Homozygosity mapping with SNP arrays identifies TRIM32 an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11)
Homozygosity mapping with SNP arrays identifies TRIM32 an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11)
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DOI：
10.1073/pnas.0600158103
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发表时间：
2006-04-18
影响因子：
11.1
通讯作者：
Sheffield, VC
中科院分区：
文献类型：
--
作者：
Chiang, AP;Beck, JS;Sheffield, VC
通过使用位置克隆来实现引起人类疾病的基因突变的鉴定，这取决于链接映射。在稀有疾病的研究中，连锁映射的分辨率受到可用的质量和信息标记密度的数量的限制。最近的一个进步是开发用于基因分型的高密度SNP微阵列。 SNP阵列通过使用大量标记来克服低标记信息，以在更精细的分辨率下获得更大的覆盖率。我们使用SNP微阵列基因分型用于与常染色体隐性bardet-biedl综合征（BBS；肥胖，色素性视网膜病，多性性，多性，多层疗法，肾脏和心脏异常的链接），使用以前的链接，使用以前的链接，以前的链接），使用以前的链接，以前串联重复多态性无法识别疾病基因座。 SNP基因分型揭示了一个纯合候选区域。纯合性区域中的突变分析确定了TRIM32基因中保守的纯合错义突变，这是一种编码E3泛素连接酶的基因。在斑马鱼和表达相关分析中，该基因在表达定量性状基因座数据集中的其他BBS基因的功能分析表明，TRIM32是BBS基因。这项研究表明，高密度SNP基因分型在纯合性映射中的值以及使用表达相关数据评估候选基因的值，并将蛋白酶体降解途径鉴定为涉及BBS的途径。
The identification of mutations in genes that cause human diseases has largely been accomplished through the use of positional cloning, which relies on linkage mapping. In studies of rare diseases, the resolution of linkage mapping is limited by the number of available meioses and informative marker density. One recent advance is the development of high-density SNP microarrays for genotyping. The SNP arrays overcome low marker informativity by using a large number of markers to achieve greater coverage at finer resolution. We used SNP microarray genotyping for homozygosity mapping in a small consanguineous Israeli Bedouin family with autosomal recessive Bardet-Biedl syndrome (BBS; obesity, pigmentary retinopathy, polydactyly, hypogonadism, renal and cardiac abnormalities, and cognitive impairment) in which previous linkage studies using short tandem repeat polymorphisms failed to identify a disease locus. SNP genotyping revealed a homozygous candidate region. Mutation analysis in the region of homozygosity identified a conserved homozygous missense mutation in the TRIM32 gene, a gene coding for an E3 ubiquitin ligase. Functional analysis of this gene in zebrafish and expression correlation analyses among other BBS genes in an expression quantitative trait loci data set demonstrate that TRIM32 is a BBS gene. This study shows the value of high-density SNP genotyping for homozygosity mapping and the use of expression correlation data for evaluation of candidate genes and identifies the proteasome degradation pathway as a pathway involved in BBS.