Phenotype of the Williams-Beuren syndrome associated with hemizygosity at the elastin locus

Kotzot, Dieter; Bernasconi, F.; Brecevic, Lukrecija; Robinson, Wendy P.; Kiss, P; Kosztolányi, György; Lurie, Iosif W.; Superti‐Furga, Andrea; Schinzel, Albert

doi:10.1007/bf02029360

Cited by 50 publications

(18 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Histological examination of the skin in cutis laxa often reveals marked fragmentation or diminution of elastic fibers (6,17,32). This is a considerably different phenotype than that found in SVAS, a pathology arising from elastin mutations that lead to functional hemizygosity (15,16,23,34,35). Skin fibroblast cultures from many cutis laxa patients exhibit reduced ELN mRNA levels or tropoelastin production, but fibroblasts from other affected individuals exhibit normal levels of elastin production with abnormal elastic fiber morphology (17,36).…”

Section: Discussionmentioning

confidence: 99%

Cutis Laxa Arising from Frameshift Mutations in Exon 30 of the Elastin Gene (ELN)

Zhang¹,

He²,

Giro³

et al. 1999

Journal of Biological Chemistry

164

114

View full text Add to dashboard Cite

Congenital cutis laxa, a rare syndrome with marked skin laxity and pulmonary and cardiovascular compromise, is due to defective elastic fiber formation. In several cases, skin fibroblast tropoelastin production is markedly reduced yet reversed in vitro by transforming growth factor-␤ treatment. We previously showed that this reversal was due to elastin mRNA stabilization in one cell strain, and here this behavior was confirmed in skin fibroblasts from two generations of a second family. cDNA sequencing and heteroduplex analysis of elastin gene transcripts from three fibroblast strains in two kindreds now identify two frameshift mutations (2012⌬G and 2039⌬C) in elastin gene exon 30, thus leading to missense C termini. No other mutations were present in the ELN cDNA sequences of all three affected individuals. Transcripts from both alleles in each kindred were unstable and responsive to transforming growth factor-␤. Exons 22, 23, 26A, and 32 were always absent. Since exon 30 underwent alternative splicing in fibroblasts, we speculate that a differential splicing pattern could conceivably lead to phenotypic rescue. These two dominant-acting, apparently de novo mutations in the elastin gene appear to be responsible for qualitative and quantitative defects in elastin, resulting in the cutis laxa phenotype.

show abstract

Section: Discussionmentioning

confidence: 99%

Cutis Laxa Arising from Frameshift Mutations in Exon 30 of the Elastin Gene (ELN)

Zhang¹,

He²,

Giro³

et al. 1999

Journal of Biological Chemistry

164

114

View full text Add to dashboard Cite

show abstract

“…WS is generally sporadic with an incidence of 1/20,000-1/50,000 live births, although familial cases have been reported with appar- [Curren et al, 1993;Morris et al, 1993b;Ewart et al, 1994;Olson et al, 1995;Li et al, 1997;Tassabehji et al, 1997]. Further investigations of SVAS and WS have shown that hemizygosity at the elastin locus occurs in most WS patients Keating, 1994;Borg et al, 1995;Kotzot et al, 1995;Nickerson et al, 1995;Lowery et al, 1995;Mari et al, 1995]. Elastin haploinsufficiency provides an explanation for some of the anomalies found in WS, including SVAS, and a hoarse voice and rapidly aged-appearing skin, which may occur in part because elastin is required for the normal ultrastructure in the vocal ligaments and the skin.…”

mentioning

confidence: 95%

Delineation of the common critical region in Williams syndrome and clinical correlation of growth, heart defects, ethnicity, and parental origin

et al. 1998

View full text Add to dashboard Cite

Williams syndrome (WS) is a neurodevelopmental disorder with a variable phenotype. Molecular genetic studies have indicated that hemizygosity at the elastin locus (ELN) may account for the cardiac abnormalities seen in WS, but that mental retardation and hypercalcemia are likely caused by other genes flanking ELN. In this study, we defined the minimal critical deletion region in 63 patients using 10 microsatellite markers and 5 fluorescence in situ hybridization (FISH) probes on chromosome 7q, flanking ELN. The haplotype analyses showed the deleted cases to have deletions of consistent size, as did the FISH analyses using genomic probes for the known ends of the commonly deleted region defined by the satellite markers. In all informative cases deleted at ELN, the deletion extends from D7S489U to D7S1870. The genetic distance between these two markers is about 2 cM. Of the 51 informative patients with deletions, 29 were maternal and 22 were paternal in origin. There was no evidence for effects on stature by examining gender, ethnicity, cardiac status, or parental origin of the deletion. Heteroduplex analysis for LIMK1, a candidate gene previously implicated in the WS phenotype, did not show any mutations in our WS patients not deleted for ELN. LIMK1 deletions were found in all elastin-deletion cases who had WS. One case, who has isolated, supravalvular aortic stenosis and an elastin deletion, was not deleted for LIMK1. It remains to be determined if haploinsufficiency of LIMK1 is responsible in part for the WS phenotype or is simply deleted due to its close proximity to the elastin locus.

show abstract

“…Generally, seizures are not associated with WS. Autosomal dominant inheritance has been found in familial WS patients (Sadler et al 1993, almost all patients with WS having hemizygosity at the elastin (ELN) locus and submicroscopic deletions of chromosome 7q11.23 (Ewart et al 1993, Kotzot et al 1995, Nickerson et al 1995. LIM-kinase 1 (LIMK1) and the replication factor C subunit 2 (RFC2), have recently been identified in the deleted chromosomal region of the 3Ј flanking ELN gene (Frangiskakis et al 1996, Tassabehji et al 1996, Osborne et al 1996.…”

Section: Introductionmentioning

confidence: 99%

Interstitial deletion of chromosome 7q in a patient with Williams syndrome and infantile spasms

et al. 1998

View full text Add to dashboard Cite

Interstitial deletion of 7q11.23-q21.11 was identified by cytogenetic methods in a 4-year-old boy with Williams syndrome (WS) and infantile spasms. Deletion of the elastin (ELN) gene and the DNA polymorphic markers, D7S1870, D7S2490, D7S2518, and D7S2421, were identified in the patient, but the loci for D7S653 and D7S675 were not involved. Zackowski et al. (1990) reported that 6 of 16 patients with the interstitial deletion of 7q11.2-q22 had abnormal electro encephalograms, or seizures, or both, and that infantile spasms were present in 2 of the 6 patients. WS is a well defined developmental disorder characterized by distinct facial features, gregarious personality, and congenital heart defects. Seizures are not generally associated with this syndrome. WS commonly is characterized by deletion of the loci for ELN and D7S1870, but not those for D7S2490, D7S2518, or D7S2421. This suggests that a gene responsible for infantile spasms is located in the 2.7-cM interval between loci D7S1870 and D7S675.

show abstract

Phenotype of the Williams-Beuren syndrome associated with hemizygosity at the elastin locus

Cited by 50 publications

References 12 publications

Cutis Laxa Arising from Frameshift Mutations in Exon 30 of the Elastin Gene (ELN)

Cutis Laxa Arising from Frameshift Mutations in Exon 30 of the Elastin Gene (ELN)

Delineation of the common critical region in Williams syndrome and clinical correlation of growth, heart defects, ethnicity, and parental origin

Interstitial deletion of chromosome 7q in a patient with Williams syndrome and infantile spasms

Contact Info

Product

Resources

About