Assuntos
Artrogripose/genética , Proteínas Musculares/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Selenoproteínas/genética , Artrogripose/diagnóstico , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Testes Genéticos/métodos , Humanos , Mutação , Prognóstico , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Mutations in protein-O-mannose-beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) have been found in muscle-eye-brain disease, a congenital muscular dystrophy with structural eye and brain defects and severe mental retardation. OBJECTIVE: To investigate whether mutations in POMGnT1 could be responsible for milder allelic variants of muscular dystrophy. DESIGN: Screening for mutations in POMGnT1. SETTING: Tertiary neuromuscular unit. PATIENT: A patient with limb-girdle muscular dystrophy phenotype, with onset at 12 years of age, severe myopia, normal intellect, and decreased alpha-dystroglycan immunolabeling in skeletal muscle. RESULTS: A homozygous POMGnT1 missense mutation (c.1666G>A, p.Asp556Asn) was identified. Enzyme studies of the patient's fibroblasts showed an altered kinetic profile, less marked than in patients with muscle-eye-brain disease and in keeping with the relatively mild phenotype in our patient. CONCLUSIONS: Our findings widen the spectrum of disorders known to result from mutations in POMGnT1 to include limb-girdle muscular dystrophy with no mental retardation. We propose that this condition be known as LGMD2M. The enzyme assay used to diagnose muscle-eye-brain disease may not detect subtle abnormalities of POMGnT1 function, and additional kinetic studies must be carried out in such cases.
Assuntos
Distrofia Muscular do Cíngulo dos Membros/genética , N-Acetilglucosaminiltransferases/genética , Alelos , Western Blotting , Criança , Análise Mutacional de DNA , Distroglicanas/metabolismo , Fibroblastos/enzimologia , Testes Genéticos , Humanos , Imuno-Histoquímica , Cinética , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/complicações , Distrofia Muscular do Cíngulo dos Membros/psicologia , Mutação , Mutação de Sentido Incorreto/genética , Miopia/etiologia , FenótipoRESUMO
The region of the dystrophin gene containing introns 45-50 is characterized by a high rate of recombination events that give rise to large deletions causing dystrophinopathy. The nucleotide sequence of this intronic region has recently been released in GenBank. With the aim of further understanding the mechanism favoring the occurrence of these deletions, we have characterized the distribution of introns 47 and 48 deletion endpoints in 39 dystrophinopathy patients. In 14 of these patients we were able to sequence the break junction. On these sequences we were able to identify several intronic motifs that could predispose to DNA double-strand breaks. Our results, combined with other literature data, show that unequal homologous recombination is a very poorly represented event in the dystrophin gene, whereas junction features are suggestive of a model of recombination in which DNA double-strand breaks are incorrectly repaired by a nonhomologous end-joining mechanism. The correlation among recombination rate, deletion frequency, and percentage of repetitive elements is discussed.
