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A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations.

Publication ,  Journal Article
Gallione, CJ; Solatycki, A; Awad, IA; Weber, JL; Marchuk, DA
Published in: Genet Med
July 2011

PURPOSE: Cerebral cavernous malformations can occur sporadically or are caused by mutations in one of three identified genes. Cerebral cavernous malformations often remain clinically silent until a mutation carrier suffers a stroke or seizure. Presymptomatic genetic testing has been valuable to follow and manage cerebral cavernous malformation mutation carriers. During routine diagnostic testing, we identified a two base pair change in seven unrelated people of Ashkenazi Jewish heritage. Because of the location of the variant beyond the invariant splice donor sequence, the change was reported as a variant of unknown significance. In this study, we determined whether this change was a disease-causing mutation and whether it represents a founder mutation in the Ashkenazi Jewish population. METHODS: Transcripts arising from the normal and mutant alleles were examined by reverse transcription-polymerase chain reaction from affected and unaffected Ashkenazi Jewish cerebral cavernous malformation family members. A synthetic splicing system using a chimeric exon was used to visualize the effects of the change on splice donor site utilization. RESULTS: The two base pair change in CCM2, c.30 + 5_6delinsTT, segregated with affected status in the study families. Reverse transcription-polymerase chain reaction revealed loss of the transcript allele that was in phase with the mutation. The two base pair change, when tested in an in vitro synthetic splicing system, altered splice donor site utilization. Resequencing of the genomic region proximal and distal to the CCM2 gene mutation revealed a common single-nucleotide polymorphism haplotype in affected individuals. CONCLUSIONS: The two base pair change in CCM2, c.30 + 5_6delinsTT, disrupted proper splice donor utilization leading to a degraded transcript. Single nucleotide polymorphism haplotype analysis demonstrated that this mutation was due to a founder in the Ashkenazi Jewish population. These data have the potential to simplify genetic testing for cerebral cavernous malformation in the Ashkenazi Jewish population.

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Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

July 2011

Volume

13

Issue

7

Start / End Page

662 / 666

Location

United States

Related Subject Headings

  • RNA Splicing
  • Polymorphism, Single Nucleotide
  • Pedigree
  • Mutation
  • Male
  • Jews
  • Humans
  • Haplotypes
  • Genetics & Heredity
  • Genetic Predisposition to Disease
 

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Gallione, C. J., Solatycki, A., Awad, I. A., Weber, J. L., & Marchuk, D. A. (2011). A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations. Genet Med, 13(7), 662–666. https://doi.org/10.1097/GIM.0b013e318211ff8b
Gallione, Carol J., Ann Solatycki, Issam A. Awad, James L. Weber, and Douglas A. Marchuk. “A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations.Genet Med 13, no. 7 (July 2011): 662–66. https://doi.org/10.1097/GIM.0b013e318211ff8b.
Gallione, Carol J., et al. “A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations.Genet Med, vol. 13, no. 7, July 2011, pp. 662–66. Pubmed, doi:10.1097/GIM.0b013e318211ff8b.

Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

July 2011

Volume

13

Issue

7

Start / End Page

662 / 666

Location

United States

Related Subject Headings

  • RNA Splicing
  • Polymorphism, Single Nucleotide
  • Pedigree
  • Mutation
  • Male
  • Jews
  • Humans
  • Haplotypes
  • Genetics & Heredity
  • Genetic Predisposition to Disease