脊柱侧凸第一个相关基因浮出水面

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脊柱侧凸第一个相关基因浮出水面 人们认识脊柱侧凸（scoliosis）的历史能够追溯到古希腊希波克拉底（古希腊名医）时代，但直到今天，脊柱侧凸的病因仍旧是个谜。最近，华盛顿大学医学院、德州大学西南医学院等单位的研究人员发现，基因CHD7缺陷会导致脊柱C和S型弯曲。遗传学、医学和耳科学副教授AnneBowcock说，掌握了基因影响脊柱发育的机制，就能理论预测胎儿脊柱侧凸的可能性，提早进行治疗。详细内容刊登于5月份出版的《美国人类遗

  生物谷报道：人们认识脊柱侧凸（scoliosis）的历史能够追溯到古希腊希波克拉底（古希腊名医）时代，但直到今天，脊柱侧凸的病因仍旧是个谜。最近，华盛顿大学医学院、德州大学西南医学院等单位的研究人员发现，基因CHD7缺陷会导致脊柱C和S型弯曲。遗传学、医学和耳科学副教授Anne Bowcock说，掌握了基因影响脊柱发育的机制，就能理论预测胎儿脊柱侧凸的可能性，提早进行治疗。详细内容刊登于5月份出版的《美国人类遗传学杂志》。

  尽管脊柱侧凸有家族倾向，但研究人员一直不清楚其遗传机制。主要原因是这种疾病看起来像是几种不同基因和环境共同作用的结果。CHD7基因在许多基本的细胞功能中发挥关键作用。研究人员发现CHARGE综合症（一种罕见的综合症）患者体内，CHD7基因缺失或发生损伤严重。CHARGE综合症婴儿经常幼年夭折，即使幸存也会罹患心脏缺陷、智力迟钝等疾病，并伴随晚期的脊柱侧凸。Bowcock等感觉CHD7的适度突变与其它类型的脊柱侧凸有关。

   Scottish Rite医院Carol Wise博士率领的研究小组，收集来自52个家庭成员中有脊柱侧凸患者的家族资料。患者脊柱弯曲平均为40度，没有Marfan综合症或大脑性麻痹等与脊柱侧凸有关的其它疾病。研究人员执行全基因组扫描，对这些家族成员两套染色体的60亿个碱基对进行测序并分析数据。

   研究结果显示，脊柱侧凸患者的基因非编码区有缺陷，这意味着CHD7蛋白的生成不受影响。研究人员推测这种特定突变会改变控制基因表达起始位点的分子的结合情况，进而导致基因关闭频率上升，CHD7产量下降。

  遗传学和儿科学教授Michael Lovett说，蛋白产量的变化很微妙，与经常发生的某种脊柱侧凸高度相关，这种特异缺陷或许是脊柱侧凸的真正或极为重要的原因。目前，研究人员正在其他脊柱侧凸家族中寻找这种疾病的其它遗传突变。

原始出处:

Am. J. Hum. Genet., 80:957-965, 2007


CHD7 Gene Polymorphisms Are Associated with Susceptibility to Idiopathic Scoliosis

Xiaochong Gao, Derek Gordon, Dongping Zhang, Richard Browne, Cynthia Helms, Joseph Gillum, Samuel Weber, Shonn Devroy, Saralove Swaney, Matthew Dobbs, Jose Morcuende, Val Sheffield, Michael Lovett, Anne Bowcock, John Herring, and Carol Wise

From the Seay Center for Musculoskeletal Research (X.G.; D.Z.; R.B.; J.G.; S.W.; S.D.; S.S.; C.W.), Orthopaedics, Texas Scottish Rite Hospital (J.H.), and Department of Orthopaedic Surgery (J.H.; C.W.) and McDermott Center for Human Growth and Development (C.W.), University of Texas Southwestern Medical Center, Dallas; Department of Genetics, Rutgers, The State University of New Jersey, Piscataway (D.G.); Departments of Genetics (C.H.; M.L.; A.B.) and Orthopaedic Surgery (M.D.), Washington University School of Medicine, St. Louis; and Departments of Orthopaedic Surgery and Rehabilitation (J.M.) and Pediatrics (V.S.), University of Iowa School of Medicine, Iowa City

Received November 3, 2006; accepted for publication February 6, 2007; electronically published March 12, 2007.

Idiopathic scoliosis (IS) is the most common spinal deformity in children, and its etiology is unknown. To refine the search for genes underlying IS susceptibility, we ascertained a new cohort of 52 families and conducted a follow-up study of genomewide scans that produced evidence of linkage and association with 8q12 loci (multipoint LOD 2.77; P = .0028). Further fine mapping in the region revealed significant evidence of disease-associated haplotypes (P < 1.0 × 10-4) centering over exons 2–4 of the CHD7 gene associated with the CHARGE (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness) syndrome of multiple developmental anomalies. Resequencing CHD7 exons and conserved intronic sequence blocks excluded coding changes but revealed at least one potentially functional polymorphism that is overtransmitted (P = .005) to affected offspring and predicts disruption of a caudal-type (cdx) transcription-factor binding site. Our results identify the first gene associated with IS susceptibility and suggest etiological overlap between the rare, early-onset CHARGE syndrome and common, later-onset IS.