Alternative titles; symbols
HGNC Approved Gene Symbol: KRIT1
Cytogenetic location: 7q21.2 Genomic coordinates (GRCh38) : 7:92,198,969-92,246,100 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.2 | Cavernous malformations of CNS and retina | 116860 | Autosomal dominant | 3 |
| Cerebral cavernous malformations-1 | 116860 | Autosomal dominant | 3 | |
| Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations | 116860 | Autosomal dominant | 3 |
The CCM complex, which includes CCM1, CCM2 (607929), and CCM3 (PDCD10; 609118), is associated with cytoskeletal elements, signal transduction components, and cell junctions (Hogan et al., 2008).
In a 2-hybrid screen of a HeLa cell cDNA library designed to identify KREV1 (RAP1A; 179520) activity, Serebriiskii et al. (1997) isolated a novel cDNA, called KRIT1 for 'Krev interaction trapped-1.' The deduced 529-amino acid KRIT1 protein contains an N-terminal ankyrin repeat domain and a novel C-terminal domain required for association with KREV1. KRIT1 mRNA was expressed endogenously at low levels, with tissue-specific variation.
Laberge-Le Couteulx et al. (1999) detected a KRIT1 transcript of 5 to 6 kb in all tissues, although it was less abundant in brain, kidney, and lung. A 3.5-kb band was also observed in heart, skeletal muscle, and pancreas.
Sahoo et al. (2001) extended the N terminus of the KRIT1 protein by 207 amino acids. The deduced full-length 736-amino acid protein has a calculated molecular mass of about 81 kD.
Zhang et al. (2000) cloned mouse Krit1. The deduced 736-amino acid protein contains an ankyrin repeat, FERM motifs, and 2 potential nuclear localization signals.
Retta et al. (2004) identified Krit1b, a splice variant of mouse Krit1 that lacks exon 15. Compared with the full-length protein, which the authors called Krit1a, the deduced 697-amino acid Krit1b protein has a 39-amino acid deletion in a C-terminal region required for association with Rap1a. RT-PCR detected strongest Krit1b expression in thymus and brain and weaker expression in several other mouse tissues. KRIT1B was expressed at a low level in some human cell lines, but it was not detected in any adult or fetal human tissues examined.
Serebriiskii et al. (1997) found that KRIT1 interacted strongly with KREV1 but only weakly with Ras (see 190020), suggesting that KRIT1 might specifically regulate KREV1 activities.
By 2-hybrid analysis and coimmunoprecipitation, Zhang et al. (2001) found that full-length KRIT1 failed to interact with KREV1/RAP1A but showed strong interaction with integrin cytoplasmic domain-associated protein-1 (ICAP1; 607153). ICAP1 binds to an NPXY (asn-pro-X-tyr, where X is any amino acid) sequence motif in the cytoplasmic domain of beta-1 integrin (ITGB1; 135630) and participates in beta-1-mediated cell adhesion and migration. The novel N terminus of KRIT1 also contains an NPXY motif that was found to be required for ICAP1 interaction. Like ITGB1, KRIT1 interacted with the 200-amino acid isoform of ICAP1 (ICAP1-alpha), but not a 150-amino acid form that results from alternative splicing (ICAP1-beta). In a competition assay, induced expression of KRIT1 diminished the interaction between ICAP1A and ITGB1. The authors hypothesized that ITGB1 and KRIT1 may compete for the same site on ICAP1A, perhaps constituting a regulatory mechanism. Loss-of-function KRIT1 mutations, as observed in cerebral cavernous malformation-1 (CCM1; 116860), may shift the balance with predicted consequences for endothelial cell performance during ITGB1-dependent angiogenesis.
Zawistowski et al. (2002) confirmed the interaction of KRIT1 and ICAP1 using a yeast 2-hybrid screen. Mutagenesis of the N-terminal KRIT1 NPXY sequence completely abrogated the KRIT1-ICAP1 interaction. The authors hypothesized that KRIT1 may be involved in bidirectional signaling between integrin molecules and the cytoskeleton, and that KRIT1 may affect cell adhesion processes via integrin signaling in CCM1 pathogenesis.
To study the biologic functions of KRIT1, Gunel et al. (2002) investigated KRIT1 expression in endothelial cells with the use of specific anti-KRIT1 antibodies. By both microscopy and coimmunoprecipitation, they showed that KRIT1 colocalizes with microtubules. In interphase cells, KRIT1 was found along the length of microtubules. During metaphase, KRIT1 was located on spindle pole bodies and the mitotic spindle. During late phases of mitosis, KRIT1 localized in a pattern indicative of association with microtubule plus ends. In anaphase, the plus ends of the interpolar microtubules showed strong KRIT1 staining and, in late telophase, KRIT1 stained the midbody remnant most strongly; this is the site of cytokinesis where plus ends of microtubules from dividing cells overlap. These results established that KRIT1 is a microtubule-associated protein; its location at plus ends in mitosis suggested a possible role in microtubule targeting. These findings, coupled with evidence of interaction of KRIT1 with KREV1 and ICAP1A, suggested that KRIT1 may help determine endothelial cell shape and function in response to cell-cell and cell-matrix interactions by guiding cytoskeletal structure. Gunel et al. (2002) proposed that the loss of this targeting function leads to abnormal endothelial tube formation, thereby explaining the mechanism of formation of cerebral cavernous malformation lesions.
Hereditary hemorrhagic telangiectasia (see 187300) and cerebral cavernous malformations (see 116860) are disorders involving disruption of normal vascular morphogenesis. The autosomal dominant mode of inheritance in both of these disorders suggested to Marchuk et al. (2003) that their underlying genes might regulate critical aspects of vascular morphogenesis. The authors summarized the roles of these genes, KRIT1, endoglin (131195), and ALK1 (601284), in the genetic control of angiogenesis.
Zawistowski et al. (2005) used coimmunoprecipitation, fluorescence resonance energy transfer, and subcellular localization strategies to show that KRIT1 interacted with the CCM2 gene (607929) product, malcavernin. Analogous to the established interactions of KRIT1/ITGB1 and KRIT1/ICAP1, the KRIT1/CCM2 association was dependent upon phosphotyrosine-binding (PTB) domain of CCM2. A familial CCM2 L198R mutation (607929.0007) abrogated the KRIT1/CCM2 interaction, suggesting that loss of this interaction may be critical in CCM pathogenesis. CCM2 and ICAP1, when bound to KRIT1 via their respective PTB domains, differentially influenced KRIT1 subcellular localization. The authors expanded upon the established involvement of CCM2 in the p38 MAPK (600289) signaling module by demonstrating that KRIT1 associated with CCM2 and MEKK3 (602539) in a ternary complex. Zawistowski et al. (2005) proposed that the genetic heterogeneity observed in familial CCM may reflect mutation of different molecular members of a coordinated signaling complex.
Borikova et al. (2010) showed that knockdown of Ccm1, Ccm2, or Ccm3 in mouse embryonic endothelial cells induced RhoA (165390) overexpression and persistent RhoA activity at the cell edge, as well as in the cytoplasm and nucleus. RhoA activation was especially pronounced following Ccm1 knockdown. Knockdown of Ccm1, Ccm2, or Ccm3 inhibited formation of vessel-like tubes and invasion of extracellular matrix. Knockdown or inhibition of Rock2 (604002) countered these effects and was associated with inhibition of RhoA-stimulated phosphorylation of myosin light chain-2 (MLC2; see 160781). Borikova et al. (2010) concluded that the CCM protein complex regulates RhoA activation and cytoskeletal dynamics.
Maddaluno et al. (2013) demonstrated that endothelial-specific disruption of the KRIT1 gene in mice induces endothelial-to-mesenchymal transition, which contributes to the development of vascular malformations. Endothelial-to-mesenchymal transition in KRIT1-ablated endothelial cells is mediated by the upregulation of endogenous bone morphogenetic protein-6 (BMP6; 112266) that, in turn, activates the transforming growth factor-beta (TGF-beta; 190180) and BMP signaling pathway. Inhibitors of the TGF-beta and BMP pathway prevented endothelial-to-mesenchymal transition both in vitro and in vivo and reduced the number and size of vascular lesions in KRIT1-deficient mice. Thus, increased TGF-beta and BMP signaling, and the consequent endothelial-to-mesenchymal transition of KRIT1-null endothelial cells, are crucial events in the onset and progression of cerebral cavernous malformation disease.
Mleynek et al. (2014) used small interfering RNA to suppress CCM1 expression in human umbilical vein endothelial cells (HUVECs) and exposed the cells to laminar shear stress to simulate arterial shear. Unlike wildtype HUVECs, cells depleted of CCM1 failed to align with the direction of flow in the medium.
Laberge-Le Couteulx et al. (1999) identified 12 exons in the KRIT1 gene. Sahoo et al. (2001) determined that the KRIT1 gene has 19 exons, the first 3 of which are noncoding.
Serebriiskii et al. (1997) mapped the KRIT1 gene to 7q21-q22 by FISH. The authors noted that this region is frequently deleted or amplified in multiple forms of cancer.
Zhang et al. (2000) mapped the mouse Krit1 gene to a region of chromosome 5 that shares homology of synteny with human chromosome 7q21-q22.
In 12 of 20 pedigrees with cerebral cavernous malformations-1 (CCM1; 116860), Laberge-Le Couteulx et al. (1999) identified mutations in the CCM1 gene (see, e.g., 604214.0001) that segregated with the affected phenotype. Laberge-Le Couteulx et al. (1999) suggested that the mutations in the CCM1 gene might result in a dominant-negative effect or a loss of function; they favored the second hypothesis. Sporadic forms of cavernous angiomas manifest as unique lesions and familial forms as multiple lesions, which evokes a Knudson double-hit mechanism and would be consistent with the need for a complete loss of CCM1 function for the appearance of cavernous angiomas. All the mutations they reported predicted truncated CCM1 proteins completely or partially devoid of the putative RAP1A-interacting region. The data suggested the involvement of the RAP1A signal transduction pathway in vasculogenesis or angiogenesis.
Sahoo et al. (1999) observed that 7 different KRIT1 mutations had been identified in 23 distinct CCM1 families.
In 29 families and 5 sporadic cases with CCM, Davenport et al. (2001) identified 10 novel mutations and 1 previously described mutation in the KRIT1 gene (see, e.g., 604214.0008). The high frequency of loss-of-function mutations suggested loss of a tumor suppressor mechanism. In a follow-up study, Verlaan et al. (2002) reported 7 additional novel mutations and 1 previously described mutation in the KRIT1 gene in families with CCM. In combination with the previous study, Verlaan et al. (2002) found that approximately 47% of CCM families harbor KRIT1 mutations. The authors noted that the majority of mutations in the KRIT1 gene lead to a substantial alteration of the gene product, supporting a loss-of-function mechanism consistent with a tumor suppressor gene.
Sahoo et al. (2001) identified several novel frameshift mutations in the KRIT1 gene in patients with CCM1.
Cave-Riant et al. (2002) screened the KRIT1 gene in 121 unrelated CCM probands having at least 1 affected relative and/or showing multiple lesions on cerebral MRI. Fifty-two individuals (43%) were shown to have a KRIT1 mutation, and 42 distinct mutations were identified. Three-quarters of the mutations were located in the C-terminal half of the gene, primarily within exons 13, 15, and 17. All of them were predicted to result in premature stop codons. Cave-Riant et al. (2002) concluded that the underlying mechanism of CCM may be KRIT1 mRNA decay due to the presence of premature stop codons and KRIT1 haploinsufficiency.
Almost all KRIT1 mutations causing CCM lead to a premature stop codon, and severe impairment of KRIT1 protein functions is likely to be involved in the pathogenesis of the disorder. In 20 patients with CCM, Marini et al. (2004) failed to find loss of heterozygosity (LOH) in cavernous angiomas, validating the hypothesis that KRIT1 haploinsufficiency is the underlying mechanism of CCM.
Verlaan et al. (2004) identified a pathogenic mutation in the KRIT1 gene in 4 (29%) of 14 unrelated patients with sporadic CCM and multiple malformations. None of 21 unrelated sporadic patients with a single malformation had a KRIT1 mutation. Verlaan et al. (2004) concluded that genetic analysis is warranted in sporadic cases of CCM with multiple malformations. In 2 additional patients of the 14 sporadic CCM patients reported by Verlaan et al. (2004), Felbor et al. (2007) used multiplex ligation-dependent probe amplification to detect a large duplication and a large deletion, respectively, within the KRIT1 gene. Thus, 6 (42%) of the 14 sporadic patients had KRIT1 mutations.
Battistini et al. (2007) identified 5 different heterozygous KRIT1 mutations (see, e.g., 604214.0009) in affected individuals from 5 unrelated families with CCM1. The families included 33 mutation carriers, 57.6% of whom had no symptoms. Brain MRI revealed lesions in 82.3% of symptom-free mutation carriers.
Among 24 Italian families with CCM, Liquori et al. (2008) identified 5 with deletions in the CCM1 gene, including 1 complete deletion of the gene.
For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete localized loss of either KRIT1, CCM2/malcavernin, or PDCD10 (609118) protein expression depending on the respective inherited mutation. Cavernous but not adjacent normal or reactive endothelial cells of known germline mutation carriers displayed immunohistochemical negativity only for the corresponding CCM protein, but stained positively for the 2 other proteins. Immunohistochemical studies demonstrated endothelial cell mosaicism as neoangiogenic vessels within caverns from a CCM1 patient, normal brain endothelium from a CCM2 patient, and capillary endothelial cells of vessels in a revascularized thrombosed cavern from a CCM3 patient stained positively for KRIT1, CCM2/malcavernin, and PDCD10 respectively. Pagenstecher et al. (2009) suggested that complete lack of CCM protein in affected endothelial cells from CCM germline mutation carriers supports a 2-hit mechanism for CCM formation.
Through repeated cycles of amplification, subcloning, and sequencing of multiple clones per amplicon, Akers et al. (2009) identified somatic mutations that were otherwise invisible by direct sequencing of the bulk amplicon. Biallelic germline and somatic mutations were identified in CCM lesions from all 3 forms of inherited CCMs. The somatic mutations were found only in a subset of the endothelial cells lining the cavernous vessels and not in interstitial lesion cells. Although widely expressed in the different cell types of the brain, the authors also suggested a unique role for the CCM proteins in endothelial cell biology. Akers et al. (2009) suggested that CCM lesion genesis may require complete loss of function for 1 of the CCM genes.
Cau et al. (2009) identified 2 different mutations in the KRIT1 gene (see, e.g., C329X; 604214.0011) in 5 (71%) of 7 Sardinian families with CCM. Haplotype analysis of patients from 4 of the affected families indicated a founder effect for the C329X mutation.
Hogan et al. (2008) found that deletion of ccm1 in zebrafish caused dilation of embryonic vessels. Vascular dilation was associated with progressive spreading of endothelial cells and thinning of vessel walls. Determination of cell fate, cell number, and endothelial cell-cell contacts appeared normal. Ccm1 mutants, ccm2 mutants, and ccm1/ccm2 double mutants had indistinguishable vascular phenotypes, suggesting conservation of function.
Boulday et al. (2011) noted that deletion of Ccm1, Ccm2, or Ccm3 in mice is embryonic lethal. They generated mice with an endothelial-specific Ccm2 deletion at postnatal day 1, which resulted in vascular lesions mimicking human CCM lesions. Deletion of Ccm1 or Ccm3 at postnatal day 1 resulted in similar cerebellar and retinal lesions. Ccm2 lesion development was restricted to the venous bed. Boulday et al. (2011) concluded that the consequences of Ccm2 deletion depend on the developmental timing of the ablation and are associated with a developmental stage with intense angiogenesis.
By examining the initial stages of vascular lesion development in conditional Ccm1-knockout mice and in ccm1-morphant zebrafish, Mleynek et al. (2014) found that loss of Ccm1 resulted in vasculature that exhibited stereotypic hypersprouting prior to dilation. The authors observed that this sprouting behavior was similar to that seen in troponin T2 (TNNT2; 191045)-morphant zebrafish, which have a nonbeating heart and completely lack blood flow. Mleynek et al. (2014) hypothesized that CCM1 is required for endothelial cells to sense blood flow.
To study the requirement for endothelial TLR4 in spontaneous CCM formation, Tang et al. (2017) bred mice with floxed Tlr4 and Krit1 alleles using mice from the CCM-susceptible Krit1(ECKO) colony (endothelial-specific deletion of Krit1). Tang et al. (2017) observed that loss of a single endothelial Tlr4 allele resulted in an approximately 75% reduction in CCM lesion burden at postnatal day 10, whereas loss of both alleles resulted in virtually complete prevention of CCM lesion formation. Although less complete, global loss of Cd14, a soluble TLR4 coreceptor that binds lipopolysaccharide and facilitates TLR4 signaling, also prevented CCM formation in susceptible Krit1(ECKO) mice. Seven of 8 Krit1(ECKO) neonates who had been delivered and raised in a germ-free environment did not develop any CCM lesions. In contrast, all Krit1(ECKO) neonates who had been delivered in a germ-free environment but raised by conventional mothers exhibited robust CCM formation at postnatal day 10. Tang et al. (2017) found that CCM susceptibility associated with gram-negative bacteria, and that either Tlr4 blockade or altering the microbiome prevented CCM formation in susceptible mice. They concluded that while KRIT1 mutation predisposes to the formation of cerebral cavernous malformations, endothelial TLR4 and the microbiome drive their development.
In 3 probands with cerebral cavernous malformations-1 (CCM1; 116860), Laberge-Le Couteulx et al. (1999) found nonsense stop codons in the CCM1 gene, one of which was a C-to-T transition in nucleotide 1283.
In 5 probands with cerebral cavernous malformations-1 (CCM1; 116860), Laberge-Le Couteulx et al. (1999) found deletions causing frameshifts resulting in premature stop codons in CCM1 gene. One of these was a 1-bp deletion involving nucleotide 1342.
In 2 probands with cerebral cavernous malformations-1 (CCM1; 116860), Laberge-Le Couteulx et al. (1999) found, in the CCM1 gene, insertions leading to frameshift and premature termination, one of which was insertion of a cytosine after nucleotide 1271 in one pedigree.
In 16 of 21 Mexican American families with cerebral cavernous malformations (CCM1; 116860) analyzed, Sahoo et al. (1999) found that the KRIT1 gene harbored a 1-bp transition (742C-T), changing a gln to a premature termination codon (Q248X). Distinct mutations in KRIT1 were identified in other Mexican American families, as well as in non-Hispanic Caucasian families. The apparently high frequency of cerebral cavernous malformations in Mexican Americans had been noted by Rigamonti et al. (1988) and Kattapong et al. (1995). The finding of a common disease haplotype in affected kindreds from this population had suggested a founder effect.
Due to numbering differences, this mutation is also known as gln455 to ter (Q455X, rs267607203).
Eerola et al. (2000) reported 2 of 4 individuals in a family with inherited cerebral capillary malformations who also manifested hyperkeratotic cutaneous capillary-venous malformations (see 116860). The latter are distinguished by extension into dermis and hypodermis, and have hyperkeratosis of overlying skin. All 4 affected individuals were heterozygous for a 1-bp deletion of a G in exon 1 of the KRIT1 gene that resulted in a frameshift after amino acid 26 and a premature stop at codon 37.
Eerola et al. (2000) reported a 3-generation family with cerebral cavernous malformations (CCM1; 116860) in which affected members were heterozygous for a T-to-C transition in the splice donor site of intron 2 of the KRIT1 gene. RT-PCR analysis of lymphoblastoid cells from affected individuals yielded aberrant cDNA products from the mutant allele that lacked either exon 2 or both exons 2 and 3.
Lucas et al. (2001) investigated the possibility that de novo mutations in CCM1 cause cavernous angioma (116860). They described a patient with 2 cerebral malformations who carried a heterozygous 2-bp deletion (741delTC) in exon 6 of the CCM1 gene. The deletion initiated a frameshift that produced a TAA stop triplet 23 amino acids downstream, replacing a CAT triplet of histidine in exon 7 (H271X). MRI of the parents were normal, and neither parent carried the 741delTC mutation.
Verlaan et al. (2002) pointed out that all KRIT1 mutations causing cerebral cavernous malformations (CCM1; 116860) identified to that time, except for 2, asp137 to gly (D137G) and gln201 to glu (Q201E; 604214.0009), led to a truncated and presumably inactive protein. They reinvestigated these 2 cases, originally reported by Davenport et al. (2001) and Verlaan et al. (2002), and found that, in fact, both point mutations activated cryptic splice donor sites, causing aberrant splicing and leading to a frameshift and protein truncation. Thus, no simple missense mutation had been detected in KRIT1. In the family in which the change was interpreted as a D137G missense mutation, affected members were heterozygous for an A-to-G substitution in exon 7 at nucleotide position 410 of the coding sequence. The migration pattern of the cDNA showed that affected individuals had 2 different-sized alleles, whereas the unaffected individual was homozygous for the larger allele. Sequencing of the different cDNA alleles showed that alternative splicing had occurred in the mutated allele. The A-to-G shift created an alternative splice site, which, when used, resulted in premature splicing of exon 7 and in splicing of exon 8 at the correct position but in an incorrect reading frame. This resulted in a frameshift, leading to a truncated protein of 138 amino acids that had 2 novel amino acids and contained no structural domains of KRIT1.
The second case of apparent missense mutation causing cerebral cavernous malformations (CCM1; 116860), shown by Verlaan et al. (2002), in fact, to be an instance of splicing error, was found to have, in members of the family, heterozygosity for a C-to-G substitution in exon 8 at nucleotide position 601 of the coding sequence. As in the other case, affected individuals had 2 different-sized alleles, and sequencing of the different cDNA alleles showed alternative splicing resulting in premature splicing of exon 8 and splicing of exon 9 at the correct position but in an incorrect reading frame. This resulted in a frameshift, which was predicted to lead to a truncated protein of 201 amino acids that had a novel amino acid and contained only the NPXY motif.
Battistini et al. (2007) identified a heterozygous Q201E mutation in 3 members of an Italian family with CCM1. The proband developed seizures at age 20 years, whereas her affected mother, aged 79 years, and her daughter were symptom-free. However, brain MRI showed lesions in both the unaffected individuals.
In a family in which 5 individuals had both retinal and cerebral cavernous angiomas (see 116860), Laberge-Le Couteulx et al. (2002) identified a heterozygous insertion of cytosine after nucleotide 1374 in exon 10 of the KRIT1 gene, causing a frameshift that led to a premature stop codon.
In 7 affected individuals from 4 Sardinian families with cerebral cavernous malformations (CCM1; 116860), Cau et al. (2009) identified a heterozygous 987C-A transversion in exon 10 of the KRIT1 gene, resulting in a cys329-to-ter (C329X) substitution. Two asymptomatic individuals also carried the mutation. Haplotype analysis indicated a founder effect. Clinical features of those affected included seizures, headache, diplopia, and hearing loss.
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