{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T03:22:14Z","timestamp":1770348134843,"version":"3.49.0"},"reference-count":27,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2003,7]]},"abstract":"<jats:p content-type=\"fine-print\"><jats:italic>Object.<\/jats:italic> A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, <jats:italic>KRIT1<\/jats:italic> (an acronym for <jats:italic>Krev Interaction Trapped 1<\/jats:italic>), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the <jats:italic>KRIT1<\/jats:italic> gene.<\/jats:p>\n<jats:p content-type=\"fine-print\"><jats:italic>Methods.<\/jats:italic> The authors used single-strand conformational polymorphism analysis to identify genomic variants in <jats:italic>KRIT1<\/jats:italic>, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Mexico. These findings establish the key role of a recent founder mutation in Hispanic persons with CCM who live in the US.<\/jats:p>\n<jats:p content-type=\"fine-print\">Although nearly all Hispanic families in the US in which there are multiple CCM cases linked to the <jats:italic>CCM1<\/jats:italic> locus, only 13 of 25 non-Hispanic CCM-carrying families have displayed evidence of linkage to the <jats:italic>CCM1<\/jats:italic> locus. Among these 13 families, the authors identified eight independent mutations in nine kindreds. They identified four additional mutations among 22 familial CCM kindreds with no linkage information, bringing the total number of independent mutations to 12. Inherited <jats:italic>KRIT1<\/jats:italic> mutations were not detected among 103 non-Hispanic persons in whom a family history of CCM was rigorously excluded.<\/jats:p>\n<jats:p content-type=\"fine-print\"><jats:italic>Conclusions.<\/jats:italic> All mutations were nonsense mutations, frame-shift mutations predicting premature termination, or splicesite mutations located throughout the <jats:italic>KRIT1<\/jats:italic> gene, suggesting that these are genetic loss-of-function mutations. These genetic findings, in conjunction with the clinical phenotype, are consistent with a two-hit model for the occurrence of CCM.<\/jats:p>","DOI":"10.3171\/jns.2003.99.1.0038","type":"journal-article","created":{"date-parts":[[2009,5,13]],"date-time":"2009-05-13T17:53:09Z","timestamp":1242237189000},"page":"38-43","source":"Crossref","is-referenced-by-count":64,"title":["Mutational analysis of 206 families with cavernous malformations"],"prefix":"10.3171","volume":"99","author":[{"given":"Maxwell S. H.","family":"Laurans","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael L.","family":"DiLuna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Shin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faheem","family":"Niazi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer R.","family":"Voorhees","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol","family":"Nelson-Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric W.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian M.","family":"Siegel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary K.","family":"Steinberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel J.","family":"Berg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. Michael","family":"Scott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gioacchino","family":"Tedeschi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T. Peter","family":"Enevoldson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Anson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy A.","family":"Rouleau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Ogilvy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Issam A.","family":"Awad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard P.","family":"Lifton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murat","family":"Gunel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1754","reference":[{"key":"b1","series-title":"Eur J Hum 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study over a 5-year period.","volume":"11","author":"Hayman","year":"1982"},{"key":"b14","series-title":"Genome Res","first-page":"368","article-title":"Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig.","volume":"5","author":"Johnson","year":"1995"},{"key":"b15","series-title":"Nat Genet","first-page":"189","article-title":"Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.","volume":"23","author":"Laberge-le Couteulx","year":"1999"},{"key":"b16","series-title":"Proc Natl Acad Sci USA","first-page":"3443","article-title":"Strategies for multilocus linkage analysis in humans.","volume":"81","author":"Lathrop","year":"1984"},{"key":"b17","series-title":"Ann Neurol","first-page":"836","article-title":"Spanish families with cerebral cavernous angioma do not bear 742C\u2192T Hispanic American mutation of the KRIT1 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repeat-containing protein encoded by a gene mapping to 7q21-22.","volume":"15","author":"Serebriiskii","year":"1997"},{"key":"b23","series-title":"Neurology","first-page":"853","article-title":"Cerebral cavernous malformations: mutations in Krit1.","volume":"58","author":"Verlaan","year":"2002"},{"key":"b24","series-title":"Am J Hum Genet","first-page":"1564","article-title":"Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation.","volume":"70","author":"Verlaan","year":"2002"},{"key":"b25","series-title":"Neurosurgery","first-page":"1454","article-title":"Ultrastructural pathological features of cerebrovascular malformations: a preliminary report.","volume":"46","author":"Wong","year":"2000"},{"key":"b26","series-title":"Genomics","first-page":"392","article-title":"Cloning of the murine Krit1 cDNA reveals novel mammalian 5\u2032 coding exons.","volume":"70","author":"Zhang","year":"2000"},{"key":"b27","series-title":"Neurosurgery","first-page":"1272","article-title":"Mutations in KRIT1 in familial cerebral cavernous malformations.","volume":"46","author":"Zhang","year":"2000"}],"container-title":["Journal of 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