Journal of the Chinese Medical Association : JCMA · 2026
An in trans NOTCH3 loss-of-function variant modifies disease severity in CADASIL: A family-based study.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Lan Shih-Chun, Liu Yi-Hong, Lan Jui, Liao Yi-Chu, Lan Min-Yu, Lee Yi-Chung
Аннотация
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by pathogenic NOTCH3 variants, most commonly heterozygous cysteine-altering variants. Disease severity varies widely, and the impact of reduced NOTCH3 dosage on CADASIL severity remains unclear. We describe a family of four individuals carrying a cysteine-altering NOTCH3 variant and/or a frameshift loss-of-function (LoF) variant, demonstrating marked intrafamilial phenotypic heterogeneity.
METHODS: Four related individuals underwent standardized clinical assessment, brain magnetic resonance imaging (MRI), genetic analysis, skin biopsy, and NOTCH3 complementary DNA (cDNA) sequencing.
RESULTS: The proband, carrying p.Cys1146Ser and p.Cys1024Valfs248 in trans, developed progressive gait disturbance, dysphagia, and slurred speech beginning in his mid-thirties. Brain MRI demonstrated extensive white matter hyperintensities, multiple lacunar infarcts, and numerous cerebral microbleeds. In contrast, the father (carrying p.Cys1146Ser alone) and the mother and brother (carrying p.Cys1024Valfs248 alone) exhibited milder clinical and imaging phenotypes. Only the carriers of the cysteine-altering variant demonstrated NOTCH3 extracellular domain (NOTCH3 ECD ) immunoreactivity in skin vessels. NOTCH3 cDNA sequencing from the skin tissue demonstrated reduced LoF allele expression.
CONCLUSION: Reduced NOTCH3 dosage may modify the disease severity of CADASIL.
METHODS: Four related individuals underwent standardized clinical assessment, brain magnetic resonance imaging (MRI), genetic analysis, skin biopsy, and NOTCH3 complementary DNA (cDNA) sequencing.
RESULTS: The proband, carrying p.Cys1146Ser and p.Cys1024Valfs248 in trans, developed progressive gait disturbance, dysphagia, and slurred speech beginning in his mid-thirties. Brain MRI demonstrated extensive white matter hyperintensities, multiple lacunar infarcts, and numerous cerebral microbleeds. In contrast, the father (carrying p.Cys1146Ser alone) and the mother and brother (carrying p.Cys1024Valfs248 alone) exhibited milder clinical and imaging phenotypes. Only the carriers of the cysteine-altering variant demonstrated NOTCH3 extracellular domain (NOTCH3 ECD ) immunoreactivity in skin vessels. NOTCH3 cDNA sequencing from the skin tissue demonstrated reduced LoF allele expression.
CONCLUSION: Reduced NOTCH3 dosage may modify the disease severity of CADASIL.