Disease relevance of KRIT1

• Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas [1].
• Mutations in Krev1 interaction trapped gene 1 (KRIT1) cause cerebral cavernous malformation, an autosomal dominant disease featuring malformation of cerebral capillaries resulting in cerebral hemorrhage, strokes, and seizures [2].
• In cases of Prader-Willi syndrome (PWS), a total of 24 patients with PWS, as well as 205 control individuals from the general population, were analyzed by use of multiplex quantitative PCR to amplify the FGFR2 gene, the KRIT1 gene, and the SNRPN gene simultaneously [3].
• The authors present the proband, in an affected family with a previously reported KRIT1 mutation, in whom vertebral hemangiomas in addition to cerebral and cutaneous lesions were found [4].
• Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits [5].

Psychiatry related information on KRIT1

• Surgical decision-making on cerebral cavernous malformations [6].

High impact information on KRIT1

• A strong founder effect was observed in the Hispano-American population, all families being linked to CCM1 on 7q (refs 4,7) [1].
• We identified a total of 15 deletions: 1 in the CCM1 gene, 0 in the CCM3 gene, and 14 in the CCM2 gene [7].
• Three CCM loci have been mapped, and loss-of-function mutations were identified in the KRIT1 (CCM1) and MGC4607 (CCM2) genes [8].
• Its implication in cerebral cavernous malformations strongly suggests that it is a new player in vascular morphogenesis and/or remodeling [8].
• Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations [5].

Biological context of KRIT1

• As the function of the KRIT1 protein and its role in CCM pathogenesis remain unknown, we performed yeast two-hybrid screens to identify additional protein binding partners [9].
• These data also raise the possibility that KRIT1 plays a part in the formation of endothelial cell junctions and expression of a mature vascular phenotype [10].
• BLAST analysis revealed that conceptual translation of a fragment of human genomic DNA upstream of the 5' end of the reported KRIT1 coding sequence predicts extension of the human open reading frame by 207 codons with 95% amino acid identity between the novel putative human and murine amino termini [11].
• Altogether these data suggest that KRIT1 mRNA decay due to the presence of premature stop codons and Krit1 haploinsufficiency may be the underlying mechanism of CCM [12].
• Our finding suggests a SNX17 involvement in the indicated KRIT1 function in cell adhesion processes by integrin signaling [13].

Anatomical context of KRIT1

• Loss-of-function KRIT1 mutations, as observed in CCM1, would shift the balance with predicted consequences for endothelial cell performance during integrin beta1-dependent angiogenesis [14].
• The interaction between ICAP-1 and KRIT1, and the presence of a FERM domain in the latter, suggest that KRIT1 might be involved in the bidirectional signaling between integrin molecules and the cytoskeleton [9].
• OBJECTIVE: Mutations in KRIT1 cause familial cerebral cavernous malformation, an autosomal dominant disorder affecting primarily the central nervous system vasculature [15].
• KRIT1 antibody fails to stain fenestrated capillaries in the kidney, the liver, or the red pulp of the spleen, where endothelial cells do not to adhere to one another [15].
• RESULTS: Immunostaining demonstrates that although KRIT1 is expressed in a broad variety of human organs, it localizes to the vascular endothelium of each, specifically to capillaries and arterioles [15].

Associations of KRIT1 with chemical compounds

• MGC4607, similar to the KRIT1 binding partner ICAP1alpha, encodes a protein with a phosphotyrosine-binding domain [5].
• Sorting nexin 17, a non-self-assembling and a PtdIns(3)P high class affinity protein, interacts with the cerebral cavernous malformation related protein KRIT1 [13].
• RESULTS: Analysis of the KRIT1 gene revealed a point mutation in exon 6 that predicts the substitution of a premature termination codon for glutamine at codon 248 in all four Hispanic-American families, confirming previous findings [16].
• Results: Genetic evaluation of CCM1/KRIT1 revealed a single guanine-to-cytosine transversion in the invariant splice acceptor consensus sequence of intron 8 (c.1146-1G-->C), which is predicted to result in abnormal protein splicing [17].
• Expression profiling-based identification of CO2-responsive genes regulated by CCM1 controlling a carbon-concentrating mechanism in Chlamydomonas reinhardtii [18].

Physical interactions of KRIT1

• Like beta1 integrin, krit1 interacts with the 200 amino acid isoform of icap1 (icap1alpha), but not a 150 amino acid form that results from alternative splicing (icap1beta) [14].
• Krit1 interacted strongly with Krev-1 but only weakly with Ras, suggesting it might specifically regulate Krev-1 activities [19].

Regulatory relationships of KRIT1

• Small interfering RNA-mediated depletion of KRIT-1 blocked the ability of Rap1 to stabilize endothelial junctions associated with increased actin stress fibers [20].

Other interactions of KRIT1

• Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations [8].
• The novel N-terminus of krit1 contains a NPXY motif that it is required for icap1 interaction [14].
• Using a genomic sequence-based positional cloning strategy, we have identified KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor suppressor, as the CCM1 gene [21].
• Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22 [19].
• OBJECTIVE: Cerebral cavernous malformations (CCMs) are focal dysmorphic blood vessel anomalies predisposing individuals to hemorrhagic stroke and epilepsy [22].

Analytical, diagnostic and therapeutic context of KRIT1

• We then investigated CCM2 protein expression in cerebral and extracerebral tissues by Western blot analysis as well as immunohistochemistry and compared these results with CCM1 (KRIT1) protein expression [23].
• METHODS: We used Western blotting and immunohistochemistry with specific KRIT1 polyclonal antibodies to investigate KRIT1 protein expression in diverse cerebral and extracerebral tissues [15].
• The expression pattern of KRIT1 was analyzed by Northern blotting [16].
• METHODS: In the present study, we screened five families with dominantly inherited CCM for CCM1 gene mutations with denaturing high performance liquid chromatography (DHPLC) [24].
• We report here that sequence analysis of PDCD10 in a panel of 29 probands lacking Krit1 and MGC4607 mutations revealed only three mutations [25].

References