Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig.

Johnson, Eric W.; Iyer, Leslie M.; Rich, Stephen S.; Orr, Harry T.; Gil‐Nagel, Antonio; Kurth, Janice H.; Zabramski, Joseph M.; Marchuk, Douglas A.; Weissenbach, Jean; Clericuzio, Carol L.

doi:10.1101/gr.5.4.368

Cited by 75 publications

(40 citation statements)

References 36 publications

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“…Genetic analysis of kindreds with familial CCM has mapped three autosomal dominant loci causing this disease. CCM1 is located at 7q21 (17)(18)(19)(20)(21), CCM2 at 7p13-15 (18), and CCM3 at 3q25-27 (18). Apparent loss of function mutations in KRIT1 (Krev1 interaction trapped gene 1) have recently been shown to be the cause of disease mapping to CCM1 (22)(23)(24)(25)(26)(27); the genes underlying CCM2 and CCM3 have not yet been identified.…”

mentioning

confidence: 99%

KRIT1 , a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein

Günel

Laurans

Shin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

111

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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. The biological functions of KRIT1 are unknown. We have investigated KRIT1 expression in endothelial cells by using specific anti-KRIT1 antibodies. By both microscopy and coimmunoprecipitation, we show that KRIT1 colocalizes with microtubules. In interphase cells, KRIT1 is found along the length of microtubules. During metaphase, KRIT1 is located on spindle pole bodies and the mitotic spindle. During late phases of mitosis, KRIT1 localizes in a pattern indicative of association with microtubule plus ends. In anaphase, the plus ends of the interpolar microtubules show strong KRIT1 staining and, in late telophase, KRIT1 stains the midbody remnant most strongly; this is the site of cytokinesis where plus ends of microtubules from dividing cells overlap. These results establish that KRIT1 is a microtubule-associated protein; its location at plus ends in mitosis suggests a possible role in microtubule targeting. These findings, coupled with evidence of interaction of KRIT1 with Krev1 and integrin cytoplasmic domain-associated protein-1 alpha (ICAP1 ␣), suggest that KRIT1 may help determine endothelial cell shape and function in response to cell-cell and cell-matrix interactions by guiding cytoskeletal structure. We propose that the loss of this targeting function leads to abnormal endothelial tube formation, thereby explaining the mechanism of formation of cerebral cavernous malformation (CCM) lesions. C erebral cavernous malformation (CCM) is a disease affecting brain vasculature. Characteristic lesions affect capillaries and have grossly dilated vascular channels lined by only a single layer of endothelium without normal vessel wall elements such as smooth muscle or intervening neural parenchyma (1). The nature of these lesions suggests an abnormality in normal development of these capillaries; however, the mechanism of their occurrence and an explanation for their focal nature have remained elusive.The aberrant channels in CCM lesions are fragile, commonly resulting in intracranial hemorrhage. Clinical signs and symptoms are largely determined by the size and location of the hemorrhage, and range from incidental findings on MRI (Fig. 1) to rare catastrophic cerebral hemorrhage resulting in death. The disease has been recognized as a common clinical entity because of the advent of MRI (2). Both MRI and autopsy studies suggest a prevalence of cavernous malformation up to 0.5%, although only 20-30% of affected individuals develop symptomatic disease (3-8).Symptomatic patients typically present in the third through the fifth decades of life (3) with headaches, seizures, or focal neurological deficits. Treatment ranges from therapy with anti-epileptic drugs in patients with seizures, to surgical excision of accessible lesions in patients who suffer from hemorrhage or intractable seizures (9-13).Si...

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mentioning

confidence: 99%

KRIT1 , a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein

Günel

Laurans

Shin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Cox, unpubl.). Together, these maps provide a highly integrated framework for constructing an extensive transcript map, which in turn would benefit efforts to identify genes associated with genetic disorders mapping to chromosome 7, such as WilliamsBeuren syndrome (Ewart et al 1993), cerebral cavernous malformations (Dubovsky et al 1995;Gunel et al 1995;Johnson et al 1995;Marchuk et al 1995), Saethre-Chotzen syndrome (Lewanda et al 1994;Rose et al 1994), two forms of retinitis pigmentosa (Inglehearn et al 1993(Inglehearn et al , 1994Jordan et al 1993;McGuire et al 1996), syndromic and nonsyndromic forms of hearing loss (Baldwin et al 1995;Van Camp et al 1995;Coyle et al 1996;Sheffield et al 1996), and several others. To date, only 212 genes (Genome Database, September 1996) have been assigned to chromosome 7, and even fewer to more precise subchromosomal locations.…”

mentioning

confidence: 99%

2006 expressed-sequence tags derived from human chromosome 7-enriched cDNA libraries.

Touchman¹,

Bouffard²,

Weintraub³

et al. 1997

Genome Res.

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The establishment and mapping of gene-specific DNA sequences greatly complement the ongoing efforts to map and sequence all human chromosomes. To facilitate our studies of human chromosome 7, we have generated and analyzed 2006 expressed-sequence tags (ESTs) derived from a collection of direct selection cDNA libraries that are highly enriched for human chromosome 7 gene sequences. Similarity searches indicate that approximately two-thirds of the ESTs are not represented by sequences in the public databases, including those in dbEST. In addition, a large fraction (68%) of the ESTs do not have redundant or overlapping sequences within our collection. Human DNA-specific sequence-tagged sites (STSs) have been developed from 190 of the ESTs. Remarkably, 180 (96%) of these STSs map to chromosome 7, demonstrating the robustness of chromosome enrichment in constructing the direct selection cDNA libraries. Thus far, 140 of these EST-specific STSs have been assigned unequivocally to YAC contigs that are distributed across the chromosome. Together, these studies provide > 2000 ESTs highly enriched for chromosome 7 gene sequences, 180 new chromosome 7 STSs corresponding to ESTs, and a definitive demonstration of the ability to enrich for chromosome-specific cDNAs by direct selection. Furthermore, the libraries, sequence data, and mapping information will contribute to the construction of a chromosome 7 transcript map.

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“…This genetic mapping was further confirmed in a large number of HispanoAmerican families and a strong founder effect was observed in that ethnic group. [3][4][5][6][7] The size of the genetic interval likely to contain CCM1 was reduced to 4 cM, between markers D7S2410 and D7S689. 5 Only eight non Hispano-American families have been analysed so far.…”

Section: Introductionmentioning

confidence: 99%

“…[3][4][5][6][7] The size of the genetic interval likely to contain CCM1 was reduced to 4 cM, between markers D7S2410 and D7S689. 5 Only eight non Hispano-American families have been analysed so far. 4,5,[8][9][10] Two of them were not linked to CCM1, establishing the genetic heterogeneity of this condition.…”

Section: Introductionmentioning

confidence: 99%

“…5 Only eight non Hispano-American families have been analysed so far. 4,5,[8][9][10] Two of them were not linked to CCM1, establishing the genetic heterogeneity of this condition. 9 We report linkage data on 36 French Caucasian CCM families using a panel of eight polymorphic microsatellite markers mapping within the D7S2410-D7S689 interval.…”

Section: Introductionmentioning

confidence: 99%

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Genetic heterogeneity and absence of founder effect in a series of 36 French cerebral cavernous angiomas families

et al. 1999

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Cerebral cavernous angiomas malformations (CCM) can be inherited as an autosomal dominant condition. CCM1, a yet unidentified gene mapping on 7q21-q22, was shown to be involved in all CCM Hispano-American families, with a strong founder effect. Genetic heterogeneity in non Hispano-American families was established in two families.We conducted a genetic linkage analysis on 36 French CCM families using eight microsatellite markers mapping within the CCM1 interval. Admixture analysis showed that 65% of these families were linked to the CCM1 locus. Haplotypes analysis of CCM1-linked families did not show any evidence for a strong founder effect.

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Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig.

Cited by 75 publications

References 36 publications

KRIT1 , a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein

KRIT1 , a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein

2006 expressed-sequence tags derived from human chromosome 7-enriched cDNA libraries.

Genetic heterogeneity and absence of founder effect in a series of 36 French cerebral cavernous angiomas families

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