title: Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations.
abstract: Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations (CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance.
authors.affiliation: AP-HP, Groupe Hospitalier Saint Louis, Lariboisière, Fernand Widal, Laboratoire de Génétique, Paris, France; INSERM UMR-S740, Paris, France; Centre de référence pour les maladies rares des vaisseaux du cerveau et de l'œil (CERVCO), INSERM U740, CHU Lariboisière, APHP, Paris, France; Paris Sorbonne Cité, Université Paris Diderot, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Riant
authors.forename: S
authors.initials: S
authors.lastname: Odent
authors.forename: M
authors.initials: M
authors.lastname: Cecillon
authors.forename: L
authors.initials: L
authors.lastname: Pasquier
authors.forename: C
authors.initials: C
authors.lastname: de Baracé
authors.forename: M P
authors.initials: MP
authors.lastname: Carney
authors.forename: E
authors.initials: E
authors.lastname: Tournier-Lasserve
mesh_terms: D018076:DNA, Complementary; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics*; D006801:Humans; D007438:Introns; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins
keywords: CCM; KRIT1; cerebral cavernous malformations; deep intronic mutation