Vance Caroline, Al-Chalabi Ammar, Ruddy Deborah, Smith Bradley N, Hu Xun, Sreedharan Jemeen, Siddique Teepu, Schelhaas H Jurgen, Kusters Benno, Troost Dirk, Baas Frank, de Jong Vianney, Shaw Christopher E
Department of Neurology, King's College London School of Medicine, London, UK.
Brain. 2006 Apr;129(Pt 4):868-76. doi: 10.1093/brain/awl030. Epub 2006 Feb 22.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both relentlessly progressive and ultimately fatal neurological disorders. ALS is familial in approximately 10% of cases and FTD in approximately 30%. Inheritance is usually autosomal dominant with variable penetrance. Phenotypic overlap between ALS and FTD can occur within the same kindred. Mutations in copper/zinc superoxide dismutase 1 (SOD1) are found in approximately 20% of familial and approximately 3% of sporadic ALS cases but are not associated with dementia. Mutations in microtubule associated protein tau (MAPT) are detected in approximately 30% of familial FTD kindreds. Dominant ALS with FTD has previously been linked to 9q21 and pure ALS to loci on 16q21, 18q21, 20p13. Here we report the results of a genome-wide linkage study in a large ALS and FTD kindred using Affymetrix 10K GeneChip microarrays. Linkage analysis of single nucleotide polymorphism (SNP) data identified consistently positive log of the odds (LOD) scores across chromosome 9p (maximal LOD score of 2.4). Fine mapping the region with microsatellite markers generated a maximal multipoint LOD score of 3.02 (theta = 0) at D9S1878. Recombination narrowed the conserved haplotype to 12 cM (11 Mb) at 9p13.2-21.3 (flanking markers D9S2154 and D9S1874). Bioinformatic analysis of the region has identified 103 known genes.
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）都是无情进展且最终致命的神经疾病。约10%的ALS病例和约30%的FTD病例为家族性。遗传方式通常为常染色体显性遗传，外显率可变。ALS和FTD之间的表型重叠可出现在同一家族中。约20%的家族性ALS病例和约3%的散发性ALS病例中可发现铜/锌超氧化物歧化酶1（SOD1）突变，但这些突变与痴呆无关。约30%的家族性FTD家族中可检测到微管相关蛋白tau（MAPT）突变。伴FTD的显性ALS此前与9q21相关，而单纯ALS与16q21、18q21、20p13上的位点相关。在此，我们报告了一项使用Affymetrix 10K基因芯片微阵列对一个大型ALS和FTD家族进行全基因组连锁研究的结果。单核苷酸多态性（SNP）数据的连锁分析在9号染色体短臂上一致发现了阳性对数优势（LOD）分数（最大LOD分数为2.4）。用微卫星标记对该区域进行精细定位，在D9S1878处产生了最大多点LOD分数3.02（θ = 0）。重组将保守单倍型缩小至9p13.2 - 21.3处的12厘摩（11兆碱基）（侧翼标记为D9S2154和D9S1874）。对该区域的生物信息学分析已鉴定出103个已知基因。
