscular dystrophy. Dystrophin is bound to a complex of proteins in the muscle membrane, and primary abnormalities of these proteins have now been identified as the cause of some autosomally inherited forms of muscular dystrophy. A group of transmembrane proteins known as alpha- (adhalin) beta-, gamma- and delta-sarcoglycan are deficient in autosomal recessive limb-girdle muscular dystrophy, and the extracellular matrix protein merosin (alpha2-laminin), is deficient in a subset of patients with congenital muscular dystrophy. Identification of primary deficiencies in these 'dystrophin associated proteins' will result in improved diagnostic accuracy, more accurate genetic counselling and, in some cases, the availability of prenatal diagnosis.
Journal of Paediatrics and Child Health 07/1997; 33(3):195-201. · 1.28 Impact Factor
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ABSTRACT: The extraocular muscles have a number of structural and functional properties that distinguish them from skeletal and cardiac muscle and these differences may be important in the differential involvement of extraocular muscles in various disease states. We present a case of congenital external ophthalmoplegia associated with non progressive generalised weakness. Skeletal muscle biopsy at 4 years of age showed type 1 fibre predominance, variation in fibre size and increased interstitial fibrosis, suggestive of a primary myopathic process. During the investigation of this patient we reviewed the differential diagnosis of neuromuscular disorders with extraocular muscle involvement, and developed an algorithm to assist the clinician in investigation and diagnosis of external ophthalmoplegia. Our patient does not satisfy the diagnostic criteria of any previously described disorders and may thus represent a new syndrome.
Neuromuscular Disorders 06/1997; 7(3):143-51. · 2.80 Impact Factor
