期刊
JOURNAL OF MOLECULAR NEUROSCIENCE
卷 71, 期 9, 页码 1876-1883出版社
SPRINGERNATURE
DOI: 10.1007/s12031-021-01814-w
关键词
CCM; KRIT1 gene; Novel variants; De novo mutation; Functional studies; Cutaneous angioma
资金
- Universita degli Studi di Siena within the CRUI-CARE Agreement
Cerebral cavernous malformations (CCMs) can cause symptoms such as headaches and seizures, with mutations in the KRIT1 gene accounting for a majority of familial cases and resulting in premature stop codons. Phenotypic variability and incomplete penetrance of symptoms in mutation carriers were observed among CCM patients.
Cerebral cavernous malformations (CCMs) are vascular malformations that may result in headaches, seizures, focal neurological deficits, and hemorrhage. CCMs occur sporadically (80%) or in familial form (20%), with autosomal dominant inheritance. Among the three CCM-related genes, mutations in KRIT1 account for 53-65% of familial cases and more than 100 different mutations have been identified so far. In the present work, we describe the clinical, neuroradiological, and genetic findings of sixteen CCM Italian patients, 13 belonging to 4 unrelated families and 3 sporadic cases. Six distinct KRIT1 gene variants, two novel (c.1730+1_1730+3del, c.1664 C>T) and four previously described (c.966G>A, c.1255-1G>A c.1197_1200del, c.1255-1_1256del), were identified, including a possible de novo mutation. All the variants resulted in a premature stop codon. Cerebral 1.5 T magnetic resonance imaging showed multiple CCMs in all the mutation carriers for whom it was available, including sporadic cases. One patient had also cutaneous angiomas. Among the mutation carriers, symptomatic patients constituted 66% and a variable phenotypic expression was observed. Our data confirms phenotypic variability and incomplete penetrance of neurological symptoms in KRIT1-positive families, expands the mutational spectrum of this gene, and highlights how sporadic cases with multiple lesions need an approach similar to individuals with familial CCM.
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