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K Azibi

Publications and source records attributed to K Azibi.

12 recordsLinked to original sources
PubMed1997

Mutational diversity and hot spots in the alpha-sarcoglycan gene in autosomal recessive muscular dystrophy (LGMD2D).

Sarcoglycanopathies are a genetically heterogeneous group of autosomal recessive muscular dystrophies in which the primary defect may reside in any of the genes coding for the different partners of the sarcolemmal sarcoglycan (SG) complex: the alpha-SG (LGMD2D at 17q21.2), the beta-SG (LGMD2E at 4q12), the gamma-SG (LGMD2C at 13q12), and the delta-SG (LGMD2F at 5q33). We report a series of 20 new unrelated families with 14 different mutations in the alpha-SG gene. Along with the mutations that we previously reported this brings our cohort of patients with alpha-sarcoglycanopathy to a total of 31 unrelated patients, carrying 25 different mutations. The missense mutations reside in the extracellular domain of the protein. Five of 15 missense mutations, carried by unrelated subjects on different haplotype backgrounds and of widespread geographical origins, account for 58% of the mutated chromosomes, with a striking prevalence of the R77C substitution (32%). The severity of the disease varies strikingly and correlates at least in part with the amount of residual protein and the type of mutation. The recurrent R284C substitution is associated with a benign disease course.

Base Sequence↗
PubMed1997

Primary adhalinopathy (alpha-sarcoglycanopathy): clinical, pathologic, and genetic correlation in 20 patients with autosomal recessive muscular dystrophy.

Primary adhalin (or alpha-sarcoglycan) deficiency due to a defect of the adhalin gene localized on chromosome 17q21 causes an autosomal recessive myopathy. We evaluated 20 patients from 15 families (12 from Europe and three from North Africa) with a primary adhalin deficiency with two objectives: characterization of the clinical phenotype and analysis of the correlation with the level of adhalin expression and the type of gene mutation. Age at onset and severity of the myopathy were heterogeneous: six patients were wheel-chair bound before 15 years of age, whereas five other patients had mild disease with preserved ambulation in adulthood. The clinical pattern was similar in all the patients with symmetric characteristic involvement of trunk and limb muscles, calf hypertrophy, and absence of cardiac dysfunction. Immunofluorescence and immunoblot studies of muscle biopsy specimens showed a large variation in the expression of adhalin. The degree of adhalin deficiency was fairly correlated with the clinical severity. There were 15 different mutations (10 missense, five null). Double null mutations (three patients) were associated with severe myopathy, but in the other cases (null/missense and double missense) there was a large variation in the severity of the disease.

Adolescent↗
PubMed1996

Absence of gamma-sarcoglycan (35 DAG) in autosomal recessive muscular dystrophy linked to chromosome 13q12.

We have partially sequenced rabbit skeletal muscle gamma-sarcoglycan, an integral component of the dystrophin-glycoprotein complex. Specific antibodies were produced against a gamma-sarcoglycan peptide and used to examine the expression of gamma-sarcoglycan in skeletal muscle of patients with severe childhood autosomal muscular dystrophy linked to chromosome 13q12 (SCARMD). We show by immunofluorescence and Western blotting that in skeletal muscle from these patients gamma-sarcoglycan is completely absent and alpha- and beta-sarcoglycan are greatly reduced in abundance, whereas other components of the DGC are preserved. In addition, we show that in normal muscle alpha-, beta-, and gamma-sarcoglycan constitute a tightly associated sarcolemma complex which cannot be disrupted by SDS treatment.

Animals↗
PubMed1996

A founder mutation in the gamma-sarcoglycan gene of gypsies possibly predating their migration out of India.

We investigated the molecular basis of a severe form of early onset autosomal recessive muscular dystrophy with sarcoglycan (SG) deficiency in seven large Gypsy families living in different parts of Western Europe and apparently not closely related. They were linked to the LGMD2C locus (13q12) suggesting a primary defect in the gamma-SG gene coding for the 35 kDa dystrophin-associated glycoprotein. All of the 18 investigated patients were homozygous for the same G-->A transition in codon 283 producing the replacement of a conserved cysteine of the extra-cellular domain of the protein by a tyrosine. All affected chromosomes in homozygous and heterozygous relatives carried the same allele 5 of the intragenic marker D13S232. Flanking markers were studied to delineate a common ancestral haplotype, the size of which was used to compute the date of the founding mutation. We found evidence that the mutation occurred between 60 and 200 generations ago, therefore possibly predating the commonly accepted date of migration of the Gypsy ancestors out of India.

Biomarkers↗
PubMed1995

Primary adhalinopathy: a common cause of autosomal recessive muscular dystrophy of variable severity.

Marked deficiency of muscle adhalin, a 50 kDa sarcolemmal dystrophin-associated glycoprotein, has been reported in severe childhood autosomal recessive muscular dystrophy (SCARMD). This is a Duchenne-like disease affecting both males and females first described in Tunisian families. Adhalin deficiency has been found in SCARMD patients from North Africa Europe, Brazil, Japan and North America (SLR & KPC, unpublished data). The disease was initially linked to an unidentified gene on chromosome 13 in families from North Africa, and to the adhalin gene itself on chromosome 17q in one French family in which missense mutations were identified. Thus there are two kinds of myopathies with adhalin deficiency: one with a primary defect of adhalin (primary adhalinopathies), and one in which absence of adhalin is secondary to a separate gene defect on chromosome 13. We have examined the importance of primary adhalinopathies among myopathies with adhalin deficiency, and describe several additional mutations (null and missense) in the adhalin gene in 10 new families from Europe and North Africa. Disease severity varies in age of onset and rate of progression, and patients with null mutations are the most severely affected.

Adolescent↗
PubMed1995

Laminin abnormality in severe childhood autosomal recessive muscular dystrophy.

BACKGROUND: In skeletal muscle, dystrophin exists in a large oligomeric complex tightly associated with several novel sarcolemmal proteins, including the 50-kDa transmembrane glycoprotein called adhalin. The dystrophin-glycoprotein complex links the subsarcolemmal actin cytoskeleton to the basal lamina component laminin, thus providing stability to the sarcolemma. Disturbance of this linkage due to the absence of dystrophin plays a crucial role in the molecular pathogenesis of muscle fiber necrosis in Duchenne muscular dystrophy. Severe childhood autosomal recessive muscular dystrophy (SCARMD) is similar to Duchenne muscular dystrophy in phenotype but is characterized by the deficiency of adhalin. At present, the status of the link between the dystrophin-glycoprotein complex and laminin is unclear in SCARMD. EXPERIMENTAL DESIGN: We investigated, by immunohistochemistry using confocal laser scanning microscopy, the status of the expression of laminin subunits, A, M, B1, B2, and S chains, in skeletal muscle biopsy specimens of eight SCARMD patients from various human populations. In addition, we correlated the severity of laminin abnormality with the severity of both clinical symptoms and histopathologic changes in these patients. RESULTS: The reduction of laminin B1 chain and the overexpression of the S chain, a homologue of B1, in the extrajunctional basal lamina were observed in the five patients who had advanced clinical symptoms and histopathologic changes. Abnormalities in the expression of laminin were not observed in the three less affected patients. CONCLUSIONS: The expression of laminin is greatly disturbed in severely diseased SCARMD muscle deficient in adhalin. Disturbance of sarcolemma-basal lamina interaction may play an important role in the molecular pathogenesis of muscle fiber necrosis in SCARMD.

Adolescent↗
PubMed1994

Linkage analysis of families with severe childhood autosomal recessive muscular dystrophy in Morocco indicates genetic homogeneity of the disease in north Africa.

It has been previously shown in Tunisian and Algerian families that the locus for SCARMD maps to the proximal part of 13q, and in Algerian families that the disease is associated with deficiency of the 50 kDa dystrophin associated glycoprotein (50DAG). We have tested this linkage in six families from Morocco where this disease is also prevalent. In one family the 50DAG was tested and found to be negative in a muscle biopsy. Our results showed similar linkage in this country, with statistical tests indicating genetic homogeneity between the three Maghreb countries.

Algeria↗
PubMed1994

Genetic heterogeneity of severe childhood autosomal recessive muscular dystrophy with adhalin (50 kDa dystrophin-associated glycoprotein) deficiency.

Severe autosomal recessive muscular dystrophy (SCARMD), McKusick n. 253700, has been originally described in North-African populations, in which significant linkage has been established with DNA markers mapping to the proximal region of the long arm of chromosome 13, without evidence for heterogeneity of the SCARMD locus in these populations. A striking feature of this disease is the isolated deficiency of adhalin, a sarcolemmal 50 kDa dystrophin-associated glycoprotein. We report a non-inbred French family with a milder progressive form of muscular dystrophy affecting subjects of both sexes. The parents are not affected suggesting an autosomal recessive transmission. In 4 siblings displaying mild to overt clinical signs of muscular dystrophy, serum creatine kinase was high, and muscle specimens showed variable degree of necrosis-regeneration with little fibrosis. In the 4 cases adhalin was completely absent in muscle sections, whereas dystrophin and the other members of the dystrophin-associated protein complex were normal, except for the 35 kDa dystrophin-associated glycoprotein which was decreased as usually observed in SCARMD. Linkage and homogeneity analysis using 4 microsatellite markers of chromosome 13q that are linked to the North-African SCARMD locus were performed in this family. Results show that the morbid locus involved in this family does not map to the same region as the SCARMD locus. This second locus may be involved in sporadic cases of muscular dystrophy with adhalin deficiency that have been reported in Europe.

Adolescent↗
PubMed1993

Severe childhood autosomal recessive muscular dystrophy with the deficiency of the 50 kDa dystrophin-associated glycoprotein maps to chromosome 13q12.

We have recently demonstrated the specific deficiency for the 50 kDa dystrophin-associated glycoprotein (50DAG) in Algerian patients afflicted with severe childhood autosomal recessive muscular dystrophy with DMD-like phenotype (SCARMD). A similar disease affecting Tunisian patients was linked to chromosome 13q but the status of the 50DAG was not investigated. Here we show by linkage analysis of Algerian families that the genetic defect which leads, either directly or indirectly, to the deficiency of the 50DAG in skeletal muscle is localized to the proximal part of chromosome 13q. We have not found any evidence of genetic heterogeneity among the thirteen families studied. It remains to be demonstrated whether the 50DAG gene maps at 13q12, and to determine if it is mutated in this disease.

Child↗
PubMed1992

Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy.

X-linked recessive Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, a membrane cytoskeletal protein. Dystrophin is associated with a large oligomeric complex of sarcolemmal glycoprotein. The dystrophin-glycoprotein complex has been proposed to span the sarcolemma to provide a link between the subsarcolemmal cytoskeleton and the extracellular matrix component, laminin. In DMD, the absence of dystrophin leads to a large reduction in all of the dystrophin-associated protein. We have investigated the possibility that a deficiency of a dystrophin-associated protein could be the cause of severe childhood autosomal recessive muscular dystrophy (SCARMD) with a DMD-like phenotype. Here we report the specific deficiency of the 50K dystrophin-associated glycoprotein (M(r) 50,000) in sarcolemma of SCARMD patients. Therefore, the loss of this glycoprotein is a common denominator of the pathological process leading to muscle cell necrosis in two forms of muscular dystrophy, DMD and SCARMD.

Biopsy↗