Lam Ching-Wan, Tong Sui-Fan, Wong Keong, Luo Y F, Tang Hoi-Yin, Ha Shau-Yin, Chan Michael Ho-Ming
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
Department of Obstetrics and Gynecology, Centro Hospitalar Conde S. Januario, Macau, China.
J Hum Genet. 2007;52(1):98-101. doi: 10.1007/s10038-006-0075-4. Epub 2006 Oct 11.
Malignant osteopetrosis, a severe disease causing early infantile death in humans, is caused by mutations in the TCIRG1, CLCN7, or OSTM1 genes. We have established the molecular basis of malignant osteopetrosis in a Chinese family by means of whole-genome scans based on high-density single-nucleotide polymorphism (SNP) microarrays. Because the parents were consanguineous, the disease-causing locus should be located in an autozygous chromosomal region. Mapping revealed that among the three possible causal loci, only the CLCN7 gene was located in an autozygous region. Mutational analysis of the CLCN7 gene showed that the proband was homozygous for a novel missense mutation, p.I261F. p.I261 is located in helix F of the chloride channel, near a critical site for gating of the channel. This mapping study prepares the ground for future mutation studies by decreasing the burden of completely sequencing all possible loci for this disease. This approach can be used to standardize molecular investigations of genetic diseases due to consanguinity to a whole-genome scan and subsequent sequencing of the mapped disease gene.
恶性骨硬化症是一种导致人类早期婴儿死亡的严重疾病，由TCIRG1、CLCN7或OSTM1基因的突变引起。我们通过基于高密度单核苷酸多态性（SNP）微阵列的全基因组扫描，确定了一个中国家庭中恶性骨硬化症的分子基础。由于父母是近亲，致病基因座应位于纯合染色体区域。定位显示，在三个可能的致病基因座中，只有CLCN7基因位于纯合区域。对CLCN7基因的突变分析表明，先证者对于一个新的错义突变p.I261F是纯合的。p.I261位于氯离子通道的F螺旋中，靠近通道门控的关键位点。这项定位研究通过减少对该疾病所有可能基因座进行完全测序的负担，为未来的突变研究奠定了基础。这种方法可用于将因近亲结婚导致的遗传疾病的分子研究标准化为全基因组扫描以及对定位的疾病基因进行后续测序。
