Elastin: mutational spectrum in supravalvular aortic stenosis

Metcalfe, Kay; Rucka, A; Smoot, Leslie; Hofstadler, Guenter; Tuzler, Gerald; McKeown, Pascal; Siu, Victoria Mok; Rauch, Anita; Dean, John; Dennis, N R; Ellis, Ian; Reardon, William; Cytrynbaum, Cheryl; Osborne, Lucy R.; Yates, John R.; Read, Andrew P.; Donnai, Dian; Tassabehji, Mayada

doi:10.1038/sj.ejhg.5200564

Cited by 150 publications

(126 citation statements)

References 20 publications

(27 reference statements)

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“…Intriguingly, previous studies have shown a clustering of ELN mutation in exon 20. 1,5,9 The mutation identified here expands the number of nucleotide variations identified in this putative hot spot mutation region. c.838_839insG was present in two siblings diagnosed with isolated SVAS.…”

Section: Mutational Analysismentioning

confidence: 71%

“…1 SVAS may occur as a sporadic disease or it may be inherited in an autosomal dominant manner. It is also classically associated with the Williams-Beuren syndrome (WBS) (OMIM 194050), a complex developmental disorder caused by a microdeletion of B1.5 Mb of chromosome 7q11.23, which encompasses at least 25 genes, including the ELN gene.…”

Section: Introductionmentioning

confidence: 99%

“…Among the point mutations described, there is a prevalence of premature termination mutations that result in null alleles through the nonsense-mediated mRNA decay (NMD) mechanism leading to functional elastin haploinsufficiency. 1,4 Here, by using DHPLC and directed sequencing of genomic DNA, we identified seven novel ELN mutations in a screening of a total of 31 patients mainly affected with familial (13) and sporadic (18) nonsyndromic SVAS, associated in a few cases with other clinical features ( Table 1). Functional assay and expression analysis using minigenes and real-time quantitative PCR (QPCR) showed that two selected frameshift mutant alleles are substrates of NMD, confirming that the haploinsufficiency of the ELN gene is the main pathomechanism underlying nonsyndromic SVAS.…”

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis

et al. 2009

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Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta, which can occur sporadically as an autosomal dominant condition or as one component of the Williams-Beuren syndrome, a complex developmental genomic disorder associated with cardiovascular, neurobehavioral, craniofacial, and metabolic abnormalities, caused by a microdeletion at 7q11.23. We report the identification of seven novel mutations within the elastin gene in 31 familial and sporadic cases of nonsyndromic SVAS. Five are frameshift mutations within the coding region of the ELN gene that result in premature stop codons (PTCs); the other two mutations abolish the donor splice site of introns 3 and 28, respectively, and are predicted to alter splicing efficiency resulting in the generation of a PTC within the same introns of the gene. In vitro analysis using minigenes and cycloheximide showed that some selected frameshift mutant alleles are substrates of nonsense-mediated mRNA decay (NMD), confirming that the functional haploinsufficiency of the ELN gene is the main pathomechanism underlying SVAS. Interestingly, molecular analysis on patient fibroblasts showed that the c.2044+5G4C mutant allele encodes for an aberrant shorter form of the elastin polypeptide that may hamper the normal assembly of elastin fibers in a dominant-negative manner.

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Section: Mutational Analysismentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis

et al. 2009

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“…59). Point mutations of the elastin gene (ELN) have been identified in numerous cases with supravalvular aortic stenosis, but none of the additional, characteristic WBS features was present in these individuals (Refs 60,61,62 Mouse models of WBS-In an attempt to understand more about the function of each of the genes from the WBS commonly deleted region, investigators have utilised mouse models. Several knock-out models have been generated and characterised, and some have semi-dominant phenotypes that suggest the gene may be haploinsufficient in WBS (Refs 75, 76, 77).…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

Rearrangements of the Williams–Beuren syndrome locus: molecular basis and implications for speech and language development

Osborne

Mervis

2007

Expert Rev. Mol. Med.

128

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The Williams-Beuren syndrome (WBS) locus on human chromosome 7q11.23 is flanked by complex chromosome-specific low-copy repeats that mediate recurrent genomic rearrangements of the region. Common genomic rearrangements arise through unequal meiotic recombination and result in complex but distinct behavioural and cognitive phenotypes. Deletion of 7q11.23 results in WBS, which is characterised by mild to moderate intellectual disability or learning difficulties, with relative cognitive strengths in verbal short-term memory and in language and extreme weakness in visuospatial construction, as well as anxiety, attention-deficit hyperactivity disorder and overfriendliness. By contrast, duplication results in severely delayed speech and expressive language, with relative strength in visuospatial construction. Although deletion and duplication of the WBS region have very different effects, both cause forms of language impairment and suggest that dosage-sensitive genes within the region are important for the proper development of human speech and language. The spectrum and frequency of genomic rearrangements at 7q11.23 presents an exceptional opportunity to identify gene(s) directly involved in human speech and language development.Although childhood disorders of cognition, language and behaviour are extremely common (WHO: http://www.who.int/en/), causative genes have remained particularly refractory to traditional genetic approaches since the disorders themselves are often sporadic in nature and their causes complex and both genetically and environmentally heterogeneous. Genomic disorders, caused by the gain, loss or inversion of specific chromosome regions, are often characterised by neurodevelopmental phenotypes and present a unique opportunity to identify genes and pathways that are necessary for proper brain development and function (Ref. 1).One such region that is prone to genomic rearrangement is the Williams-Beuren syndrome (WBS) locus at chromosome 7q11.23. This 1.5 million base pair region has been shown to commonly undergo deletion, duplication or inversion through unequal meiotic recombination between highly similar flanking segments of DNA (Refs 2,3,4 CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptthe region is not associated with any clinical features, but can predispose the chromosome to subsequent unequal recombination during the next round of meiosis. The inversion is estimated to be present at a frequency of 1 in 20, but there is a fivefold increase in carrier frequency in the parents of children with the WBS deletion (Refs 3,5). Deletion and duplication of 7q11.23 result in distinct patterns of cognitive impairment, both of which impact on language and speech abilities, albeit in very different ways (Refs 4, 6, 7). The WBS deletion has an estimated frequency of between 1 in 7500 and 1 in 20 000 (Refs 8, 9). As a result of the mechanism of genomic rearrangement, duplication should occur at a similar frequency; however, owing to its very recent discovery, the population fre...

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“…No other of the WBS features is seen in patients with isolated ELN deficiency. 18,19 The identification of individuals with smaller deletions and other aberrations may contribute to elucidate the pathogenesis of WBS and help to understand which of the genes in the common WBS deletion are dosage sensitive and contribute to particular features of the phenotype. 3 Here we report a family with a cytogenetically balanced translocation t(7;16)(q11.23;q13).…”

Section: Introductionmentioning

confidence: 99%

The elastin gene is disrupted in a family with a balanced translocation t(7;16)(q11.23;q13) associated with a variable expression of the Williams-Beuren syndrome

et al. 2002

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The Williams-Beuren syndrome (WBS) is a complex developmental disorder with multisystemic manifestations including supravalvular aortic stenosis (SVAS), a so-called elfin face, a hoarse voice, and a specific cognitive phenotype. Most WBS patients have a 41 Mb deletion on one of their chromosomes 7 in q11 but except for elastin, whose haploinsufficiency causes the cardiovascular malformations, it is unknown which genes in the deletion area contribute to the phenotype. We have investigated a family with a cytogenetically balanced translocation t(7;16)(q11.23;q13) in which affected individuals manifested a broad spectrum of clinical phenotypes ranging from a hoarse voice as the only feature to the full WBS phenotype. Molecular cytogenetic and DNA sequence analyses of the translocation breakpoint showed that the cytogenetic rearrangement disrupts the elastin gene locus within intron 5 in the exact same manner in all translocation carriers. The recently described large inversion of the 7q11.23 region was not present in this family. Our data demonstrate that disruption of the elastin gene by a translocation breakpoint may cause classical WBS, atypical WBS, SVAS, or no recognisable phenotype, and provide a clear example for extensive phenotypic variability associated with a position effect in humans.

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Elastin: mutational spectrum in supravalvular aortic stenosis

Abstract: Supravalvular aortic stenosis (SVAS) is

Cited by 150 publications

References 20 publications

Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis

Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis

Rearrangements of the Williams–Beuren syndrome locus: molecular basis and implications for speech and language development

The elastin gene is disrupted in a family with a balanced translocation t(7;16)(q11.23;q13) associated with a variable expression of the Williams-Beuren syndrome

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