A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy -: Genetic and magnetic resonance spectroscopic findings
A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy -: Genetic and magnetic resonance spectroscopic findings
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DOI：
10.1001/archneur.58.9.1418
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发表时间：
2001-09-01
影响因子：
--
通讯作者：
Quattrone, A
中科院分区：
文献类型：
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作者：
Oliveri, RL;Muglia, M;Quattrone, A
背景：脑常染色体显性动脉病变伴皮质下梗死和白质脑病（CADASIL）是一种由Notch3基因突变引起的遗传性综合征，通常定位于外显子3和4。目的：报道发生在Notch3基因外显子6上的一种新的致病突变，这是以前在CADASIL患者中未发现的位置，并报道CADASIL的磁共振波谱结果。方法：对2例CADASIL大家族患者、7例临床未受影响的家族成员和200条对照染色体进行Notch3基因突变分析。质子磁共振波谱用于估计2名受影响受试者的代谢物共振强度。结果：Notch3基因序列分析显示，在第6外显子332密码子出现新的错义突变CGC—> TGC，导致精氨酸残基被半胱氨酸取代。该突变从未在该家族的7名未受影响的成员和检查的200条对照染色体中观察到。质子磁共振波谱显示脑n -乙酰天冬氨酸弥漫性减少，提示存在广泛的轴突损伤。结论：我们的研究结果强调了直接DNA序列分析在CADASIL诊断中的作用。此外，质子磁共振波谱的结果表明，广泛的轴突损伤可能是疾病的早期发现。
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary syndrome caused by mutations of the Notch3 gene, usually localized to exons 3 and 4.Objectives: To report a novel pathogenetic mutation occurring in exon 6 of the Notch3 gene, a location not previously recognized in patients with CADASIL, and to report the results of magnetic resonance spectroscopy in CADASIL.Methods: Mutation analysis of the Notch3 gene was performed in 2 patients belonging to a large kindred manifesting CADASIL, as well as in 7 clinically unaffected members of the family and 200 control chromosomes. Proton magnetic resonance spectroscopy was used to estimate metabolite resonance intensities in the 2 affected subjects.Results: Sequence analysis of the Notch3 gene showed a new missense mutation CGC --> TGC in codon 332 of exon 6, resulting in the replacement of an arginine residue with a cysteine. This mutation was never observed in the 7 unaffected members of the family and the 200 control chromosomes examined. Proton magnetic resonance spectroscopy showed a diffuse decrease in cerebral N-acetylaspartate, indicating the presence of wide-spread axonal damage.Conclusions: Our findings emphasize the role of direct DNA sequence analysis for the diagnosis of CADASIL. Moreover, the results of proton magnetic resonance spectroscopy suggest that widespread axonal damage may be an early finding of the disease.