C329X in KRIT1 is a founder mutation among CCM patients in Sardinia

Cau, Milena; Loi, Mario; Melis, Maurizio; Congiu, Rita; Loi, Alberto; Meloni, Chantal; Serrenti, Marianna; Addis, Maria; Melis, Maria Paola

doi:10.1016/j.ejmg.2009.05.002

Cited by 13 publications

(12 citation statements)

References 20 publications

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“…Twelve different germ‐line heterozygous mutations were identified in familial cases: six novels and six previously described (5, 6, 23, 29, 39). Nine mutations were exonic: c.268 C > T, c.413T > C, c.601C > T, c.987C > A, c.1204‐1208delAACAA, c.1254delA, c.1277‐1280delGAAT, c.1362‐1363delTC and c.1681‐1682delTA; of these eight leading to PTC through nucleotide substitution or small deletions, one was a nucleotide transition (c.413T > C) apparently leading to a missense mutation.…”

Section: Resultsmentioning

confidence: 99%

“…Comprehensive molecular screenings of these genes in CCM patients have led to the identification of more than 150 different mutations, which are characterized by an even distribution over the whole genes and a very low degree of redundancy among different families. An exception is the c.742T > C transition in CCM1 gene, the prevalent mutation in Hispano‐Mexican families (23); more recently, a founder effect in four Sardinia families was observed for the transversion c.987C > A in CCM1 gene, and the c .554del14 bp in CCM2 gene was found in 11 families from the Iberian Peninsula (5, 32).…”

Section: Introductionmentioning

confidence: 99%

“…To date, little is known about the Italian population: genetic analysis allowed identification in 12 unrelated Italian families with CCM, eight different heterozygous CCM1 mutations and one deletion in CCM2 (2, 5, 31).…”

Section: Introductionmentioning

confidence: 99%

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Mutation Analysis of CCM1, CCM2 and CCM3 Genes in a Cohort of Italian Patients with Cerebral Cavernous Malformation

D’Angelo

Marini²,

Rinaldi

et al. 2010

Brain Pathology

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Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities. CCMs can occur as sporadic or familial autosomal dominant form. Familial cases are associated with mutations in CCM1[K-Rev interaction trapped 1 (KRIT1)], CCM2 (MGC4607) and CCM3 (PDCD10) genes. In this study, a three-gene mutation screening was performed by direct exon sequencing, in a cohort of 95 Italian patients either sporadic or familial, as well as on their at-risk relatives. Sixteen mutations in 16 unrelated CCM patients were identified,nine mutations are novel: c.413T > C; c.601C > T; c.846 + 2T > G; c.1254delA; c.1255-4delGTA; c.1682-1683 delTA in CCM1; c.48A > G; c.82-83dupAG in CCM2; and c.395 + 1G > A in CCM3 genes [corrected].The samples, negative to direct exon sequencing, were investigated by MLPA to search for intragenic deletions or duplications. One deletion in CCM1 exon 18 was detected in a sporadic patient. Among familial cases 67% had a mutation in CCM1, 5.5% in CCM2, and 5.5% in CCM3, whereas in the remaining 22% no mutations were detected, suggesting the existence of either undetectable mutations or other CCM genes. This study represents the first extensive research program for a comprehensive molecular screening of the three known genes in an Italian cohort of CCM patients and their at-risk relatives.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutation Analysis of CCM1, CCM2 and CCM3 Genes in a Cohort of Italian Patients with Cerebral Cavernous Malformation

D’Angelo

Marini²,

Rinaldi

et al. 2010

Brain Pathology

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“…These mutations are highly stereotyped as premature stop codons. Surprisingly, our patient did not show the Sardinian C329X typical mutation [5], though we identified a first-ever described mutation: p.R140X (c.418C>T).…”

Section: Introductionmentioning

confidence: 81%

Cerebral Cavernous Malformations and Unilateral Moyamoya in a Patient with a New Mutation in the <b><i>KRIT-1</i></b>/CCM1 Gene

Melis

Cau²,

Corraine³

et al. 2014

Cerebrovasc Dis

Self Cite

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“…Here, we presented the largest molecular study in Italian patients with CCM and expanded the previously defined mutational spectrum of KRIT1, CCM2, and PDCD10 in our country (Battistini et al, 2007;Cau et al, 2009;Nannucci et al, 2009;Riant et al, 2013;Spiegler et al, 2014). We also explored the cellular effect of a novel PDCD10 large deletion, which associated with significant reduction of interactions between KRIT1 and CCM2, and impaired autophagy process.…”

Section: Discussionmentioning

confidence: 99%

A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

et al. 2018

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Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single-center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2%) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4-10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM.

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C329X in KRIT1 is a founder mutation among CCM patients in Sardinia

Cited by 13 publications

References 20 publications

Mutation Analysis of CCM1, CCM2 and CCM3 Genes in a Cohort of Italian Patients with Cerebral Cavernous Malformation

Mutation Analysis of CCM1, CCM2 and CCM3 Genes in a Cohort of Italian Patients with Cerebral Cavernous Malformation

Cerebral Cavernous Malformations and Unilateral Moyamoya in a Patient with a New Mutation in the <b><i>KRIT-1</i></b>/CCM1 Gene

A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

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