Dataset Information

An intron mutation in the ACVRL1 may be associated with a transcriptional regulation defect in a Chinese family with hereditary hemorrhagic telangiectasia.

ABSTRACT:

Purpose

To identify a novel pathogenic gene mutation present in a Chinese family with hereditary hemorrhagic telangiectasia (HHT) and to determine if an intron mutation may influence the transcriptional activity of the ACVRL1 gene.

Methods

HHT family members were ascertained following the presentation of proband and involved subjects. All family members (n?=?5) and 113 healthy individuals were genotyped for the variant in intron 6 c.772+27G>C of ACVRL1 gene. The genomic structure of ACVRL1 in affected HHT patients and healthy individuals was determined by long range PCR and sequencing. The expression of ACVRL1 mRNA and protein in patients with HHT was evaluated using real-time polymerase chain reaction and immunoblot analysis. Luciferase activity assay and electrophoretic mobility shift assay (EMSA) were performed to uncover the mechanism of intron-related transcriptional regulation.

Results

Only one novel mutation in intron 6 (c.772+27G>C) of ACVRL1 gene, no other mutation, abnormal splice, gross genomic deletion or rearrangement was found in this HHT2 family. Compared with healthy individuals, ACVRL1 mRNA and protein were significantly decreased in affected HHT2 individuals. Luciferase activity assay demonstrated that the transcriptional activity of the mutated ACVRL1 was significantly lower than that of the wild-type of intron 6; EMSA results showed that intron 6 c.772+27G>C mutation was able to inhibit the binding of transcriptional factor Sp1.

Conclusions

A novel intron mutation in ACVRL1 gene is associated with familial HHT2. The mechanisms may be involved in the down-regulation of ACVRL1 gene transcription.

SUBMITTER: Yu Q

PROVIDER: S-EPMC3584037 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

An intron mutation in the ACVRL1 may be associated with a transcriptional regulation defect in a Chinese family with hereditary hemorrhagic telangiectasia.

Yu Qian Q Shen Xiao-Hui XH Li Ying Y Li Rui-Juan RJ Li Ji J Luo Yun-Ya YY Liu Su-Fang SF Deng Ming-Yang MY Pei Min-Fei MF Zhang Guang-Sen GS

PloS one 20130227 2

<h4>Purpose</h4>To identify a novel pathogenic gene mutation present in a Chinese family with hereditary hemorrhagic telangiectasia (HHT) and to determine if an intron mutation may influence the transcriptional activity of the ACVRL1 gene.<h4>Methods</h4>HHT family members were ascertained following the presentation of proband and involved subjects. All family members (n = 5) and 113 healthy individuals were genotyped for the variant in intron 6 c.772+27G>C of ACVRL1 gene. The genomic structure ...[more]

PMID: 23460919

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Project description:BackgroundHereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs.MethodsWe selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs.ResultsThe proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383).ConclusionsIn this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.

Dataset Information

An intron mutation in the ACVRL1 may be associated with a transcriptional regulation defect in a Chinese family with hereditary hemorrhagic telangiectasia.

Purpose

Methods

Results

Conclusions

Publications

An intron mutation in the ACVRL1 may be associated with a transcriptional regulation defect in a Chinese family with hereditary hemorrhagic telangiectasia.

Similar Datasets

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