Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa
Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa
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DOI：
10.1093/hmg/11.1.87
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发表时间：
2002-01-01
影响因子：
3.5
通讯作者：
Bhattacharya, SS
中科院分区：
文献类型：
--
作者：
Chakarova, CF;Hims, MM;Bhattacharya, SS
色素性视网膜炎（RP）是遗传性视网膜营养不良最常见的形式，是一种临床和遗传异质性疾病。其特点是周围视网膜进行性变性，导致夜盲症和周围视野丧失。RP以常染色体显性、常染色体隐性或x连锁方式遗传。常染色体显性RP的一个位点（RP18）先前通过连锁分析在两个大家系中定位到染色体1p13-q21。人类HPRP3基因是酵母pre-mRNA剪接因子（PRP3）的同源基因，定位于RP18疾病区间。最近人类剪接因子PRPF31和PRPC8突变的鉴定使我们在三个染色体1q连锁家族中筛选HPRP3作为候选基因。到目前为止，已经在两个英国人、一个丹麦家庭和三个RP个体中发现了两种不同的错义突变。这两个突变都聚集在HPRP3基因第11外显子的两个密码子内。有趣的是，其中一种突变（T494M）在明显不相关的家庭中反复出现，这增加了突变热点的可能性。单倍型分析证实了这一点，该分析使用跨越HPRP3基因区域的snp，支持该突变的多个起源。改变的HPRP3氨基酸在所有已知的HPRP3同源物中高度保守，表明该结构域在剪接过程中的主要功能。第三个pre-mRNA剪接因子基因突变的鉴定进一步强调了剪接过程中缺陷导致光感受器变性的新机制。
Retinitis pigmentosa (RP), the commonest form of inherited retinal dystrophies is a clinically and genetically heterogeneous disorder. It is characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of peripheral visual field. RP is inherited either in an autosomal dominant, autosomal recessive or X-linked mode. A locus (RP18) for autosomal dominant RP was previously mapped by linkage analysis in two large pedigrees to chromosome 1p13-q21. The human HPRP3 gene, the orthologue of the yeast pre-mRNA splicing factor (PRP3), localizes within the RP18 disease interval. The recent identification of mutations in human splicing factors, PRPF31 and PRPC8, led us to screen HPRP3 as a candidate in three chromosome 1q-linked families. So far, two different missense mutations in two English, a Danish family and in three RP individuals have been identified. Both mutations are clustered within a two-codon stretch in the 11th exon of the HPRP3 gene. Interestingly, one of the mutations (T494M) is seen repeatedly in apparently unlinked families raising the possibility of a mutation hot spot. This has been confirmed by haplotype analysis using SNPs spanning the HPRP3 gene region supporting multiple origins of the mutation. The altered HPRP3 amino acids, which are highly conserved in all known HPRP3 orthologues, indicate a major function of that domain in the splicing process. The identification of mutations in a third pre-mRNA splicing factor gene further highlights a novel mechanism of photoreceptor degeneration due to defects in the splicing process.