Molecular Genetics of Williams–Beuren Syndrome


The Williams–Beuren syndrome is a rare genomic disorder caused by a hemizygous microdeletion of approximately 30 genes at 7q11.23 occurring by nonallelic homologous recombination between low copy repeats flanking that region. The 7q11.23 region has been also found duplicated, triplicated and inverted in patients with different and, in some instances, reciprocal phenotypes.

Complementary strategies including mouse models, functional and biochemical studies have been pursued in the recent years to delineate the individual and/or combined contribution of hemizygous genes to the wide spectrum of phenotypes that characterises this syndrome. Haploinsufficiency of several of these genes has been reported to account for parts of the overall phenotypes, suggesting their sensitivity to gene dosage. Notably, MLXIPL, GTF2IRD1 and GTF2I hemizygous genes act as transcription factors, therefore is likely that their haploinsufficiency is responsible for some of clinical features by regulating gene expression of a wide number of target genes.

Key Concepts:

  • Williams–Beuren syndrome is a genomic disorder characterised by a unique cognitive profile and it involves approximately 30 hemizygous genes at 7q11.23.

  • The 7q11.23 Williams–Beuren syndrome region has been found deleted, duplicated, triplicated and inverted in patients with different phenotypes.

  • Patients with atypical deletions and mouse models have provided insights about the genotype–phenotype correlations.

  • Haploinsufficiency of the Williams–Beuren syndrome genes is correlated with the clinical signs.

  • BAZ1B has been linked to cardiac, craniofacial and hypercalcemia defects; hemizygosity of MLXIPL could be related to the diabetic phenotype of Williams–Beuren syndrome patients through regulation of glucose metabolism.

  • The GTF2IRD1 transcription factor modulates genes involved in tissue development and differentiation and is a strong candidate for the craniofacial and neurobehavioral features.

Keywords: Williams–Beuren syndrome; 7q11.23; haploinsufficiency; genotype–phenotype correlation; neurodevelopmental disorder; segmental duplication; low copy repeats; nonallelic homologous recombination

Figure 1.

Schematic representation of the Williams–Beuren syndrome deletion region. The centromeric (c), middle (m) and telomeric (t) LCRs blocks A–C are shown as coloured arrows with their relative location and orientation to each other. The single‐copy gene region is located between the blocks Cm and Bm and spans a region of approximately 1.2 Mb. The common deletions of 1.5 Mb and 1.8 Mb are depicted: breakpoints within the centromeric and the medial copy of LCRs block B and within the centromeric and the medial copy of LCRs block A are shown.

Figure 2.

Interchromosomal or interchromatid NAHR between the LCR blocks B. (a) Unequal crossing over results in a deletion and a reciprocal duplication of the WBS region with creation of a fusion of LCR block Bc and Bm. SCGR, single‐copy gene region. (b) Intrachromatid NAHR between the LCR block Bm and Bc from the same chromatid results in a deletion of the WBS region with creation of a fusion of LCR block Bc and Bm and a reciprocal acentric chromosome. A crossover between Bc and Bm blocks is depicted.

Figure 3.

Intrachromatid misalignment of inverted repeats. The WBS inversion is generated by meiotic or mitotic intrachromatid misalignment between the inverted homologous centromeric and telomeric LCR blocks, resulting in NAHR between paired LCR blocks. In the figure, a crossover involving block Bc and Bt is illustrated.

Figure 4.

Domains of BAZ1B, ChREBP, LIMK1 and TFII family related proteins. (a) BAZ1B: LH, helix–loop–helix motif; WAC, (ATP)‐utilising chromatin assembly domain; DDT, DNA‐binding homeobox and different transcription factors; BAZ1 and BAZ2, bromodomain adjacent to zinc finger domain; WAKZ domain; PHD, plant homeodomain finger motif; BD, bromodomain. (b) MXLIPL: NES1; MCR, Mondo Conserved Region containing NES2 and NLS; GRACE, glucose response conserved element; polyproline domain; bHLH/Zip, basic loop–helix–leucine‐zipper; ZIP‐like, leucine‐zipper‐like domain. (c) LIMK1: LIM, two homeodomains‐containing proteins Lin‐11, Isl‐1 and Mec; NES, nuclear export signal; PDZ, post‐synaptic density/disc‐large/ZO; P/S, proline/serine‐rich sequence; KD, kinase domain containing a NLS and a NES, nuclear export signal. (d) GTF2I: LZ, leucine zipper motif; HLH1‐6, six‐member group of multiple helix–loop–helix I‐repeat domains; NLS between HLH1 and HLH2 repeats. (e) GTF2RD1: LZ; HLH1‐5; NLS. (f) GTF2RD2: LZ1 and LZ2, N‐terminal and C‐terminal leucine zipper motifs; HLH1‐2; Zing Finger motif.

Figure 5.

Schematic representation of major biological pathways involving BAZ1B, ChREBP, LIMK1 and TFII family proteins. (a) When stimulated by MAPK effectors (ERK, JNK and p38), BAZ1B factor is able to associate to the chromatin‐remodelling complex WINAC, also essential for the regulation of vitamin D receptor (VDR) transcription. In the absence of the extracellular stresses stimulating MAPK signallings, WSTF may be recruited into the WICH complex for DNA replication and repair. (b) ChREBP and Max‐like (MLX) proteins function together as a glucose‐responsive transcription factor which binds and activates, in a glucose‐dependent manner, carbohydrate responsive elements (ChoRE) located in the promoter of several genes involved in hepatic glycolysis, lipogenesis and gluconeogenesis, such as Lpk, Acc1, Fasn, Elovl6, G6pdh, Gys‐2, PP1GL and G6Pase. (c) Cofilin is a major regulator of actin dynamics with a key role in depolymerisation events. Upon LIMK1‐mediated phosphorylation conditions, cofilin is inactive and G‐actin can be switched to F‐actin, thus promoting various cellular processes, such as cell migration, cell cycle progression and neuronal differentiation. PAK, p21‐activated kinase, exerts a stimulatory effect on cofilin phosphorylation and LIMK1 activity, which is, instead, negatively regulated by brain‐specific miR‐134, inducing repression of LIMK1 mRNA translation. Cofilin activity is restored by phosphatases such as (SSH) and (CIN). (d) GTF2IRD1 protein is implicated in the regulation of the genes involved in embryo development, such as TroponinISLOW (TNNI1), Hoxc8 and (GSC), through its binding to GTF2IRD1 upstream control elements (GUCEs). In response to specific signaling events, both GTF2IRD1 and GTF2I, which binds core promoter (Inr) and enhancer (E‐box) elements, can be recruited to the promoter sequence of TGF_RII/Alk1/Smad5 and Vegfr2 cascades genes, which participate to many developmental processes, including early vasculogenesis and angiogenesis and craniofacial growth.



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Further Reading

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Merla, Giuseppe, Micale, Lucia, Fusco, Carmela, and Loviglio, Maria Nicla(Jan 2012) Molecular Genetics of Williams–Beuren Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022436]