title: Identification of a c.601C>G mutation in the CCM1 gene in a kindred with multiple skin, spinal and cerebral cavernous malformations.
abstract: Cerebral cavernous malformations (CCM) are congenital vascular anomalies predominantly of the central nervous system but may include lesions in other tissues such as the retina, skin, and liver. These hamartomatous dysplasias, generally occurring sporadically, consist of dynamic clustered convoluted capillary cavities without intervening brain parenchyma that may lead to headaches, seizures, paresis, cerebral hemorrhages and focal neurological deficits. Familial forms of CCM, inherited in an autosomal dominant manner with incomplete penetrance and variable expression, are attributed to mutations in three genes, CCM1, CCM2 and CCM3. Here, we report a kindred of Persian descent exhibiting a range of clinical symptoms and features that include seizures, multiple lesions of the brain and spinal cord, and severe hyperkeratotic cutaneous capillary-venous malformations. Sanger DNA sequencing and deletion/duplication testing of the CCM1, CCM2, and CCM3 genes in the proband revealed a CCM1 c.601C>G mutation. Targeted mutation analysis in family members confirmed that this mutation segregated with the disease in the family. This family illustrates the phenotypic heterogeneity that has been observed in other reported CCM-pedigrees and highlights the importance of genetic testing for early diagnosis in familial CCM. To our knowledge, this is the first genetic investigation of CCM in the Persian population.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women's Hospital, USA; Department of Genetics, Harvard Medical School, USA. Electronic address: haghighi@genetics.med.harvard.edu.
authors.forename: Alireza
authors.initials: A
authors.lastname: Haghighi
authors.forename: Davood
authors.initials: D
authors.lastname: Fathi
authors.forename: Majid
authors.initials: M
authors.lastname: Shahbazi
authors.forename: Mohammad-Mahdy
authors.initials: MM
authors.lastname: Motahari
authors.forename: Bethany
authors.initials: B
authors.lastname: Friedman
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics*; D006801:Humans; D007492:Iran; D000075927:KRIT1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012868:Skin Abnormalities / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C502544:CCM2 protein, human; D002352:Carrier Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins
keywords: CCM1; Cerebral cavernous malformations; Cutaneous vascular malformation; Krit1; Persian