Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas

Laberge, Sophie; Jung, Hojin; Labauge, Pierre; Houtteville, J P; Lescoat, Christelle; Cécillon, Michaelle; Maréchal, Emmanuelle; Joutel, Anne; Bach, Jean‐François; Tournier‐Lasserve, Elisabeth

doi:10.1038/13815

Cited by 430 publications

(71 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Hereditary forms of cerebral CMs are caused by mutations in one of three genes, KRIT1 ( CCM1 ), CCM2 ( MGC4607 ), and PDCD10 ( CCM3 ), that may have a role in the genesis of vascular endothelial cells. Their critical importance to lesion development is underlined by the observation that at least one of the CCM genes is mutated in most familial CMs [10-12]. The association of Poland syndrome with multiple CMs described in our patient offers support to the vascular theory as the underlying mechanism for this pathological entity, but pointing to a genetic rather than a mechanistic origin of the proposed vascular disruption.…”

Section: Introductionsupporting

confidence: 57%

Multiple cavernous malformations presenting in a patient with Poland syndrome: A case report

Lizárraga

Salles

2011

J Med Case Reports

View full text Add to dashboard Cite

IntroductionPoland syndrome is a congenital disorder related to chest and hand anomalies on one side of the body. Its etiology remains unclear, with an ipsilateral vascular alteration (of unknown origin) to the subclavian artery in early embryogenesis being the currently accepted theory. Cavernous malformations are vascular hamartomas, which have been linked to a genetic etiology, particularly in familial cases, which commonly present with multiple lesions. Our case report is the first to describe multiple cavernous malformations associated with Poland syndrome, further supporting the vascular etiology theory, but pointing to a genetic rather than a mechanistic factor disrupting blood flow in the corresponding vessels.Case presentationA 41-year-old Caucasian man with Poland syndrome on the right side of his body presented to our hospital with a secondary generalized seizure and was found to have multiple cavernous malformations distributed in his brain, cerebellum, and brain stem, with a predominance of lesions in the left hemisphere.ConclusionThe distribution of cavernous malformations in the left hemisphere and the right-sided Poland syndrome in our patient could not be explained by a mechanistic disruption of one of the subclavian arteries. A genetic alteration, as in familial cavernous malformations, would be a more appropriate etiologic diagnosis of Poland syndrome in our patient. Further genetic and pathological studies of the involved blood vessels in patients with Poland syndrome could lead to a better understanding of the disease.

show abstract

Section: Introductionsupporting

confidence: 57%

Multiple cavernous malformations presenting in a patient with Poland syndrome: A case report

Lizárraga

Salles

2011

J Med Case Reports

View full text Add to dashboard Cite

show abstract

“…The Heg-CCM pathway is so-named because mutations in the human CCM1 and CCM2 genes cause vascular anomalies called cerebral cavernous malformations (CCMs) (Denier et al, 2004, Laberge-le Couteulx et al, 1999, Liquori et al, 2003 and Sahoo et al, 1999). CCMs, which affect approximately 0.5% of the population, are malformations of the brain vasculature characterized by an expanded endothelial vessel that can result in headache, seizure, hemorrhage and death (Revencu and Vikkula, 2006).…”

Section: Introductionmentioning

confidence: 99%

ccm2-like is required for cardiovascular development as a novel component of the Heg-CCM pathway

Rosen

Sogah

et al. 2013

Developmental Biology

View full text Add to dashboard Cite

The Heart of Glass-Cerebral Cavernous Malformation (Heg-CCM) pathway is essential for normal cardiovascular development in zebrafish and mouse. In zebrafish, the Heg-CCM pathway mutants santa(ccm1/san), valentine (ccm2/vtn), and heart of glass (heg) exhibit severely dilated hearts and inflow tracts and a complete absence of blood circulation. We identified a novel gene based on its sequence identity with ccm2, which we have named ccm2-like (ccm2l), and characterized its role in cardiovascular development. Disruption of ccm2l by morpholino injection causes dilation of the atrium and inflow tract and compromised blood circulation. Morpholino co-injection experiments identify ccm2l as an enhancer of the characteristic Heg-CCM dilated heart phenotype, and we find that ccm2 overexpression can partially rescue ccm2l morphant defects. Finally, we show that Ccm2l binds Ccm1 and perform deletion and mutational analyses to define the regions of Ccm1 that mediate its binding to Ccm2l and its previously established interactors Ccm2 and Heg. These genetic and biochemical data argue that ccm2l is a necessary component of the Heg-CCM pathway.

show abstract

“…Translation of such mRNAs may result in proteins prone to malfunction and deleterious effects on cells234. To mitigate these errors, cells have developed quality-control processes to monitor translating mRNAs and detect aberrant mRNAs, such as those with premature polyA tails within their CDS.…”

mentioning

confidence: 99%

The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs

et al. 2017

View full text Add to dashboard Cite

Cryptic polyadenylation within coding sequences (CDS) triggers ribosome-associated quality control (RQC), followed by degradation of the aberrant mRNA and polypeptide, ribosome disassembly and recycling. Although ribosomal subunit dissociation and nascent peptide degradation are well-understood, the molecular sensors of aberrant mRNAs and their mechanism of action remain unknown. We studied the Zinc Finger Protein 598 (ZNF598) using PAR-CLIP and revealed that it cross-links to tRNAs, mRNAs and rRNAs, thereby placing the protein on translating ribosomes. Cross-linked reads originating from AAA-decoding tRNALys(UUU) were 10-fold enriched over its cellular abundance, and poly-lysine encoded by poly(AAA) induced RQC in a ZNF598-dependent manner. Encounter with translated polyA segments by ZNF598 triggered ubiquitination of several ribosomal proteins, requiring the E2 ubiquitin ligase UBE2D3 to initiate RQC. Considering that human CDS are devoid of >4 consecutive AAA codons, sensing of prematurely placed polyA tails by a specialized RNA-binding protein is a novel nucleic-acid-based surveillance mechanism of RQC.

show abstract

Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas

Cited by 430 publications

References 17 publications

Multiple cavernous malformations presenting in a patient with Poland syndrome: A case report

Multiple cavernous malformations presenting in a patient with Poland syndrome: A case report

ccm2-like is required for cardiovascular development as a novel component of the Heg-CCM pathway

The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs

Contact Info

Product

Resources

About