Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome
Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome
复制标题
DOI：
10.1086/375178
复制
发表时间：
2003-05-01
影响因子：
9.8
通讯作者：
Katsanis, N
中科院分区：
文献类型：
--
作者：
Beales, PL;Badano, JL;Katsanis, N
Bardet-Biedl综合征是一种遗传和临床异质性疾病，由至少7个基因座（BBS 1 -7）突变引起，其中5个基因座（BBS 1、BBS 2、BBS 4、BBS 6和BBS 7）被克隆。遗传和突变分析表明，在某些家族中，两个基因座上的三个突变等位基因的组合（三等位基因遗传）是致病所必需的。迄今为止，五个已知的BBS位点中有四个与这种寡基因疾病传播模式有关。我们提出了一个全面的分析的频谱，分布，并参与非孟德尔性状传递的突变等位基因在BBS 1，最常见的BBS基因座。对259个分离BBS表型的独立家庭的分析表明，BBS 1参与复杂的遗传，并且在不同的家庭中，BBS 1中的突变可以与其他已知BBS基因以及未知基因座的突变在遗传上相互作用，从而导致表型。与该模型一致，我们在两个家族的无症状个体中鉴定了纯合M390 R等位基因，这是最常见的BBS 1突变。此外，我们的统计分析表明，M390 R等位基因在一般人群中的流行率与寡基因而不是隐性疾病传播模型一致。BBS寡基因等位基因的分布也表明，所有的BBS基因座可能相互作用，但一些基因，特别是BBS 2和BBS 6，更有可能参与三等位基因遗传，这表明一个可变的能力的BBS蛋白质相互作用的遗传。
Bardet-Biedl syndrome is a genetically and clinically heterogeneous disorder caused by mutations in at least seven loci (BBS1-7), five of which are cloned (BBS1, BBS2, BBS4, BBS6, and BBS7). Genetic and mutational analyses have indicated that, in some families, a combination of three mutant alleles at two loci (triallelic inheritance) is necessary for pathogenesis. To date, four of the five known BBS loci have been implicated in this mode of oligogenic disease transmission. We present a comprehensive analysis of the spectrum, distribution, and involvement in non-Mendelian trait transmission of mutant alleles in BBS1, the most common BBS locus. Analyses of 259 independent families segregating a BBS phenotype indicate that BBS1 participates in complex inheritance and that, in different families, mutations in BBS1 can interact genetically with mutations at each of the other known BBS genes, as well as at unknown loci, to cause the phenotype. Consistent with this model, we identified homozygous M390R alleles, the most frequent BBS1 mutation, in asymptomatic individuals in two families. Moreover, our statistical analyses indicate that the prevalence of the M390R allele in the general population is consistent with an oligogenic rather than a recessive model of disease transmission. The distribution of BBS oligogenic alleles also indicates that all BBS loci might interact genetically with each other, but some genes, especially BBS2 and BBS6, are more likely to participate in triallelic inheritance, suggesting a variable ability of the BBS proteins to interact genetically with each other.