特发性脊柱侧凸的流行病学调查及多个候选基因的序列比对分析。

Epidemiological survey of idiopathic scoliosis and sequence alignment analysis of multiple candidate genes.

机构信息

Department of Orthopaedic, Southwest Hospital, Third Military University, No. 30 Gaotanyanzhengjie RAOD, Shapingba District, Chongqing, 400038, China.

出版信息

Int Orthop. 2012 Jun;36(6):1307-14. doi: 10.1007/s00264-011-1419-z. Epub 2011 Dec 20.

DOI:10.1007/s00264-011-1419-z

PMID:22183150

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3353077/

Abstract

PURPOSE

To investigate the effects of genetic factors on idiopathic scoliosis (IS) and genetic modes through genetic epidemiological survey on IS in Chongqing City, China, and to determine whether SH3GL1, GADD45B, and FGF22 in the chromosome 19p13.3 are the pathogenic genes of IS through genetic sequence analysis.

METHODS

214 nuclear families were investigated to analyse the age incidence, familial aggregation, and heritability. SH3GL1, GADD45B, and FGF22 were chosen as candidate genes for mutation screening in 56 IS patients of 214 families. The sequence alignment analysis was performed to determine mutations and predict the protein structure.

RESULTS

The average age of onset of 10.8 years suggests that IS is a early onset disease. Incidences of IS in first-, second-, third-degree relatives and the overall incidence in families (5.68%) were also significantly higher than that of the general population (1.04%). The U test indicated a significant difference, suggesting that IS has a familial aggregation. The heritability of first-degree relatives (77.68 ±10.39%), second-degree relatives (69.89 ±3.14%), and third-degree relatives (62.14 ±11.92%) illustrated that genetic factors play an important role in IS pathogenesis. The incidence of first-degree relatives (10.01%), second-degree relatives (2.55%) and third-degree relatives (1.76%) illustrated that IS is not in simple accord with monogenic Mendel's law but manifests as traits of multifactorial hereditary diseases. Sequence alignment of exons of SH3GL1, GADD45B, and FGF22 showed 17 base mutations, of which 16 mutations do not induce open reading frame (ORF) shift or amino acid changes whereas one mutation (C→T)occurred in SH3GL1 results in formation of the termination codon, which induces variation of protein reading frame. Prediction analysis of protein sequence showed that the SH3GL1 mutant encoded a truncated protein, thus affecting the protein structure.

CONCLUSION

IS is a multifactorial genetic disease and SH3GL1 may be one of the pathogenic genes for IS.

摘要

目的

通过对中国重庆市特发性脊柱侧凸（IS）的遗传流行病学调查，探讨遗传因素对 IS 的影响及其遗传方式，并通过遗传序列分析，确定染色体 19p13.3 上的 SH3GL1、GADD45B 和 FGF22 是否为 IS 的致病基因。

方法

对 214 个核家庭进行调查，分析年龄发病、家族聚集和遗传度。选择 214 个家庭中的 56 个 IS 患者的 SH3GL1、GADD45B 和 FGF22 作为突变筛选的候选基因。进行序列比对分析，确定突变并预测蛋白质结构。

结果

平均发病年龄为 10.8 岁，提示 IS 为早发疾病。一级、二级、三级亲属的 IS 发病率以及家族总体发病率（5.68%）均显著高于一般人群（1.04%）。U 检验表明存在显著差异，提示 IS 具有家族聚集性。一级亲属（77.68±10.39%）、二级亲属（69.89±3.14%）和三级亲属（62.14±11.92%）的遗传度表明，遗传因素在 IS 的发病机制中起重要作用。一级亲属（10.01%）、二级亲属（2.55%）和三级亲属（1.76%）的发病率表明，IS 不符合单基因孟德尔遗传规律，而是表现为多基因遗传疾病的特征。SH3GL1、GADD45B 和 FGF22 外显子序列比对显示 17 个碱基突变，其中 16 个突变不引起开放阅读框（ORF）移位或氨基酸变化，而一个突变（C→T）发生在 SH3GL1 导致终止密码子的形成，从而导致蛋白质阅读框的变异。蛋白质序列预测分析表明，SH3GL1 突变编码的截短蛋白影响了蛋白质结构。