Mutations in the activin receptor–like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2

@article{Johnson1996MutationsIT,
  title={Mutations in the activin receptor–like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2},
  author={D. W. Johnson and Jonathan Berg and Marjorie A. Baldwin and Carol J. Gallione and Ivonne Marondel and S.-j. Yoon and Timothy T. Stenzel and Marcy C. Speer and Margaret A. Pericak-Vance and Austin G. Diamond and Alan Guttmacher and Charles E. Jackson and Liliana Attisano and Raju Kucherlapati and Mary E.M. Porteous and Douglas A. Marchuk},
  journal={Nature Genetics},
  year={1996},
  volume={13},
  pages={189-195}
}
Hereditary haemorrhagic telangiectasia, or Osler–Rendu–Weber (ORW) syndrome, is an autosomal dominant vascular dysplasia. So far, two loci have been demonstrated for ORW. Linkage studies established an ORW locus at chromosome 9q3; endoglin was subsequently identified as the ORW1 gene. A second locus, designated ORW2, was mapped to chromosome 12. Here we report a new 4 cM interval for ORW2 that does not overlap with any previously defined. A 1.38–Mb YAC contig spans the entire interval. It… 

The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.

The high rate of detection of mutations by genomic sequencing of ALK-1 suggests that this will be a useful diagnostic test for HHT2, particularly where preliminary linkage to chromosome 12q13 can be established.

Three novel mutations in the activin receptor-like kinase 1 (ALK-1) gene in hereditary hemorrhagic telangiectasia type 2 in Brazilian patients

The high rate of mutation detection and the small size of the ALK-1 gene make genomic sequencing a viable diagnostic test for HHT2, and data indicate that loss-of-function mutations in a single allele of theALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity.

A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5

It is concluded that classical HHT with pulmonary involvement can result from mutations in an unidentified gene on chromosome 5, which should further illuminate HHT pathogenic mechanisms in which aberrant transforming growth factor (TGF)-β signalling is implicated.

Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients

The genetic and molecular heterogeneity found in the HHT population in the Netherlands is reported here on, with mutations detected were deletions, insertions, nonsense, missense and splice site mutations.

Novel missense and frameshift mutations in the activin receptor‐like kinase‐1 gene in hereditary hemorrhagic telangiectasia

The combined data suggest that both severe and subtle changes in the ALK‐1 amino acid sequence can lead to receptor dysfunction and result in the HHT disease phenotype.

A novel endoglin mutation in hereditary hemorrhagic telangiectasia type 1: a case report.

A novel mutation in the ENG gene in a Chinese family suggested that a truncated ENG protein may cause HHT, and a genetic test was established to confirm the clinical diagnosis in individuals and provide an opportunity for early detection and management of the disease.

Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.

A transient association between these two proteins of the TGF-beta superfamily, both required at a critical level to ensure vessel wall integrity are suggested.

Mutation analysis of a family with hereditary hemorrhagic telangiectasia associated with hepatic arteriovenous malformation.

A Taiwanese HHT family with hepatic arteriovenous malformation with mutated ALK-1 gene is described, and this investigation successfully used linkage and sequencing techniques to perform molecular diagnosis of HHT.

Mutation analysis of "Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique

The genotype-phenotype correlation was consistent with a higher frequency of pulmonary arteriovenous malformations in patients with ENG mutations than in Patients with ACVRL1 mutations in the collective.

Two common endoglin mutations in families with hereditary hemorrhagic telangiectasia in the Netherlands Antilles: evidence for a founder effect

It appears that HHT in the Netherlands Antilles is due to a limited number of ancestral mutations in the endoglin gene, and that one of these mutations was introduced into the African slave population by a Dutch colonist.
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References

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A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33–34

This work has mapped the HHT gene, by linkage analysis, to markers on 9q33–34 in two large multi–generation families and provides a starting point for the eventual cloning of the gene.

A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q.

This linkage study has analysed DNA from two families, in which HHT was unlinked to chromosome 9q and 3p, and PAVMs were absent, with a series of genetic markers on the centromeric region of chromosome 12.

A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12.

A map location for a second ORW locus is established that exhibits a significantly reduced incidence of pulmonary involvement and lies in an 11-CM interval between D 12S345 and D12S339, in the pericentromeric region of chromosome 12.

Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1

Endoglin is identified as the HHT gene mapping to 9q3 and HHT is established as the first human disease defined by a mutation in a member of the TGF-β receptor complex.

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Although six of the seven families clearly meet the clinical criteria for HHT diagnosis, a significant absence of pulmonary arteriovenous malformations is seen in all three 9q3 unlinked families, suggesting genetic heterogeneity of HHT and its potential correlation with a clinical phenotype may have a significant impact on the clinical management and treatment of H HT patients.

A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3

It is concluded that HHT is a genetically heterogeneous disorder and based on its map location (9q3) and expression in vascular tissues, type V collagen is a possible candidate gene for HHT.

Linkage of hereditary haemorrhagic telangiectasia to chromosome 9q34 and evidence for locus heterogeneity.

It is concluded that HHT is a genetically heterogeneous disorder and the results indicate that the presence of PAVM may be more common in patients with a chromosome 9 linked form of HHT than in Patients with the non-linked form.

Clinical heterogeneity in hereditary haemorrhagic telangiectasia: are pulmonary arteriovenous malformations more common in families linked to endoglin?

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Hereditary hemorrhagic telangiectasia is now considered to be more common than previously thought and the associated brain and pulmonary lesions are sources of substantial morbidity and mortality.