{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T02:44:44Z","timestamp":1775011484740,"version":"3.50.1"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:00:00Z","timestamp":1614643200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:00:00Z","timestamp":1614643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012990","name":"Universit\u00e0 degli Studi di Siena","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012990","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Mol Neurosci"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 <jats:italic>KRIT1<\/jats:italic> account for 53\u201365% 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 <jats:italic>KRIT1<\/jats:italic> gene variants, two novel (c.1730+1_1730+3del, c.1664 C&gt;T) and four previously described (c.966G&gt;A, c.1255-1G&gt;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 <jats:italic>KRIT1<\/jats:italic>-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.<\/jats:p>","DOI":"10.1007\/s12031-021-01814-w","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T12:05:15Z","timestamp":1614686715000},"page":"1876-1883","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["KRIT1 Gene in Patients with Cerebral Cavernous Malformations: Clinical Features and Molecular Characterization of Novel Variants"],"prefix":"10.1007","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2431-0308","authenticated-orcid":false,"given":"Claudia","family":"Ricci","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4753-6649","authenticated-orcid":false,"given":"Alfonso","family":"Cerase","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2888-5755","authenticated-orcid":false,"given":"Giulia","family":"Riolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuditta","family":"Manasse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2887-7624","authenticated-orcid":false,"given":"Stefania","family":"Battistini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,2]]},"reference":[{"key":"1814_CR1","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1093\/neuros\/nyx091","volume":"80","author":"A Akers","year":"2017","unstructured":"Akers A, Al-Shahi Salman R, Award IA, Dahlem K, Flemming K, Hart B, Kim H, Jusue-Torres I, Kondziolka D, Lee C, Morrison L, Rigamonti D, Rebeiz T, Tournier-Lasserve E, Waggoner D, Whitehead K (2017) Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the angioma alliance scientific advisory board clinical experts panel. Neurosurgery 80:665\u2013680. https:\/\/doi.org\/10.1093\/neuros\/nyx091","journal-title":"Neurosurgery"},{"key":"1814_CR2","doi-asserted-by":"publisher","unstructured":"Battistini S, Ricci C (2020) Concern regarding classification of c.703G>A\/p.Gly235Arg as a novel missense variant in KRIT1 gene. Human Mutat 41:1069\u20131071.\u00a0https:\/\/doi.org\/10.1002\/humu.24000","DOI":"10.1002\/humu.24000"},{"key":"1814_CR3","doi-asserted-by":"publisher","unstructured":"Battistini S, Rocchi R, Cerase A, Citterio A, Tassi L, Lando G, Patrosso MC, Galli R, Brunori P, Sgr\u00f2 DL, Pitillo G, Lo Russo G, Marocchi A, Penco S (2007) Clinical, magnetic resonance imaging, and genetic study of 5 Italian families with cerebral cavernous malformation. Arch Neurol 64:843\u2013848.\u00a0https:\/\/doi.org\/10.1001\/archneur.64.6.843","DOI":"10.1001\/archneur.64.6.843"},{"key":"1814_CR4","doi-asserted-by":"publisher","unstructured":"Brunak S, Engelbrecht J, Knudsen S (1991) Prediction of human mRNA donor and acceptor sites from the DNA sequence. J Mol Biol 220:49\u201365.\u00a0https:\/\/doi.org\/10.1016\/0022-2836(91)90380-o","DOI":"10.1016\/0022-2836(91)90380-o"},{"key":"1814_CR5","first-page":"5296","volume":"7","author":"HT Bulut","year":"2014","unstructured":"Bulut HT, Sarica MA, Baykan AH (2014) The value of susceptibility weighted magnetic resonance imaging in evaluation of patients with familial cerebral cavernous angioma. Int J Clin Exp Med 7:5296\u20135302","journal-title":"Int J Clin Exp Med"},{"key":"1814_CR6","doi-asserted-by":"publisher","unstructured":"Cav\u00e9-Riant F, Denier C, Labauge P, C\u00e9cillon M, Maciazek J, Joutel A, Laberge-Le Couteulx S, Tournier-Lasserve E (2002) Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations. Eur J Hum Genet 10:733\u2013740.\u00a0https:\/\/doi.org\/10.1038\/sj.ejhg.5200870","DOI":"10.1038\/sj.ejhg.5200870"},{"key":"1814_CR7","doi-asserted-by":"publisher","unstructured":"Denier C, Labauge P, Brunereau L, Cav\u00e9-Riant F, Marchelli F, Arnoult M, Cecillon M, Maciazek J, Joutel A, Tournier-Lasserve E (2004) Clinical features of cerebral cavernous malformations patients with KRIT1 mutations. Ann Neurol 55:213\u2013220.\u00a0https:\/\/doi.org\/10.1002\/ana.10804","DOI":"10.1002\/ana.10804"},{"key":"1814_CR8","doi-asserted-by":"publisher","unstructured":"Goldmann JM, Veltman JA, Gilissen C (2019) De novo mutations reflect development and aging of the human germline. Trends Genet 35:828\u2013839. https:\/\/doi.org\/10.1016\/j.tig.2019.08.005","DOI":"10.1016\/j.tig.2019.08.005"},{"key":"1814_CR9","doi-asserted-by":"publisher","unstructured":"Guarnieri V, Muscarella LA, Amoroso R, Quattrone A, Abate ME, Coco M, Catapano D, D'Angelo VA, Zelante L, D'Agruma L (2007) Identification of two novel mutations and of a novel critical region in the KRIT1 gene. Neurogenetics 8:29\u201337.\u00a0https:\/\/doi.org\/10.1007\/s10048-006-0056-y","DOI":"10.1007\/s10048-006-0056-y"},{"key":"1814_CR10","doi-asserted-by":"publisher","unstructured":"Labauge P, Denier C, Bergametti F, Tournier-Lasserve E (2007) Genetics of cavernous angiomas. Lancet Neurol 6:237\u2013244.\u00a0https:\/\/doi.org\/10.1016\/S1474-4422(07)70053-4","DOI":"10.1016\/S1474-4422(07)70053-4"},{"key":"1814_CR11","doi-asserted-by":"publisher","unstructured":"Mabray MC, Starcevich J, Hallstrom J, Robinson M, Bartlett M, Nelson J, Zafar A, Kim H, Morrison L, Hart BL (2020) High prevalence of spinal cord cavernous Malformations in the familial cerebral cavernous malformations type 1 cohort. AJNR Am J Neuroradiol 41:1126\u20131130.\u00a0https:\/\/doi.org\/10.3174\/ajnr.A6584","DOI":"10.3174\/ajnr.A6584"},{"key":"1814_CR12","doi-asserted-by":"publisher","unstructured":"Nardella G, Visci G, Guarnieri V, Castellana S, Biagini T, Bisceglia L, Palumbo O, Trivisano M, Vaira C, Scerrati M, Debrasi D, D'Angelo V, Carella M, Merla G, Mazza T, Castori M, D'Agruma L, Fusco C (2018) A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion. Human Mutat 39:1885\u20131900. https:\/\/doi.org\/10.1002\/humu.23629","DOI":"10.1002\/humu.23629"},{"key":"1814_CR13","doi-asserted-by":"publisher","unstructured":"Rath M, Jenssen SE, Schwefel K, Spiegler S, Kleimeier D, Sperling C, Kaderali L, Felbor U (2017) High-throughput sequencing of the entire genomic regions of CCM1\/KRIT1, CCM2 and CCM3\/PDCD10 to search for pathogenic deep-intronic splice mutations in cerebral cavernous malformations. Eur J Med Genet 60:479\u2013484.\u00a0https:\/\/doi.org\/10.1016\/j.ejmg.2017.06.007","DOI":"10.1016\/j.ejmg.2017.06.007"},{"key":"1814_CR14","doi-asserted-by":"publisher","unstructured":"Riant F, Bergametti F, Ayrignac X, Boulday G, Tournier-Lasserve E (2010) Recent insights into cerebral cavernous malformations: the molecular genetics of CCM. FEBS J 277:1070\u20131075.\u00a0https:\/\/doi.org\/10.1111\/j.1742-4658.2009.07535.x","DOI":"10.1111\/j.1742-4658.2009.07535.x"},{"key":"1814_CR15","doi-asserted-by":"publisher","unstructured":"Siegel AM, Andermann E, Badhwar A, Rouleau GA, Wolford GL, Andermann F, Hess K (1998) Anticipation in familial cavernous angioma: a study of 52 families from international familial cavernous angioma study. IFCAS Group. Lancet 352:1676\u20131677.\u00a0https:\/\/doi.org\/10.1016\/s0140-6736(05)61447-x","DOI":"10.1016\/s0140-6736(05)61447-x"},{"key":"1814_CR16","doi-asserted-by":"publisher","unstructured":"Sirvente J, Enjolras O, Wassef M, Tournier-Lasserve E, Labauge P (2009) Frequency and phenotypes of cutaneous vascular malformations in a consecutive series of 417 patients with familial cerebral cavernous malformations. J Eur Acad Dermatol Venereol 23:1066\u20131072.\u00a0https:\/\/doi.org\/10.1111\/j.1468-3083.2009.03263.x","DOI":"10.1111\/j.1468-3083.2009.03263.x"},{"key":"1814_CR17","doi-asserted-by":"publisher","unstructured":"Verlaan DJ, Laurent SB, Sure U, Bertalanffy H, Andermann E, Andermann F, Rouleau GA, Siegel AM (2004) CCM1 mutation screen of sporadic cases with cerebral cavernous malformations. Neurology 62:1213\u20131215.\u00a0https:\/\/doi.org\/10.1212\/01.wnl.0000118299.55857.bb","DOI":"10.1212\/01.wnl.0000118299.55857.bb"},{"key":"1814_CR18","doi-asserted-by":"publisher","unstructured":"Verlaan DJ, Siegel AM, Rouleau GA (2002) Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation. Am J Hum Genet 70:1564\u20131567.\u00a0https:\/\/doi.org\/10.1086\/340604","DOI":"10.1086\/340604"},{"key":"1814_CR19","doi-asserted-by":"publisher","unstructured":"Yang C, Zhao J, Wu B, Zhong H, Li Y, Xu Y (2017) Identification of a novel deletion mutation (c.1780delG) and a novel splice-site mutation (c.1412\u20131G>A) in the CCM1\/KRIT1 gene associated with familial cerebral cavernous malformation in the Chinese population. J Mol Neurosci 61:8\u201315.\u00a0https:\/\/doi.org\/10.1007\/s12031-016-0836-2","DOI":"10.1007\/s12031-016-0836-2"},{"key":"1814_CR20","doi-asserted-by":"publisher","unstructured":"Zabramski JM, Wascher TM, Spetzler RF, Johnson B, Golfinos J, Drayer BP, Brown B, Rigamonti D, Brown G (1994) The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:422\u2013432.\u00a0https:\/\/doi.org\/10.3171\/jns.1994.80.3.0422","DOI":"10.3171\/jns.1994.80.3.0422"},{"key":"1814_CR21","doi-asserted-by":"publisher","unstructured":"Zhao Y, Xie L, Li P, Song J, Qu T, Fan W, Chen H, Chen D, Lu D, Zhou L, Mao Y (2011) A novel CCM1 gene mutation causes cerebral cavernous malformation in a Chinese family. J Clin Neurosci 18:61\u201365.\u00a0https:\/\/doi.org\/10.1016\/j.jocn.2010.04.051","DOI":"10.1016\/j.jocn.2010.04.051"}],"container-title":["Journal of Molecular Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12031-021-01814-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12031-021-01814-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12031-021-01814-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T11:41:35Z","timestamp":1630928495000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12031-021-01814-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,2]]},"references-count":21,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["1814"],"URL":"https:\/\/doi.org\/10.1007\/s12031-021-01814-w","relation":{},"ISSN":["0895-8696","1559-1166"],"issn-type":[{"value":"0895-8696","type":"print"},{"value":"1559-1166","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,2]]},"assertion":[{"value":"2 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was performed in line with the principles of the Declaration of Helsinki and approved by the Local Ethics Committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}},{"value":"Written informed consent was obtained from all subjects enrolled in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Not applicable, our study does not include any personal information leading to the identification of any participants.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare that they have no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interests"}}]}}