A new dominant spinocerebellar ataxia linked to chromosome 19q13.4-qter
A new dominant spinocerebellar ataxia linked to chromosome 19q13.4-qter
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DOI：
10.1001/archneur.59.8.1291
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发表时间：
2002-08-01
影响因子：
--
通讯作者：
Bird, TD
中科院分区：
文献类型：
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作者：
Brkanac, Z;Bylenok, L;Bird, TD
背景：常染色体显性脊髓小脑共济失调（SCAs）是一组临床和遗传上异质性的神经退行性疾病。尽管分子遗传学研究迄今已发现这些疾病的病因中有 16 个位点，但大约 30% 的 SCA 家族仍无关联。 目标：报告一个家族中引起“纯”常染色体显性小脑性共济失调的基因的位置，并描述临床表型。 患者：我们已鉴定出一个具有纯小脑性的 4 代美国英国和荷兰裔家庭 共济失调表现出常染色体显性遗传模式。这种疾病通常在生命的第三个和第四个十年发病，没有任何预期的证据，进展缓慢，并且似乎不会降低预期寿命。临床 DNA 检测排除了 SCA1、2、3、6、7 和 8。方法：对 26 名家庭成员（11 名受影响者、10 名临床上未受影响的风险者和 5 名配偶）的样本进行了 10 厘摩 (cM) 水平的全基因组连锁分析。结果：假设外显率为 90%，我们发现了与 19 号染色体连锁的提示性证据，lod 得分为 2.49为了 D19S571。该区域中更详细的映射为 D19S254 提供了 2.57 的最大 2 点 led 分数（在 theta = 0 处），以及在 D19S926 处的最大多点 lod 分数为 4.72。通过单倍型构建，定义了从 D19S601 到 q 端粒的 22-cM 关键区域。结论：我们已将常染色体显性 SCA 的基因定位到一个家族中的染色体 19q13.4-qter。该关键区域与 SCA14 的基因座重叠，SCA14 是一种在一个日本家族中描述的疾病，其特征是轴性肌阵挛。在我们研究的家族中没有发现肌阵挛，但这两种疾病仍然有可能是等位基因变异。
Background: The autosomal dominant spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. Although molecular genetic studies have so far implicated 16 loci in the etiology of these diseases, approximately 30% of families with SCAs remain unlinked.Objectives: To report the location of a gene causing a "pure" autosomal dominant cerebellar ataxia in one family and to describe the clinical phenotype.Patients: We have identified a 4-generation American family of English and Dutch ethnicity with a pure cerebellar ataxia displaying an autosomal dominant pattern of inheritance. The disease typically has its onset in the third and fourth decades of life, shows no evidence of anticipation, progresses slowly, and does not appear to decrease life expectancy. Clinical DNA testing excluded SCA1, 2, 3, 6, 7, and 8.Methods: A genome-wide linkage analysis at a 10 centimorgan (cM) level was performed with samples from 26 family members (11 affected, 10 clinically unaffected at risk, and 5 spouses)Results: Assuming 90% penetrance, we found suggestive evidence of linkage to chromosome 19, with a lod score of 2.49 for D19S571. More detailed mapping in this region provided a maximum 2-point led score of 2.57 at theta = 0 for D19S254 and a maximum multipoint lod score of 4.72 at D19S926. By haplotype construction a 22-cM critical region from D19S601 to the q telomere was defined.Conclusions: We have mapped a gene for an autosomal dominant SCA to chromosome 19q13.4-qter in one family. The critical region overlaps with the locus for SCA14, a disease described in a single Japanese family and characterized by axial myoclonus. Myoclonus was not seen in the family we studied, but it remains possible that the 2 disorders are allelic variants.