calpain and Syndrome

Topics: Blood Coagulation Disorders; Blood Platelets; Calpain; Diagnosis, Differential; Genes, Dominant; Humans; Platelet Aggregation; Prognosis; Syndrome; Thrombocytosis

Topics: Antibodies; Blood Platelets; Calpain; Endopeptidases; Factor VIII; Glycoproteins; Hemorrhagic Disorders; Humans; Membrane Proteins; Platelet Adhesiveness; Platelet Aggregation; Platelet Glycoprotein GPIb-IX Complex; Platelet Membrane Glycoproteins; Quinidine; Quinine; Receptors, Cell Surface; Receptors, Immunologic; Receptors, Thrombin; Syndrome; Thrombocytopenia

Topics: Calpain; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 4; Female; Humans; Middle Aged; Muscle Proteins; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Facioscapulohumeral; Mutation; Phenotype; Syndrome

The authors describe a family with six patients with muscular dystrophy with a variable course. One is a compound heterozygote for CAPN3 mutations (calpainopathy) and the others have a single CAPN3 mutation. Linkage analysis and sequencing revealed a XK gene mutation (McLeod syndrome). This illustrates the variable phenotype of XK mutations and suggests the possibility that CAPN3 heterozygotes may have their condition caused by nonallelic mutations in other unrelated genes.

Topics: Adolescent; Adult; Amino Acid Transport Systems, Neutral; Calpain; Chorea; Chromosome Mapping; Codon, Nonsense; DNA Mutational Analysis; Genetic Diseases, X-Linked; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Isoenzymes; Male; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Mutation; Pedigree; Phenotype; Syndrome

The concept of limb-girdle muscular dystrophy (LGMD) is changing rapidly due to the advances in molecular genetics. Recently, seven different gene loci have been described, demonstrating that limb-girdle muscular dystrophy is a heterogeneous syndrome, which includes different diseases with a similar phenotype. In isolated populations which have little genetic exchange with neighbouring populations, an accumulation of cases may be found. We carried out an epidemiological study in Guipúzcoa, a small mountainous Basque province in northern Spain, and found the highest prevalence rate of LGMD described so far: 69 per million. Genetic studies demonstrated that 38 cases corresponded to the LGMD2A type, due to calpain-3 gene mutations. Only one patient with alpha-sarcoglycanopathy was found, and in 12 patients the genetic defect was not identified. Moreover, the particular calpain-3 mutation predominant in Basque chromosomes (exon 22, 2362AG-->TCATCT), has only been rarely found in the rest of the world. This observation strongly suggests a founder effect in the indigenous population of Guipúzcoa. The clinical characteristics of the patients with calpain-3 gene mutations were quite homogeneous and different from the other groups (sarcoglycanopathy and unknown gene defect), allowing for a precise clinical diagnostic. The disease onset was between the ages of 8 and 15 years, in most cases in the pelvic girdle, and the patients became wheelchair-bound between 11 and 28 years after onset. No pseudohypertrophy of calves or contractures were observed. No clear correlations were found between the nature and site of the mutation and the resulting phenotype.

Topics: Adult; Age of Onset; Aged; Base Sequence; Calpain; Chromosome Mapping; Chromosomes, Human, Pair 15; DNA Primers; Exons; Female; Genotype; Geography; Humans; Incidence; Isoenzymes; Male; Medical Records; Middle Aged; Muscle Proteins; Muscle, Skeletal; Muscular Dystrophies; Mutation; Phenotype; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Prevalence; Retrospective Studies; Spain; Syndrome

Myonephropathic metabolic syndrome (MNMS) is a serious muscle reperfusion injury associated with acute renal failure. The exact pathogenesis of MNMS has not been fully elucidated, nor effective treatment, through the renal failure is thought to be a consequence of rhabdomyolysis. In the present study, the possible involvement of calpain in the lysis was investigated in a MNMS animal model employing a cell permeable calpain antagonist calpeptin. Male rabbits were subjected to bilateral hind leg ischaemia for 5 hours by clamping the distal aorta, followed by reperfusion for 3 hours. Blood pressure, plasma N-acethyl-beta-D-glucosaminidase (NAG) and the presence of myoglobinuria were serially determined. Blood pressure remained constant during the ischemic period but dropped by about 25% immediately after reperfusion. This was significantly attenuated by intraaortic administration of calpeptin. NAG gradually increased during ischemia and during reperfusion and this was also significantly reduced by calpeptin. Myoglobinuria appeared immediately after reperfusion, and was also attenuated by calpeptin. Calpeptin prevented lytic and degenerative changes of the hind leg muscles, determined by light and electron microscopy. Thus it is concluded that activation of calpain in skeletal muscle is an important etiologic factor of MNMS and that the occurrence of MNMS may be prevented by administration of a calpain antagonist.

Topics: Acetylglucosaminidase; Acute Kidney Injury; Animals; Calpain; Dipeptides; Hindlimb; Male; Muscles; Rabbits; Reperfusion Injury; Rhabdomyolysis; Syndrome

Platelets from patients with Montreal platelet syndrome (MPS) consistently display a defect in the mechanisms that regulate platelet size during shape change and undergo spontaneous aggregation and stir-induced microaggregate formation. We now provide data that the surface glycoprotein composition of MPS platelets is indistinguishable from that of normal platelets. However, a defect in calcium-activated neutral proteinase (calpain) was detected in MPS platelets. The specific activity of calpain in the cytosolic fraction of platelets from four MPS patients was found to be only 30% of that in platelets from normal control donors (n = 18, P less than .001). Additionally, platelets from MPS patients (n = 3) contained only 50% (P less than .001) of the calpain I catalytic subunit antigen found in platelets from normal control donors (n = 9). Platelets from the asymptomatic father/grandfather of the MPS patients had normal amounts of both total calpain proteolytic activity and calpain I catalytic subunit antigen. This represents the first report of a defect in calpain in human cells. The abnormally low calpain activity in MPS platelets may account for the platelet defects characteristic of this disorder.

Topics: Blood Platelet Disorders; Blood Proteins; Calpain; Catalysis; Female; Humans; Hydrolysis; Immunoelectrophoresis, Two-Dimensional; Isoantigens; Male; Platelet Aggregation; Platelet Membrane Glycoproteins; Subcellular Fractions; Syndrome