Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndrome.
Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndrome.
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DOI：
10.1007/s00439-008-0543-3
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发表时间：
2008-10
期刊：
影响因子：
5.3
通讯作者：
Friedman TB
中科院分区：
文献类型：
--
作者：
Ahmed ZM;Riazuddin S;Aye S;Ali RA;Venselaar H;Anwar S;Belyantseva PP;Qasim M;Riazuddin S;Friedman TB
编码原钙粘蛋白15的PCDH 15突变可导致听力和视力障碍（1型Usher综合征; USH 1F）或非综合征性耳聋（DFNB 23）。据报道，人PCDH 15由35个外显子组成，编码具有3至11个胞外域（EC）、跨膜结构域和羧基末端胞质结构域（CD）的多种同种型。基于这些观察，我们描述了一个更新的基因结构，有四个额外的外显子PCDH 15和亚型，可以细分为四类。人PCDH 15编码三个可选的、进化上保守的独特胞质结构域（CD 1、CD 2或CD 3）。根据语前听力损失确定的家庭进行筛选，以确定该表型与染色体10q21.1上PCDH 15标记的连锁。在12个分离USH 1的家庭中的7个中，我们鉴定了纯合突变等位基因（1个错义突变，1个剪接位点突变，3个无义突变和2个缺失突变），其中6个是新的。一个家庭是分离的非综合征性耳聋DFNB 23由于纯合错义突变。到目前为止，在我们的557个巴基斯坦家庭的队列中，我们发现了11种不同的PCDH 15突变，这些突变导致了13个家庭的耳聋。分子建模提供了机制洞察PCDH 15错义突变的严重程度的表型变异。我们没有发现致病性突变的12个USH 1家族中的5个与USH 1F标记，这表明存在突变的PCDH 15的尚未发现的外显子，突变的内含子或调控元件的PCDH 15，或一个额外的基因座为I型USH在染色体10q21.1。
Mutations of PCDH15, encoding protocadherin 15, can cause either combined hearing and vision impairment (type 1 Usher syndrome; USH1F) or nonsyndromic deafness (DFNB23). Human PCDH15 is reported to be comprised of 35 exons and encodes a variety of isoforms with 3 to 11 ectodomains (EC), a transmembrane domain and a carboxy-terminal cytoplasmic domain (CD). Building on these observations we describe an updated gene structure that has four additional exons of PCDH15 and isoforms that can be subdivided into four classes. Human PCDH15 encodes three alternative, evolutionarily conserved unique cytoplasmic domains (CD1, CD2 or CD3). Families ascertained on the basis of prelingual hearing loss were screened for linkage of this phenotype to markers for PCDH15 on chromosome 10q21.1. In seven of twelve families segregating USH1 we identified homozygous mutant alleles (1 missense, 1 splice site, 3 nonsense and 2 deletion mutations) of which six are novel. One family was segregating nonsyndromic deafness DFNB23 due to a homozygous missense mutation. To date in our cohort of 557 Pakistani families, we have found 11 different PCDH15 mutations that account for deafness in 13 families. Molecular modeling provided mechanistic insight into the phenotypic variation in severity of the PCDH15 missense mutations. We did not find pathogenic mutations in five of the twelve USH1 families linked to markers for USH1F, which suggest either the presence of mutations of yet additional undiscovered exons of PCDH15, mutations in the introns or regulatory elements of PCDH15, or an additional locus for type I USH at chromosome 10q21.1.
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影响因子：
9.8
作者：
Ahmed, ZM;Riazuddin, S;Wilcox, ER
通讯作者：
Wilcox, ER
影响因子：
4.4
作者：
Alagramam, Kumar N.;Miller, Nathaniel D.;Smith, Richard J.
通讯作者：
Smith, Richard J.
DOI：
10.1073/pnas.0606701103
发表时间：
2006-10-17
影响因子：
11.1
作者：
Prakasam, A. K.;Maruthamuthu, V.;Leckband, D. E.
通讯作者：
Leckband, D. E.
影响因子：
4
作者：
Roux, A-F;Faugere, V.;Claustres, M.
通讯作者：
Claustres, M.
影响因子：
5.3
作者：
Ouyang, XM;Yan, D;Liu, XZ
通讯作者：
Liu, XZ