Features Of Williams-Beuren Syndrome Research Articles

Behavioral features of Williams Beuren syndrome compared to Fragile X syndrome and subjects with intellectual disability without defined etiology

Williams-Beuren syndrome (WBS) is a genetically determined neurodevelopmental disorder caused by a heterozygous deletion of 26–28 genes on chromosome band 7q11.23. During the past few years, researchers and clinicians have significantly contributed to define the phenotype of the syndrome, including its cognitive and behavioral aspects. However, it is not well known yet whether the psychological problems are specific to the syndrome or secondary to the intellectual disability (ID). The aim of our study was to better define the psychopathological profile of WBS and whether or not it is related with IQ or anxiety symptoms. Twenty-five subjects (12 girls, 13 boys) with a diagnosis of WBS were compared to 27 boys with Fragile X Syndrome and to 24 boys with ID of non-specific etiology using the Child Behavior Checklist. Anxiety, depression and attention problems were the main behavioral problems found in WBS with no gender differences. Significant differences between cohorts were observed in somatic complaints, delinquent behavior, aggressive behavior, and externalizing problems. Some associations between IQ and anxiety items were found. The findings are discussed in terms of behavioral phenotypes, genetic implications and ID.

Williams-Beuren syndrome--stretching to learn big lessons from small patients

Paediatric patients usually play a minor role in the grand arena of hypertension and cardiovascular disease. Patients with Williams–Beuren syndrome (WBS), comprising a rare small subset of the paediatric hypertensive population, would not necessarily be expected to be of outstanding interest. However, the elucidation of the small gene region which is deleted in WBS has led to fascinating pathophysiological insights, shedding light on a large array of molecular mechanisms involved in hypertension and opening treatment perspectives far beyond established antihypertensive drug therapy. WBS was first described in 1961 as a combination of stenoses of the largeand medium-sized arteries combined with facial dysmorphic signs, short stature, failure to thrive and mild to moderate mental retardation [1,2]. Other facultative features include transient hypercalcaemia in infancy, small teeth, joint stiffness, scoliosis, sensorineural hearing loss, hyperreflexia, problems of visio-spatial processing, anxiety, phobic and perseverative tendencies (for a full list of clinical features of WBS, see OMIM #194050). The syndrome is caused by heterozygous microdeletion of the ‘WBS critical region’ on the long arm of chromosome 7 encompassing about 28 genes [3,4]. The most important gene in this region in terms of cardiovascular changes is the elastin (ELN) gene. Heterozygous disruptions of ELN alone without other gene losses in the WBS critical region cause autosomal dominant familial supravalvular aortic stenosis (SVAS) without other features of WBS (for a full list of clinical features of WBS, see OMIM #194050; for a full list of clinical descriptions of familial SVAS, see OMIM #185500). Tropoelastin, the ELN gene product, is exported to the extracellular matrix, assembled on a microfibrillar scaffold and enzymatically cross-linked into large polymers named elastin, which make up the bulk of elastic fibres. Besides its structural functions, elastin interacts with surrounding cells of the extracellular matrix. Impaired elastogenesis causes smooth muscle cells to proliferate and migrate [5]. Reduced elastin synthesis combined with increased smooth muscle cell proliferation of the intima and media is not only seen in the ‘elastin arteriopathy’ of WBS, familial SVAS and their corresponding animal models [6], but also in vascular proliferative disorders such as atherosclerosis and coronary restenosis. Elastic fibres are initially deposited in plaques but later diminish with increasing lipid and calcium deposition [7]. Elastin levels are particularly low in ruptured aortic atheromas [8], suggesting that elastin could be a key to understanding why and when plaques rupture. The therapeutic potential of elastin lies in its capability to prevent the proliferation of smooth muscle cells and stabilize their mature phenotype. Covering coronary artery stents in pigs with elastin limits the neointimal proliferation which often leads to restenosis [5]. Addition of soluble elastin to cell cultures can restore their normal phenotype in Eln−/− animal cells and in human cells from patients with WBS or familial SVAS [5,6]. The inhibition of matrix metalloproteinases, which are involved in the remodelling of extracellular matrix by degrading elastin, is another therapeutic approach to vascular proliferation [9]. Other drugs such as glucocorticoids [10] and retinoids [11] can increase elastin expression, but to date have been tested exclusively in animal models of foetal and neonatal lung development. Even a number of nutritional approaches have been investigated with compounds which affect the enzymatic crosslinking, deposition or degradation of elastin, such as copper, β-aminopropionitrile, dill extract, ellagic acid and tannic acid [3]. Despite this wealth of exciting research about elastin, there are still many unanswered questions regarding WBS and the pathophysiology of many of its clinical features. The origin of arterial hypertension, for example, which is present in about 17% of WBS patients [3], is still a matter of debate. In this issue of NDT, Bouchrieb et al. report on a French series of 41 patients with WBS and hypertension. Whereas renal artery stenosis can clearly cause hypertension in WBS, it was found only in 58% of hypertensive WBS patients in this study. This corresponds well to a previous report by Rose et al. where only nine of 17 hypertensive WBS patients (53%) had renal artery stenosis, while six (35%) had narrowing of the thoracic or suprarenal aorta and two had normal aortas [12]. Rather than considering suprarenal aortic narrowing to be a

Induced Chromosome 5G2 Deletions Cause Hypersociability and Other Features of Williams-Beuren Syndrome in Mice

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WBSCR14, a putative transcription factor gene deleted in Williams-Beuren syndrome: complete characterisation of the human gene and the mouse ortholog.

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder affecting several systems caused by a heterozygous deletion in the chromosomal region 7q11.23. A common interval that includes up to 17 genes reported so far is deleted in the great majority of patients. Elastin haploinsufficiency is responsible for the cardiovascular features, but the specific contribution of other deleted genes to the WBS phenotype remains unknown. We have fully characterised a gene commonly deleted in WBS, WBSCR14, previously reported in a truncated form as WS-bHLH. The WBSCR14 cDNA encodes an 852amino acid protein with a basic helix-loop-helix-leucine-zipper motif (bHLHZip) and a bipartite nuclear localisation signal (BNLS), suggesting a function as a transcription factor. WBSCR14 is expressed as a 4.2kb transcript predominantly in adult liver and at late stages of foetal development. The WBSCR14 locus encompasses 33 kb of genomic DNA with 17 exons. Two intragenic polymorphic dinucleotide repeats have been identified and used to verify hemizygosity in WBS patients. We have also cloned the mouse ortholog and mapped its locus to mouse chromosome 5, in a region of conserved synteny with human 7q11.23. Given that other bHLHZip proteins are dosage sensitive and based on the putative function of WBSCR14 as a transcription factor, hemizygosity at this locus could be involved in some features of WBS.

A Physical Map, Including a BAC/PAC Clone Contig, of the Williams-Beuren Syndrome–Deletion Region at 7q11.23

Williams-Beuren syndrome (WBS) is a developmental disorder caused by haploinsufficiency for genes in a 2-cM region of chromosome band 7q11.23. With the exception of vascular stenoses due to deletion of the elastin gene, the various features of WBS have not yet been attributed to specific genes. Although >/=16 genes have been identified within the WBS deletion, completion of a physical map of the region has been difficult because of the large duplicated regions flanking the deletion. We present a physical map of the WBS deletion and flanking regions, based on assembly of a bacterial artificial chromosome/P1-derived artificial chromosome contig, analysis of high-throughput genome-sequence data, and long-range restriction mapping of genomic and cloned DNA by pulsed-field gel electrophoresis. Our map encompasses 3 Mb, including 1.6 Mb within the deletion. Two large duplicons, flanking the deletion, of >/=320 kb contain unique sequence elements from the internal border regions of the deletion, such as sequences from GTF2I (telomeric) and FKBP6 (centromeric). A third copy of this duplicon exists in inverted orientation distal to the telomeric flanking one. These duplicons show stronger sequence conservation with regard to each other than to the presumptive ancestral loci within the common deletion region. Sequence elements originating from beyond 7q11.23 are also present in these duplicons. Although the duplicons are not present in mice, the order of the single-copy genes in the conserved syntenic region of mouse chromosome 5 is inverted relative to the human map. A model is presented for a mechanism of WBS-deletion formation, based on the orientation of duplicons' components relative to each other and to the ancestral elements within the deletion region.

Identification of a Putative Transcription Factor Gene (WBSCR11) That Is Commonly Deleted in Williams–Beuren Syndrome

Williams–Beuren syndrome (WBS) is a complex developmental disorder involving the hemizygous deletion of genes on chromosome 7q11.23. The cardiovascular aspects of the disorder are known to be caused by haploinsufficiency forELN,but the genes contributing to the other features of WBS are still undetermined. Fifteen genes have been shown to reside within the WBS deletion, and here we report the identification and cloning of an additional gene that is commonly deleted.WBSCR11, which was identified through genomic DNA sequence analysis and cDNA library screening, was positioned toward the telomeric end of the WBS deletion. The gene is expressed in all adult tissues analyzed, including many regions of the brain. The predicted protein displays homology to another gene from the WBS deletion,GTF2I, which is known to be a transcription factor. We postulate that WBSCR11 is also a transcription factor and may contribute to the spectrum of developmental symptoms found in WBS.