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

Human Mutation
Grazia NardellaCarmela Fusco

Abstract

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 highlig...Continue Reading

References

Mar 27, 2002·Neurology·D J VerlaanG A Rouleau
Feb 17, 2007·Lancet Neurology·Pierre LabaugeElisabeth Tournier-Lasserve
Jul 31, 2007·Nature Medicine·Elisabeth M ZeisbergRaghu Kalluri
Sep 29, 2007·Journal of Proteome Research·Thomas L HilderChristine C Wu
Oct 24, 2007·The Journal of Cell Biology·Angela GladingMark H Ginsberg
Nov 11, 2008·Experimental Cell Research·Floriana FrancalanciSaverio Francesco Retta
Feb 3, 2009·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Serena NannucciLeonardo Pantoni
May 21, 2009·European Journal of Medical Genetics·Milena CauMaria Antonietta Melis
Jul 10, 2010·Proceedings of the National Academy of Sciences of the United States of America·Joycelyn WüstehubeAndreas Fischer
Aug 3, 2010·Nature Methods·Jana Marie SchwarzDominik Seelow
Jun 3, 2011·Molecular Biology of the Cell·Jian J LiuMark H Ginsberg
Jul 5, 2011·Acta Neurochirurgica. Supplement·Helen KimWilliam L Young
Aug 11, 2011·European Journal of Human Genetics : EJHG·Remco A HaasdijkHenricus J Duckers
Mar 19, 2013·Briefings in Bioinformatics·Stefano Castellana, Tommaso Mazza
Dec 18, 2013·The International Journal of Biochemistry & Cell Biology·Juyeon Hwang, David C Pallas
Jan 25, 2014·American Journal of Medical Genetics. Part a·Orazio PalumboTeresa Mattina
Feb 1, 2014·Journal of Cell Science·Kyle M DraheimDavid A Calderwood
Oct 17, 2014·The Journal of Biological Chemistry·Peter V DiStefanoAngela J Glading
Apr 1, 2015·The Journal of Cell Biology·Kyle M DraheimDavid A Calderwood
Sep 30, 2015·EMBO Molecular Medicine·Saverio MarchiPaolo Pinton
Feb 16, 2016·Oncogene·Z ShiZ Zhou
Oct 30, 2016·American Journal of Medical Genetics. Part a·Ivo J H M de VosMaurice A M van Steensel

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Citations

Dec 12, 2019·Frontiers in Neurology·Christiane D MuchMatthias Rath
Mar 3, 2020·Frontiers in Neurology·Lipeng YangJing Zhang
Apr 7, 2020·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Jing LinWenli Sheng
Sep 3, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Concetta ScimoneAntonina Sidoti
Feb 20, 2021·Clinical Genetics·Carmela FuscoMarco Castori

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