Mutations in Radial Spoke Head Protein Genes RSPH9 and RSPH4A Cause Primary Ciliary Dyskinesia with Central-Microtubular-Pair Abnormalities
Mutations in Radial Spoke Head Protein Genes RSPH9 and RSPH4A Cause Primary Ciliary Dyskinesia with Central-Microtubular-Pair Abnormalities
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DOI：
10.1016/j.ajhg.2009.01.011
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发表时间：
2009-02-13
影响因子：
9.8
通讯作者：
Mitchison, Hannah M.
中科院分区：
文献类型：
--
作者：
Castleman, Victoria H.;Romio, Leila;Mitchison, Hannah M.
原发性纤毛运动障碍（PCD）是一种由纤毛运动障碍和精子运动障碍引起的遗传异质性遗传病。这与纤毛和精子轴素的各种超微结构缺陷有关，这些缺陷会影响运动，导致呼吸道黏液纤毛清除和肺功能、生育能力和左右体轴测定的临床后果。我们对患有PCD和中央微管对异常的7个近亲家族进行了全基因组snp连锁分析。在两个间歇性缺失中心对结构的家族（染色体6p21.1, Zmax 6.7）和五个完全缺失中心对的家族（染色体6q22.1, Zmax 7.0）中鉴定了两个位点。随后在染色体6p21.1上的RSPH9和染色体6q22.1上的RSPH4A两个位置候选基因中发现了突变。单倍型分析发现，在英国-巴基斯坦家系中存在一个共同的始祖效应RSPH4A突变。RSPH9和RSPH4A都编码轴突径向辐状头的蛋白组分。小鼠Rsph9的原位杂交显示基因表达仅限于含有运动纤毛的区域。对斑马鱼和衣藻RSPH9同源基因敲除或突变影响的研究表明，放射状辐头蛋白在维持正常运动、“9+2”结构的纤毛和鞭毛中起重要作用。这种效果是通过重新引入基因表达来恢复斑马鱼的正常跳动模式来拯救的。在人类或斑马鱼中，这些基因的功能紊乱与左右轴测定缺陷无关。
primary ciliary dyskinesia (PCD) is a genetically heterogeneous inherited disorder arising from dysmotility of motile cilia and sperm. This is associated with a variety of ultrastructural defects of the cilia and sperm axoneme that affect movement, leading to clinical consequences on respiratory-tract mucociliary clearance and lung function, fertility, and left-right body-axis determination. We performed whole-genome SNP-based linkage analysis in seven consanguineous families with PCD and central-microtubular-pair abnormalities. This identified two loci, in two families with intermittent absence of the central-pair structure (chromosome 6p21.1, Zmax 6.7) and in five families with complete absence of the central pair (chromosome 6q22.1, Zmax 7.0). Mutations were subsequently identified in two positional candidate genes, RSPH9 on chromosome 6p21.1 and RSPH4A on chromosome 6q22.1. Haplotype analysis identified a common ancestral founder effect RSPH4A mutation present in UK-Pakistani pedigrees. Both RSPH9 and RSPH4A encode protein components of the axonemal radial spoke head. In situ hybridization of murine Rsph9 shows gene expression restricted to regions containing motile cilia. Investigation of the effect of knockdown or mutations of RSPH9 orthologs in zebrafish and Chlamydomonas indicate that radial spoke head proteins are important in maintaining normal movement In motile, "9+2"-structure cilia and flagella. This effect is rescued by reintroduction of gene expression for restoration of a normal beat pattern in zebrafish. Disturbance in function of these genes was not associated with defects in left-right axis determination in humans or zebrafish.