de Paula Flavia, Vieira Natássia, Starling Alessandra, Yamamoto Lydia Uraco, Lima Bruno, de Cássia Pavanello Rita, Vainzof Mariz, Nigro Vincenzo, Zatz Mayana
1Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
Eur J Hum Genet. 2003 Dec;11(12):923-30. doi: 10.1038/sj.ejhg.5201066.
Autosomal recessive limb-girdle muscular dystrophy linked to 19q13.3 (LGMD2I) was recently related to mutations in the fukutin-related protein gene (FKRP) gene. Pathogenic changes in the same gene were detected in congenital muscular dystrophy patients (MDC1C), a severe disorder. We have screened 86 LGMD genealogies to assess the frequency and distribution of mutations in the FKRP gene in Brazilian LGMD patients. We found 13 Brazilian genealogies, including 20 individuals with mutations in the FKRP gene, and identified nine novel pathogenic changes. The commonest C826A European mutation was found in 30% (9/26) of the mutated LGMD2I alleles. One affected patient homozygous for the FKRP (C826A) mutation also carries a missense R125H change in one allele of the caveolin-3 gene (responsible for LGMD1C muscular dystrophy). Two of her normal sibs were found to be double heterozygotes. In two unrelated LGMD2I families, homozygous for novel missense mutations, we identified four asymptomatic carriers, all older than 20 years. Genotype-phenotype correlation studies in the present study as well as in patients from different populations suggests that the spectrum of variability associated with mutations in the FKRP gene seems to be wider than in other forms of LGMD. It also reinforces the observations that pathogenic mutations are not always determinant of an abnormal phenotype, suggesting the possibility of other mechanisms modulating the severity of the phenotype that opens new avenues for therapeutic approaches.
与19q13.3相关的常染色体隐性肢带型肌营养不良症（LGMD2I）最近被发现与福金相关蛋白基因（FKRP）的突变有关。在先天性肌营养不良症患者（MDC1C，一种严重疾病）中也检测到了该基因的致病性变化。我们对86个LGMD系谱进行了筛查，以评估巴西LGMD患者中FKRP基因突变的频率和分布。我们发现了13个巴西系谱，其中包括20名FKRP基因突变的个体，并鉴定出9种新的致病性变化。最常见的欧洲C826A突变存在于30%（9/26）的突变LGMD2I等位基因中。一名FKRP（C826A）突变纯合的患病患者在小窝蛋白-3基因（与LGMD1C型肌营养不良症有关）的一个等位基因中还存在一个错义R125H变化。发现她的两名正常同胞为双杂合子。在两个不相关的LGMD2I家庭中，患者为新错义突变纯合子，我们鉴定出4名无症状携带者，年龄均超过20岁。本研究以及不同人群患者的基因型-表型相关性研究表明，与FKRP基因突变相关的变异性谱似乎比其他形式的LGMD更广泛。这也强化了以下观察结果，即致病性突变并不总是决定异常表型，这表明可能存在其他调节表型严重程度的机制，为治疗方法开辟了新途径。
