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Identification of Krit1B: a novel alternative splicing isoform of cerebral cavernous malformation gene-1 Scarica

Cerebral cavernous malformations (CCM) are vascular malformations, mostly located in the central nervous system, which occur in 0.1–
0.5% of the population. They are characterized by abnormally enlarged and often leaking capillary cavities without intervening neural
parenchyma. Some are clinically silent, whereas others cause seizures, intracerebral haemorrhage or focal neurological deficits. These
vascular malformations can arise sporadically or may be inherited as an autosomal dominant condition with incomplete penetrance. At least
45% of families affected with cerebral cavernous malformations harbour a mutation in Krev interaction trapped-1 (Krit1) gene (cerebral
cavernous malformation gene-1, CCM1). This gene contains 16 coding exons which encode a 736-amino acid protein containing three
ankyrin repeats and a FERM domain. Neither the CCM1 pathogenetic mechanisms nor the function of the Krit1 protein are understood so far,
although several hypotheses have been inferred from the predicted consequences of Krit1 mutations as well as from the identification of Krit1
as a binding partner of Rap1A, ICAP1A and microtubules.
Here, we report the identification of Krit1B, a novel Krit1 isoform characterized by the alternative splicing of the 15th coding exon. We
show that the Krit1B splice isoform is widely expressed in mouse cell lines and tissues, whereas its expression is highly restricted in
human. In addition, we developed a real-time PCR strategy to accurately quantify the relative ratio of the two Krit1 alternative transcripts
in different tissues, demonstrating a Krit1B/Krit1A ratio up to 20% in mouse thymus, but significantly lower ratios in other tissues.
Bioinformatic analysis using exon/gene-prediction, comparative alignment and structure analysis programs supported the existence of Krit1
alternative transcripts lacking the 15th coding exon and showed that the splicing out of this exon occurs outside of potentially important
Krit1 structural domains but in a region required for association with Rap1A, suggesting a subtle, yet important effect on the protein
Our results indicate that maintenance of a proper ratio between Krit1A and Krit1B could be functionally relevant and suggest that the
novel Krit1B isoform might expand our understanding of the role of Krit1 in CCM1 pathogenesis.
D 2003 Elsevier B.V. All rights reserved.
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Inviato il
30 Sep 2012
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Autore del file:
Saverio Francesco Retta*, Maria Avolio, Floriana Francalanci, Simone Procida, Fiorella Balzac, Simon
Inviato il
27 Jun 2011
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