A Locus for Cerebral Cavernous Malformations Maps to Chromosome 7q in Two Families

Marchuk, Douglas A.; Galllone, Carol J.; Morrison, Leslie; Clericuzio, Carol L.; Hart, Blaine L.; Kosofsky, Barry E.; Louis, David N.; Gusella, James F.; Davis, Larry E.; Prenger, Valerie L.

doi:10.1006/geno.1995.1147

Cited by 102 publications

(41 citation statements)

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“…There are two main HHT types, types 1 and 2, that are caused by mutations in endoglin (ENG) and ACVLR1 (ALK1) genes, respectively (McAllister et al, 1994;Johnson et al, 1996). In approximately 2% of all patients with HHT, the origin of the disease is a mutation in the MADH4 gene, which codes for Smad4 coactivator, leading to the combined syndrome of Juvenile Polyposis and HHT (Marchuk et al, 1995). A common property of all of these genes is that they code for proteins involved in the TGF-␤1 signaling pathway, critical for the proper development of the blood vessels.…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

Albiñana¹,

Sanz-Rodrı́guez²,

Recio-Poveda³

et al. 2011

Mol Pharmacol

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Hereditary hemorrhagic telangiectasia (HHT), or Rendu-OslerWeber syndrome, is an autosomal-dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations in internal organs. Patients show severe epistaxis, and/or gastrointestinal bleeding, both of which notably interfere with their quality of life. There are two predominant types of HHT caused by mutations in endoglin (ENG) and ACVRL1/activin receptor-like kinase 1 (ALK1) genes, named HHT1 and HHT2, respectively. ENG and ALK1 code for proteins involved in the transforming growth factor (TGF)-␤1 signaling pathway, and it is widely accepted that HHT pathogenicity results from haploinsufficiency. No cure for HHT has been found, so identification of drugs able to increase the expression of these genes is essential when proposing new therapies. We report the efficacy of tacrolimus (FK506) in increasing ENG and ALK1 expression. The rationale comes from a case report of a patient with HHT who received a liver transplantation after hepatic failure due to a liver arteriovenous malformation. The liver was transplanted, and the immunosuppressor FK506 was used to prevent the rejection. After the first month of FK506 treatment, the internal and external telangiectases, epistaxes, and anemia disappeared. Here, we find that the immunosuppressor FK506 increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells and enhances the TGF-␤1/ALK1 signaling pathway and endothelial cell functions like tubulogenesis and migration. These results suggest that the mechanism of action of FK506 involves a partial correction of endoglin and ALK1 haploinsufficiency and may therefore be an interesting drug for use in patients with HHT who undergo transplantation.

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Section: Introductionmentioning

confidence: 99%

Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

Albiñana¹,

Sanz-Rodrı́guez²,

Recio-Poveda³

et al. 2011

Mol Pharmacol

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“…Familial forms of CCM are inherited in an autosomal dominant fashion, with three known loci on chromosomes 7q21.2 (CCM1 [MIM# 116860]) (Dubovsky, et al, 1995;Günel, et al, 1995;Marchuk, et al, 1995), 7p13 (CCM2 [MIM# 603284]) (Craig, et al, 1998), and 3q25.2-q27 (CCM3 [MIM# 603285]) (Craig, et al, 1998). Based on the linkage of 20 families, Craig et al (Craig, et al, 1998) reported that CCM1 would account for 40% of all familial CCM cases, CCM2 would account for 20%, and CCM3 would account for 40%.…”

Section: Introductionmentioning

confidence: 99%

Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus

et al. 2005

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Cerebral cavernous malformations (CCMs) are vascular abnormalities of the brain that can result in a variety of neurological disabilities, including stroke and seizures. Linkage analyses using autosomal dominant families manifesting CCMs have identified three different causative loci on chromosomes 7q21.2 (CCM1), 7p13 (CCM2), and 3q25.2-q27 (CCM3). Mutations in the gene Krit1 are responsible for CCM1, mutations in the gene MGC4607 are responsible for CCM2, and mutations in the gene PDCD10 were recently reported to be responsible for CCM3. We report here that sequence analysis of PDCD10 in a panel of 29 probands lacking Krit1 and MGC4607 mutations revealed only three mutations. The frequency of identified mutations in the PDCD10 gene was surprisingly low, especially given that this panel was heavily biased towards non-CCM1, non-CCM2 probands. These data are in stark contrast with the linkage data, which suggests that 40% of inherited cases would be due to mutations in this gene. Interestingly, when examining the haplotypes of previously published CCM3 families, we found a distinct recombination event in one of the largest CCM3 families that excludes the PDCD10 gene. Although there are many potential explanations for this observation, when combined with the apparent underrepresentation of causative CCM mutations in PDCD10, this recombination event in a CCM3-linked family suggests that there may be an additional CCM gene in the same chromosomal region.

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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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A Locus for Cerebral Cavernous Malformations Maps to Chromosome 7q in Two Families

Cited by 102 publications

References 0 publications

Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus

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

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