To conduct a clinical study of a family with neurologic symptoms and findings carrying a novel NOTCH3 mutation and to analyze the molecular consequences of the mutation.

We analyzed a family with complex neurologic symptoms by MRI and neurologic examinations. Exome sequencing of the NOTCH3 locus was conducted, and whole-genome sequencing was performed to identify COL4A1, COL4A2, and HTRA1 mutations. Cell lines expressing the normal or NOTCH3^A1604T receptors were analyzed to assess proteolytic processing, cell morphology, receptor routing, and receptor signaling.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease (SVD) and caused by mutations in the NOTCH3 gene. Most CADASIL mutations alter the number of cysteine residues in the extracellular domain of the NOTCH3 receptor, but in this article, we describe a family in which some members carry a novel cysteine-sparing NOTCH3 mutation (c.4810 G>A, p.Ala1604Thr). Two of 3 siblings heterozygous for the NOTCH3^A1604T mutation presented with migraine and white matter lesions (WMLs), the latter of a type related to but distinct from what is normally observed in CADASIL. Two other members instead carried a novel COL4A1 missense mutation (c.4795 G>A; p.(Ala1599Thr)). The NOTCH3^A1604T receptor was aberrantly processed, showed reduced presence at the cell surface, and less efficiently activated Notch downstream target genes.

We identify a family with migraine and WML in which some members carry a cysteine-sparing hypomorphic NOTCH3 mutation. Although a causal relationship is not established, we believe that the observations contribute to the discussion on dysregulated Notch signaling in cerebral SVDs.

对具有神经系统症状和发现携带新型NOTCH3突变的家族进行临床研究，并分析该突变的分子后果。

我们通过 MRI 和神经系统检查分析了一个具有复杂神经系统症状的家庭。进行了NOTCH3基因座的外显子组测序，并进行了全基因组测序以鉴定COL4A1、COL4A2和HTRA1突变。分析表达正常或 NOTCH3 ^A1604T受体的细胞系以评估蛋白水解加工、细胞形态、受体路径和受体信号传导。

伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病 (CADASIL) 是最常见的遗传性脑小血管疾病 (SVD)，由NOTCH3基因突变引起。大多数 CADASIL 突变会改变 NOTCH3 受体胞外结构域中半胱氨酸残基的数量，但在本文中，我们描述了一个家族，其中一些成员携带新的保留半胱氨酸的 NOTCH3 突变 (c.4810 G>A, p.Ala1604Thr ）。^{3 个具有 NOTCH3 A1604T}突变杂合子的兄弟姐妹中的两个出现偏头痛和白质病变 (WML)，后者的类型与 CADASIL 中通常观察到的类型相关但不同。其他两个成员反而携带了一个新的 COL4A1 错义突变 (c.4795 G>A; p.(Ala1599Thr))。NOTCH3^A1604T受体被异常加工，在细胞表面的存在减少，并且激活 Notch 下游靶基因的效率较低。

我们确定了一个患有偏头痛和 WML 的家族，其中一些成员携带保留半胱氨酸的亚型NOTCH3突变。虽然因果关系尚未建立，但我们认为这些观察结果有助于讨论脑 SVD 中失调的 Notch 信号传导。