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.

TLDR
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.

Mutations in endoglin and in activin receptor‐like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia

TLDR
A denaturating gradient gel electrophoresis protocol for mutation scanning of the two loci of HHT proved to be very sensitive for mutation detection in both ENG and ALK1.

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

TLDR
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

TLDR
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.

Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles

TLDR
11 novel ENG mutations in HHT kindreds are described, which include missense and splice‐site mutations, which suggest that the nature of most ENG mutations is to create a null (nonfunctional) allele, and that there is no requirement for the synthesis of a truncated endoglin protein in the pathogenesis of HHT.

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

TLDR
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

TLDR
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.

Fine mapping of the hereditary haemorrhagic telangiectasia (HHT)3 locus on chromosome 5 excludes VE-Cadherin-2, Sprouty4 and other interval genes

TLDR
Informative genomic sequence variants were used to construct haplotypes permitting more precise citing of recombination breakpoints, and the HHT3 interval on chromosome 5 was reduced to 4.5 Mb excluding 30% of the coding genes in the original H HT3 interval.

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

TLDR
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.

TLDR
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.
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References

SHOWING 1-10 OF 35 REFERENCES

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

TLDR
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.

TLDR
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.

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

TLDR
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.

Genetic heterogeneity in hereditary haemorrhagic telangiectasia: possible correlation with clinical phenotype.

TLDR
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

TLDR
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.

TLDR
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?

TLDR
In families linked to ORW1 there is a prevalence of PAVMs among affected members of 29.2%, compared with 2.9% in families in which this locus has been excluded, and this information can be used to decide how to screen HHT patients forPAVMs.

Genetic heterogeneity in hereditary haemorrhagic telangiectasia.

TLDR
It is postulate that clinical heterogeneity may also be a feature of HHT with a significantly higher predisposition to symptomatic PAVMs associated with the HHT1 linked families.

Hereditary hemorrhagic telangiectasia.

TLDR
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.

The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals

TLDR
The results suggest that one in a hundred women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer.