Elastin: genomic structure and point mutations in patients with supravalvular aortic stenosis

Tassabehji, Mayada; Metcalfe, Kay; Donnai, Dian; Hurst, Jane A.; Reardon, William; Burch, Michael; Read, Andrew P.

doi:10.1093/hmg/6.7.1029

Cited by 141 publications

(117 citation statements)

References 17 publications

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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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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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“…We initially screened for ELN gene mutations using single-strand conformation polymorphism (SSCP) analysis (Orita et al, 1989). Each of the 34 exons of the ELN gene was amplified using intronic primers as previously described by Tassabehji et al (1997) and the PCR products separated by overnight electrophoreses on non-denaturing 10% (w/v) polyacrylamide gels (49:1 acrylamide:N, N' bisacrylamide) at 4°C and a constant 550 V, the products being detected by silver staining. Whenever an abnormal banding pattern was observed the relevant exon was directly sequenced using an ABI Prism 377 sequencer (Perkin Elmer).…”

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confidence: 99%

Elastin (ELN) gene point mutation in patients with inguinal hernia

2006

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Groin hernias emerge at the myopectineal orifice of Fruchaud which is closed off by the fascia transversalis. Our previous studies showed structural and quantitative changes of the fascia transversalis elastic fibers of inguinal hernia patients and elderly people. The present study used single-strand conformation polymorphism (SSCP) elastin (analysis to investigate the 34 exons of the ELN gene of 49 inguinal hernia patients (7 females, 42 males aged 58.7 ± 19.82 years) and 75 non-herniated controls (35 females, 40 males aged 46.2 ± 14.32 years). We found that 47 patients and 24 controls had an abnormal exon 20 pattern caused by a g28197A > G missense mutation leading to an S422G amino acid substitution in the elastin hydrophobic domain. The g28197A > G allele frequency was 0.71 ± 0.045 in hernia patients and 0.21 ± 0.030 in controls and 23 patients and 7 controls were g28197A > G homozygous and 24 patients and 17 controls were heterozygous. This point-mutation showed a statistically significant association with inguinal hernia, chi-squared being 46.89 (p < 0.001) and the odds ratio 49.93 (95% confidence interval of @11 to 223). These results indicate that the g28197A > G mutation is involved in the genesis of inguinal hernia (possibly due to abnormal elastic fiber production) and explains impaired fascia transversalis function. Key words: fascia transversalis, extracellular matrix, elastic fibers, elastin gene, inguinal hernia. All groin hernias emerge at the myopectineal orifice of Fruchaud which is closed off by the fascia transversalis, a connective tissue composed of a framework of elastic and collagen fibers, which supports the abdominal tension forces.The elastic fibers are composed of microfibrils and elastin and are responsible for the resilience of the fascia transversalis. Research by our group has shown age-related structural changes (breaching and wrapping) in the elastic fibers, with ultrastructural studies showing a large decrease in the quantity of microfibril component ( Rodrigues Jr. et al., 1990;Quintas et al., 2000). Some studies have shown reduced amounts of collagen in the fascia transversalis of patients with direct inguinal hernia compared to those with indirect hernia, suggesting that the development of some hernias might be influenced by disturbances in collagen metabolism (Pans et al., 2001;Rodrigues Jr et al., 2002). Taken together, these results indicate that there is a loss of tensile resistance and elasticity in the fascia transversalis tissue which may explain the high incidence of inguinal hernia after the fifth decade of life.Mutations in the elastin (ELN) gene may be responsible for disorders of the elastic fiber system because they have been observed in cases of supravalvular aortic stenosis and autosomal dominant cutis laxa, individuals with either of these conditions may show smooth and soft skin, hernias, gastrointestinal diverticula and genital prolapse (Ewart et al., 1994;Li et al., 1997;Meng et al., 1998;Tassabehji et al., 1998). These reports and our previous st...

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“…These studies have however not resulted in an unequivocal gene-phenotype correlation. 18 Another is the study of carriers of balanced translocations and a WBS-like phenotype. Balanced translocations are rare causes of monogenic disorders but have guided the cloning of the disease-causing gene in several instances.…”

Section: Discussionmentioning

confidence: 99%

“…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: genomic structure and point mutations in patients with supravalvular aortic stenosis

Cited by 141 publications

References 17 publications

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

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

Elastin (ELN) gene point mutation in patients with inguinal hernia

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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