Assuntos
Síndrome de Fadiga Crônica , Narcolepsia , Síndrome da Taquicardia Postural Ortostática , Adolescente , Comorbidade , Síndrome de Fadiga Crônica/epidemiologia , Síndrome de Fadiga Crônica/genética , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação , Síndrome da Taquicardia Postural Ortostática/genéticaRESUMO
BACKGROUND: We determined the clinical and molecular genetic characteristics of 8 Chinese patients with Ullrich congenital muscular dystrophy (UCMD). METHODS: Clinical data of probands were collected and muscle biopsies of patients were analyzed. Exons of COL6A1, COL6A2 and COL6A3 were analyzed by direct sequencing. Mutations in COL6A1, COL6A2 and COL6A3 were identified in 8 patients. RESULTS: Among these mutations, 5 were novel [three in the triple helical domain (THD) and 2 in the second C-terminal (C2) domain]. We also identified five known missense or in-frame deletion mutations in THD and C domains. Immunohistochemical studies on muscle biopsies from patients showed reduced level of collagen VI at the muscle basement membrane and mis-localization of the protein in interstitial and perivascular regions. CONCLUSIONS: The novel mutations we identified underscore the importance of THD and C2 domains in the assembly and function of collagen VI, thereby providing useful information for the genetic counseling of UCMD patients.
Assuntos
Colágeno Tipo VI/genética , Distrofias Musculares/genética , Mutação , Esclerose/genética , Adolescente , Alelos , Substituição de Aminoácidos , Biópsia , Criança , Pré-Escolar , China , Códon , Feminino , Mutação da Fase de Leitura , Humanos , Imuno-Histoquímica , Masculino , Distrofias Musculares/diagnóstico , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Esclerose/diagnóstico , Deleção de SequênciaRESUMO
OBJECTIVE: To explore the clinical features and gene mutation of a Chinese family with Bethlem myopathy in three generations. METHODS: The clinical data of proband and his family members was collected. Genomic DNA from the patient and his family members was extracted routinely from peripheral blood leukocytes. Polymerase chain reaction and DNA direct sequencing were employed to analyze COL6A1, A2 and A3 genes to determine the mutation. And the relationship between genotype and phenotype was analyzed. Furthermore, the patient's skin fibroblast was cultured and immunofluorescent staining was performed with anti-collagen VI antibody. And the expression pattern of type VI collagen in extracellular matrix between the control and the patient's fibroblast was compared. RESULTS: In this family, 9 patients conformed to the clinical diagnosis of Bethlem myopathy. The features included motor development delay after late infantile period, generalized muscle weakness, walking unstability, distal hyper laxity, proximal joint contractures, skin changes (including hypertrophic scars) and normal intellectual development. Serum creatine kinase (CK) level became mildly elevated and electromyography showed myogenic injury. Disease progressed slowly but the lifespan was not affected. Mutation in exon 2 of COL6A1 gene with c.111-129 deletion was detected in 7 patients in this family. Immunofluorescent staining of type VI collagen in cultured skin fibroblast showed reduced expression of collagen VI in extracellular matrix in the patient compared with the control. CONCLUSIONS: Our study has defined the clinical features of Bethlem myopathy. According to molecular genetic analysis, 7 patients in this family have in-frame deletion mutations of COL6A1 and they conform to autosomal dominant inheritance. And genetic counseling and prenatal diagnosis are available. This is the first Chinese report of Bethlem myopathy family.
