RESUMO
BACKGROUND: We have recruited a group of four living and reviewed the records of six deceased distantly related French-Canadians of Acadian descent affected by a childhood-onset form of recessive limb-girdle muscular dystrophy (LGMD). All cases originate from the small archipelago of the Magdalen Islands (population: 13,000) isolated in the Gulf of St-Lawrence. METHODS: Based on the likely sharing of the same founder mutation we completed a 319K SNPs genome-wide scan to identify the disease locus and then screen candidate genes in this region. RESULTS: All patients had normal initial motor milestones. They presented with limb girdle weakness at the average age of seven years (5-11). Progressive weakness led to loss of ambulation at a wide range of ages (10-39). Patients also developed macroglossia, large calves and mild to moderate contractures, hyperlordosis and decreased pulmonary function. Creatine kinase levels were elevated (1,800-10,000 U/L) in the first decades, but decreased with progression of disease. Homozygosity mapping uncovered a shared chromosomal region of 6.33Mb. The alpha sarcoglycan (SGCA) gene, mutated in LGMD2D, lay in this candidate interval. Sequencing of all SGCA exons uncovered a shared homozygous missense mutation (c. 229C>T, p.R77C), the most common SGCA mutation internationally reported. Using demographic data, we estimated a high carrier rate of 1/22. CONCLUSION: The p.R77C mutation has also been observed in many populations, including in France and Spain (Basques). This corresponds to the first reported recessive founder disease for the Magdalen Islands, an archipelago settled in the XIXth century, largely by Acadian immigrants.
Assuntos
Distrofia Muscular do Cíngulo dos Membros/etnologia , Distrofia Muscular do Cíngulo dos Membros/genética , Polimorfismo de Nucleotídeo Único/genética , Sarcoglicanas/genética , Adolescente , Adulto , Idoso , Canadá/epidemiologia , Canadá/etnologia , Estudos de Coortes , Creatina Quinase/metabolismo , Análise Mutacional de DNA , Progressão da Doença , Feminino , França/etnologia , Frequência do Gene , Genômica/métodos , Genótipo , Humanos , Lordose/etiologia , Pneumopatias/etiologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/complicações , Espanha/etnologiaRESUMO
Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of pathologies. We have identified a cohort of 14 French-Canadian patients from eight different families displaying a novel form of LGMD with an autosomal recessive inheritance. These patients share some features with previously described cases of 'quadriceps myopathy' that evolved into an LGMD. All demonstrate quadriceps femoris asymmetrical atrophy. Creatine kinase values were variable from normal to 6000 U/l. Clinical evaluations and MRI studies demonstrate a variable intrafamilial and interfamilial phenotype. Asymmetrical muscle involvement was clinically observed and confirmed by imaging. MRI studies suggest that the hamstrings and the adductor magnus are the first limb muscles to demonstrate fatty infiltration. Muscle pathology shows no sign of active inflammation but increased endomysial connective tissue associated with basal lamina duplication and collagen disorganization. A genome-wide scan using the two largest families uncovered linkage to marker D11S1360 on chromosome 11p12 [multipoint logarithm of the odds (LOD) score of 2.78]. Further genotyping for the eight families confirmed linkage to this new LGMD locus (multipoint LOD score of 4.56). Fine mapping subsequently defined a less than 3.3 cM candidate interval on 11p13-p12. Haplotype analysis of carrier chromosomes suggests that the most frequent mutation may account for up to 81.3% of French-Canadian mutations. In this study, we describe the chromosomal locus of a new form of recessive LGMD with prominent quadriceps femoris atrophy.
Assuntos
Cromossomos Humanos Par 11/genética , Atrofia Muscular/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Adulto , Idoso , Mapeamento Cromossômico/métodos , Feminino , Genes Recessivos , Haplótipos , Humanos , Escore Lod , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/ultraestrutura , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Distrofia Muscular do Cíngulo dos Membros/complicações , Distrofia Muscular do Cíngulo dos Membros/patologia , Mutação , Linhagem , FenótipoRESUMO
Congenital muscular dystrophies (CMDS) are a heterogeneous group of disorders. A growing number of CMDS have been found to be associated with joint hyperlaxity. We recruited 14 French-Canadian cases belonging to 11 families affected by a novel autosomal recessive congenital muscular dystrophy with hyperlaxity (CMDH). All cases come from the southwestern part of Quebec, suggesting a new French-Canadian founder effect. All patients present muscle weakness, proximal contractures coexisting with distal joint hyperlaxity. Pathological and genetic studies have excluded that mutations in the three genes coding for collagen VI subunits are responsible for this disease. A genome-wide scan established linkage of two CMDH families to a region on chromosome 3p23-21. Further linkage analysis confirmed that all families are linked to the same region (log of the odds score of 5.3). Haplotype analysis defines a 1.6-cM candidate interval and suggests that two common mutations may account for 78% of carrier chromosomes. This study describes and maps a new form of recessive CMD with joint hyperlaxity distinct from Ullrich and Bethlem myopathies with a founder effect in the French-Canadian population.
Assuntos
Cromossomos Humanos Par 3/genética , Instabilidade Articular/genética , Distrofias Musculares/genética , Adolescente , Adulto , Criança , Mapeamento Cromossômico/métodos , Colágeno Tipo VI/deficiência , Colágeno Tipo VI/genética , Feminino , Ligação Genética , Haplótipos , Humanos , Instabilidade Articular/complicações , Masculino , Fibras Musculares Esqueléticas/patologia , Distrofias Musculares/complicações , Distrofias Musculares/congênito , Distrofias Musculares/patologia , Mutação , Linhagem , FenótipoRESUMO
Lines of mice were selectively bred to diverge in their spontaneous helplessness in the tail suspension test. By the second generation of selection, only mice of the helpless line were sensitive to the antidepressant imipramine. Genetic factors substantially contribute to the susceptibility to helplessness in this mouse model. These selectively bred lines may represent potentially useful animal models to investigate behavioural, neurochemical and neuroendocrine correlates of antidepressant action.