Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13)
Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13)
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DOI：
10.1093/hmg/10.15.1555
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发表时间：
2001-07-15
影响因子：
3.5
通讯作者：
Inglehearn, CF
中科院分区：
文献类型：
--
作者：
McKie, AB;McHale, JC;Inglehearn, CF
视网膜色素变性（RP）是一种遗传异质性疾病，其特征在于周边视网膜的进行性变性，导致夜盲症和视野丧失。RIP的发病率约为1/4000，可以以X连锁、常染色体显性或常染色体隐性方式遗传。在南非一个adRP大家族中，通过连锁作图将常染色体显性RIP（adRP）的RP 13位点定位在染色体17p13.3上。使用位置克隆和候选基因的策略，我们已经确定了7个不同的错义突变的剪接因子基因PRPC 8的adRP家庭。其中三个突变共分离在三个RP 13连锁的家庭，包括原来的大型南非血统，和四个额外的突变已被确定在其他无关的adRP家庭。这七个突变聚集在这个大的7 kb转录本的最后一个外显子内的14个密码子延伸内。在C-末端的改变的氨基酸残基表现出高度的保守性，在不同的物种，如人类，拟南芥和锥虫，这表明一些功能的意义是与这部分的蛋白质。这种普遍存在且高度保守的剪接因子中的这些突变为视网膜变性的新途径提供了令人信服的证据。
Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of visual fields. With an incidence of approximately 1 in 4000, RIP can be inherited in X-linked, autosomal dominant or autosomal recessive modes. The RP13 locus for autosomal dominant RIP (adRP) was placed on chromosome 17p13.3 by linkage mapping in a large South African adRP family. Using a positional cloning and candidate gene strategy, we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families. Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree, and four additional mutations have been identified in other unrelated adRP families. The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript. The altered amino acid residues at the C-terminus exhibit a high degree of conservation across species as diverse as humans, Arabidopsis and trypanosome, suggesting that some functional significance is associated with this part of the protein. These mutations in this ubiquitous and highly conserved splicing factor offer compelling evidence for a novel pathway to retinal degeneration.