title: C329X in KRIT1 is a founder mutation among CCM patients in Sardinia.
abstract: Cerebral cavernous malformations (CCMs) are CNS vascular anomalies associated with seizures, headaches and hemorrhagic strokes and represent 10-20% of cerebral lesions. CCM is present in 0.1-0.5 of the population. This disorder most often occurs sporadically but may also be familial. Familial cases are inherited as a dominant trait with incomplete penetrance and are estimated to account for KRIT1 10-40% of the patients. The identification of the genes involved in such disorders allows to characterize carriers of the mutations without clear symptoms. The first gene involved in CCM1 is KRIT1. In addition to two other genes have been described: MGC4607 (CCM2) and PDCD10 (CCM3). We selected 13 patients belonging to seven Sardinian families on the basis of clinical symptoms and Magnetic Resonance results. In MGC4607 gene an undescribed exon five deletion likely producing a truncated protein was identified in one family. In two patients with clear phenotype and in three asymptomatic relatives a 4 bp deletion in exon 9 of KRIT1 gene, leading to a premature stop codon, was detected. A unique nonsense mutation (C329X) has been found in seven patients and two asymptomatic subjects belonging to four unrelated families. Haplotype analysis revealed a common origin of this mutation. These data suggest a "founder effect" in Sardinia for the C329X mutation, similar to other mutations described in different populations.
authors.affiliation: Dipartimento di Scienze biomediche e biotecnologie, University of Cagliari, Via Jenner s/n, 09134 Cagliari, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Cau
authors.forename: Mario
authors.initials: M
authors.lastname: Loi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Melis
authors.forename: Rita
authors.initials: R
authors.lastname: Congiu
authors.forename: Alberto
authors.initials: A
authors.lastname: Loi
authors.forename: Cristiana
authors.initials: C
authors.lastname: Meloni
authors.forename: Marianna
authors.initials: M
authors.lastname: Serrenti
authors.forename: Maria
authors.initials: M
authors.lastname: Addis
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Melis
mesh_terms: D017668:Age of Onset; D018389:Codon, Nonsense; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005091:Exons; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics*; D006801:Humans; D007407:Interviews as Topic; D007558:Italy; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D021141:Nucleic Acid Amplification Techniques; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D004247:DNA