Identification and characterization of novel elastin gene mutations in eleven families with supravalvular aortic stenosis

Abstract

Background: Supravalvular aortic stenosis (SVAS) is a rare congenital heart disease affecting approximately 1 in 25,000 live births. In some patients it is accompanied by pulmonary artery stenosis, particularly of pulmonary artery branches. Chronic stenosis can lead to cardiac hypertrophy and even circulatory failure. Familial autosomal dominant SVAS is frequently associated with elastin (ELN) gene mutations, whereas Williams-Beuren syndrome is a complex developmental disorder caused by heterozygous microdeletions of 26–28 genes at 7q11.23, including ELN.Methods: Whole-exome sequencing was performed in 42 individuals from 11 Chinese families with SVAS to identify the pathogenic gene mutations involved. Aortic tissue was obtained for histological analyses, and quantitative reverse-transcription-PCR and western blotting were used to verify the expression of elastin molecules.Results: Five point mutations and six frameshift mutations in the ELN gene were detected in the peripheral blood of all investigated families. Nine were nonsense mutations that result in premature stop codons, and the other two were missense mutations. All variants were heterozygous. Nine of the variants were novel, and have not been included in databases or previously reported. One mutation occurred in individuals from two different families. Reduced elastin protein expression was evident in patients’ aortic tissue.Conclusions: The novel mutations of ELN were found to be pathogenic, which confirmed by reduced elastin expression and leads to SVAS. Thus, detailed cardiac testing and genetic counseling are warranted for patients and asymptomatic individuals with these mutations.

Gene Eln: Aspectos Genéticos E Sua Relação Com Patologias Cardiovasculares

“…As mutações que implicam na dosagem da elastina são responsáveis pela EAS. Mais especificamente, 43 mutações já listadas, abrangendo substituições em regiões regulatórias, rearranjos, splicing, além de inserção e deleção de nucleotídeos, são responsáveis pela alteração na dosagem da 20 proteína que ocasiona a EAS (ZHOU et al, 2022).…”

Subvalvular Aortic Stenosis: Learning From Human and Canine Clinical Research

“…Meanwhile, a genome-wide DNA methylation analysis found that changes in the methylation patterns at the CpG sites of APOA5 (apolipoprotein A5) and PCSK9 (proprotein convertase subtilisin/ kexin type 9) are also associated with valvular aortic stenosis. Conversely, supravalvular aortic stenosis is characterized as an autosomal dominant disease with loss-of-function intragenic mutations or deletions in the ELN (elastin) gene, which result in premature stop codons and/or splicing inefficiency [109][110][111][112][113][114][115]. Williams syndrome (or Williams-Beuren syndrome), a complex of conditions that is comprised of supravalvular aortic stenosis and multiple other diseases, is associated with an approximately 1.5 Mb deletion, which includes the 7q11.23 deletion of ELN and contiguous genes in a region of the genome referred to as the WBSCR (Williams-Beuren syndrome critical region) [109][110][111][112][113][114][115].…”

“…Conversely, supravalvular aortic stenosis is characterized as an autosomal dominant disease with loss-of-function intragenic mutations or deletions in the ELN (elastin) gene, which result in premature stop codons and/or splicing inefficiency [109][110][111][112][113][114][115]. Williams syndrome (or Williams-Beuren syndrome), a complex of conditions that is comprised of supravalvular aortic stenosis and multiple other diseases, is associated with an approximately 1.5 Mb deletion, which includes the 7q11.23 deletion of ELN and contiguous genes in a region of the genome referred to as the WBSCR (Williams-Beuren syndrome critical region) [109][110][111][112][113][114][115]. While the aforementioned data serve as a partial blueprint for future SAS-focused genomic explorations, the absence of a definitive genetic etiology of SAS in humans only serves to further highlight the importance of determining the definitive genetic etiology in the canine model of SAS.…”

Vascular abnormalities in heart and brain are associated with cardiovascular and neurological symptoms in a novel mouse model for Williams syndrome

“…Patients with mutations restricted to the ELN gene can show similar cardiovascular abnormalities, but without the distinctive facial features observed in Williams syndrome (Tassabehji et al, 1999; Urbán et al, 2000; Terashita et al, 2019; Zhou et al, 2022), suggesting that ELN hemizygosity is the most important determinant for vascular abnormalities in Williams syndrome. ELN encodes tropoelastin that is mainly produced by vascular smooth muscle cells (Belknap et al, 1996).…”