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Copy number variations in endoglin locus: mapping of large deletions in Spanish families with hereditary hemorrhagic telangiectasia type 1.

Fontalba A, Fernández-Luna JL, Zarrabeitia R, Recio-Poveda L, Albiñana V, Ojeda-Fernández ML, Bernabéu C, Alcaraz LA, Botella LM - BMC Med. Genet. (2013)

Bottom Line: The array was designed to cover the ENG gene and surrounding areas.Interestingly, common breakpoints coincident with Alu repetitive sequences were found among these families.The systematic hybridization of DNA from HHT families, with deletions or duplications, to custom designed microarrays, could allow the mapping of breakpoints, coincident with repetitive Alu sequences that might act as "hot spots" in the development of chromosomal anomalies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. cibluisa@cib.csic.es.

ABSTRACT

Background: The hereditary hemorrhagic telangiectasia syndrome (HHT), also known as the Rendu-Osler-Weber syndrome is a multiorganic vascular disorder inherited as an autosomal dominant trait. Diagnostic clinical criteria include: epistaxis, telangiectases in mucocutaneous and gastrointestinal sites, arteriovenous malformations (AVMs) most commonly found in pulmonary, hepatic and cerebral circulations, and familial inheritance. HHT is transmitted in 90% of the cases as an autosomal dominant condition due to mutations in either endoglin (ENG), or activin receptor-like kinase 1 (ACVRL1/ALK1) genes (HHT type 1 and 2, respectively).

Methods: We have carried out a genetic analysis of four independent Spanish families with HHT clinical criteria, which has permitted the identification of new large deletions in ENG. These mutations were first detected using the MLPA technique and subsequently, the deletion breakpoints were mapped using a customized copy number variation (CNV) microarray. The array was designed to cover the ENG gene and surrounding areas.

Results: All tested families carried large deletions ranging from 3-kb to 100-kb, involving the ENG gene promoter, several ENG exons, and the two downstream genes FGSH and CDK9. Interestingly, common breakpoints coincident with Alu repetitive sequences were found among these families.

Conclusions: The systematic hybridization of DNA from HHT families, with deletions or duplications, to custom designed microarrays, could allow the mapping of breakpoints, coincident with repetitive Alu sequences that might act as "hot spots" in the development of chromosomal anomalies.

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Related in: MedlinePlus

Schematic representation of the hybridization results of the different HHT1 families containing deletions in chromosome 9q34.11. In 198, a 3,139-Kb deletion encompassing promoter and exon 1 of ENG; in 71: a 28,744-Kb deletion including promoter and exons 1 to 3 of ENG. In GUM a 100,730 Kb deletion covering from the proximal promoter of ENG, the whole ENG gene, and FPGS, CDK9, SH2D3C genes. In NMEx, a 9,313-Kb deletion of ENG promoter. Arrows mark the direction of transcription of the genes.
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Figure 3: Schematic representation of the hybridization results of the different HHT1 families containing deletions in chromosome 9q34.11. In 198, a 3,139-Kb deletion encompassing promoter and exon 1 of ENG; in 71: a 28,744-Kb deletion including promoter and exons 1 to 3 of ENG. In GUM a 100,730 Kb deletion covering from the proximal promoter of ENG, the whole ENG gene, and FPGS, CDK9, SH2D3C genes. In NMEx, a 9,313-Kb deletion of ENG promoter. Arrows mark the direction of transcription of the genes.

Mentions: A schematic representation of the final deletion map, for each family, and the genes affected is shown in Figure 3.


Copy number variations in endoglin locus: mapping of large deletions in Spanish families with hereditary hemorrhagic telangiectasia type 1.

Fontalba A, Fernández-Luna JL, Zarrabeitia R, Recio-Poveda L, Albiñana V, Ojeda-Fernández ML, Bernabéu C, Alcaraz LA, Botella LM - BMC Med. Genet. (2013)

Schematic representation of the hybridization results of the different HHT1 families containing deletions in chromosome 9q34.11. In 198, a 3,139-Kb deletion encompassing promoter and exon 1 of ENG; in 71: a 28,744-Kb deletion including promoter and exons 1 to 3 of ENG. In GUM a 100,730 Kb deletion covering from the proximal promoter of ENG, the whole ENG gene, and FPGS, CDK9, SH2D3C genes. In NMEx, a 9,313-Kb deletion of ENG promoter. Arrows mark the direction of transcription of the genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222255&req=5

Figure 3: Schematic representation of the hybridization results of the different HHT1 families containing deletions in chromosome 9q34.11. In 198, a 3,139-Kb deletion encompassing promoter and exon 1 of ENG; in 71: a 28,744-Kb deletion including promoter and exons 1 to 3 of ENG. In GUM a 100,730 Kb deletion covering from the proximal promoter of ENG, the whole ENG gene, and FPGS, CDK9, SH2D3C genes. In NMEx, a 9,313-Kb deletion of ENG promoter. Arrows mark the direction of transcription of the genes.
Mentions: A schematic representation of the final deletion map, for each family, and the genes affected is shown in Figure 3.

Bottom Line: The array was designed to cover the ENG gene and surrounding areas.Interestingly, common breakpoints coincident with Alu repetitive sequences were found among these families.The systematic hybridization of DNA from HHT families, with deletions or duplications, to custom designed microarrays, could allow the mapping of breakpoints, coincident with repetitive Alu sequences that might act as "hot spots" in the development of chromosomal anomalies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. cibluisa@cib.csic.es.

ABSTRACT

Background: The hereditary hemorrhagic telangiectasia syndrome (HHT), also known as the Rendu-Osler-Weber syndrome is a multiorganic vascular disorder inherited as an autosomal dominant trait. Diagnostic clinical criteria include: epistaxis, telangiectases in mucocutaneous and gastrointestinal sites, arteriovenous malformations (AVMs) most commonly found in pulmonary, hepatic and cerebral circulations, and familial inheritance. HHT is transmitted in 90% of the cases as an autosomal dominant condition due to mutations in either endoglin (ENG), or activin receptor-like kinase 1 (ACVRL1/ALK1) genes (HHT type 1 and 2, respectively).

Methods: We have carried out a genetic analysis of four independent Spanish families with HHT clinical criteria, which has permitted the identification of new large deletions in ENG. These mutations were first detected using the MLPA technique and subsequently, the deletion breakpoints were mapped using a customized copy number variation (CNV) microarray. The array was designed to cover the ENG gene and surrounding areas.

Results: All tested families carried large deletions ranging from 3-kb to 100-kb, involving the ENG gene promoter, several ENG exons, and the two downstream genes FGSH and CDK9. Interestingly, common breakpoints coincident with Alu repetitive sequences were found among these families.

Conclusions: The systematic hybridization of DNA from HHT families, with deletions or duplications, to custom designed microarrays, could allow the mapping of breakpoints, coincident with repetitive Alu sequences that might act as "hot spots" in the development of chromosomal anomalies.

Show MeSH
Related in: MedlinePlus