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Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2003-07-01 , DOI: 10.1086/377157
Deborah M Ruddy 1 , Matthew J Parton , Ammar Al-Chalabi , Cathryn M Lewis , Caroline Vance , Bradley N Smith , P Nigel Leigh , John F Powell , Teepu Siddique , Eelco Postumus Meyjes , Frank Baas , Vianney de Jong , Christopher E Shaw
Affiliation  

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease in which motor neurons in the brain and spinal cord degenerate by largely unknown mechanisms. ALS is familial (FALS) in 10% of cases, and the inheritance is usually dominant, with variable penetrance. Mutations in copper/zinc super oxide dismutase (SOD1) are found in 20% of familial and 3% of sporadic ALS cases. Five families with ALS and frontotemporal dementia (ALS-FTD) are linked to 9q21, whereas one family with pure ALS is linked to 18q21. We identified two large European families with ALS without SOD1 mutations or linkage to known FALS loci and conducted a genomewide linkage screen using 400 microsatellite markers. In both families, two-point LOD scores >1 and a haplotype segregating with disease were demonstrated only across regions of chromosome 16. Subsequent fine mapping in family 1 gave a maximum two-point LOD score of 3.62 at D16S3137 and a three-point LOD score of 3.85 for markers D16S415 and D16S3137. Haplotype analysis revealed no recombination > approximately 30 cM, (flanking markers at D16S3075 and D16S3112). The maximum two-point LOD score for family 2 was 1.84 at D16S415, and the three-point LOD score was 2.10 for markers D16S419 and D16S415. Definite recombination occurred in several individuals, which narrowed the shared haplotype in affected individuals to a 10.1-cM region (flanking markers: D16S3396 and D16S3112). The region shared by both families on chromosome 16q12 corresponds to approximately 4.5 Mb on the Marshfield map. Bioinformatic analysis of the region has identified 18 known genes and 70 predicted genes in this region, and sequencing of candidate genes has now begun.

中文翻译:

家族性肌萎缩性侧索硬化症的两个家族与16q号染色体上的一个新基因座相关。

肌萎缩性侧索硬化症(ALS)是一种致命的成人发病疾病,其大脑和脊髓中的运动神经元通过很大程度上未知的机制退化。在10%的病例中,ALS是家族性的(FALS),并且遗传通常占主导地位,而外et率却有所不同。在20%的家族性和3%的散发性ALS病例中发现了铜/锌超氧化物歧化酶(SOD1)突变。五个患有ALS和额颞叶痴呆(ALS-FTD)的家庭与9q21相关,而一个患有纯净ALS的家庭与18q21相关。我们确定了两个欧洲大家族,它们的ALS没有SOD1突变或与已知FALS基因座的连锁,并使用400个微卫星标记进行了全基因组连锁筛选。在两个家庭中,仅在16号染色体区域显示了两点LOD得分> 1和与疾病分离的单倍型。随后的家族1的精细作图得出D16S3137的最大两点LOD得分为3.62,标记D16S415和D16S3137的三点LOD得分为3.85。单倍型分析显示没有重组>大约30 cM(D16S3075和D16S3112的侧翼标记)。家庭2的最大两点LOD得分在D16S415为1.84,而标记D16S419和D16S415的三点LOD得分为2.10。在几个个体中发生了明确的重组,这将受影响个体的共有单倍型缩小到10.1-cM区域(侧翼标记:D16S3396和D16S3112)。两个族在染色体16q12上共享的区域在Marshfield图中对应于大约4.5 Mb。该区域的生物信息学分析确定了该区域的18个已知基因和70个预测基因,
更新日期:2019-11-01
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