Castleman Victoria H, Romio Leila, Chodhari Rahul, Hirst Robert A, de Castro Sandra C P, Parker Keith A, Ybot-Gonzalez Patricia, Emes Richard D, Wilson Stephen W, Wallis Colin, Johnson Colin A, Herrera Rene J, Rutman Andrew, Dixon Mellisa, Shoemark Amelia, Bush Andrew, Hogg Claire, Gardiner R Mark, Reish Orit, Greene Nicholas D E, O'Callaghan Christopher, Purton Saul, Chung Eddie M K, Mitchison Hannah M
General and Adolescent Paediatric Unit, University College London Institute of Child Health, Rayne Building, 5 University Street, London WC1E 6JJ, UK.
Am J Hum Genet. 2009 Feb;84(2):197-209. doi: 10.1016/j.ajhg.2009.01.011. Epub 2009 Feb 5.
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.
原发性纤毛运动障碍（PCD）是一种遗传性异质性疾病，由活动纤毛和精子运动功能障碍引起。这与纤毛和精子轴丝的多种超微结构缺陷相关，这些缺陷会影响运动，进而对呼吸道黏液纤毛清除功能、肺功能、生育能力以及左右体轴的确定产生临床影响。我们对7个患有PCD且中央微管对异常的近亲家庭进行了基于全基因组单核苷酸多态性（SNP）的连锁分析。这确定了两个位点，一个在两个中央对结构间歇性缺失的家庭中位于6号染色体p21.1（Zmax 6.7），另一个在五个中央对完全缺失的家庭中位于6号染色体q22.1（Zmax 7.0）。随后在两个定位候选基因中发现了突变，分别是位于6号染色体p21.1的RSPH9和位于6号染色体q22.1的RSPH4A。单倍型分析确定了英国-巴基斯坦家系中存在的一种常见的祖先奠基者效应RSPH4A突变。RSPH9和RSPH4A都编码轴丝放射辐条头部的蛋白质成分。小鼠Rsph9的原位杂交显示基因表达局限于含有活动纤毛的区域。对斑马鱼和衣藻中RSPH9直系同源基因敲低或突变的影响进行研究表明，放射辐条头部蛋白对于维持具有“9 + 2”结构的活动纤毛和鞭毛的正常运动很重要。通过重新引入基因表达以恢复斑马鱼正常的摆动模式可挽救这种影响。这些基因功能的紊乱与人类或斑马鱼左右轴确定的缺陷无关。
