Molecular Genetics of Williams–Beuren Syndrome

Abstract

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, adenosine triphosphate (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 slingshot (SSH) and chronophin (CIN). (d) GTF2IRD1 protein is implicated in the regulation of the genes involved in embryo development, such as TroponinISLOW (TNNI1), Hoxc8 and Goosecoid (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.

close

References

Akagawa H, Tajima A, Sakamoto Y et al. (2006) A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Human Molecular Genetics 15: 1722–1734.

Ang LH, Chen W, Yao Y et al. (2006) Lim kinase regulates the development of olfactory and neuromuscular synapses. Developmental Biology 293: 178–190.

Antonell A, de Luis O, Domingo‐Roura X and Perez‐Jurado LA (2005) Evolutionary mechanisms shaping the genomic structure of the Williams–Beuren syndrome chromosomal region at human 7q11.23. Genome Research 15: 1179–1188.

Ashe A, Morgan DK, Whitelaw NC et al. (2008) A genome‐wide screen for modifiers of transgene variegation identifies genes with critical roles in development. Genome Biology 9(12): R182.

Barnett C, and Krebs JE (2011) WSTF does it all: a multifunctional protein in transcription, repair, and replication. Biochemistry and Cell Biology 89: 12–23.

Bayarsaihan D and Ruddle FH (2000) Isolation and characterization of BEN, a member of the TFII‐I family of DNA‐binding proteins containing distinct helix–loop–helix domains. Proceedings of the National Academy of Sciences of the USA 97: 7342–7347.

Bayarsaihan D, Dunai J, Greally JM et al. (2002) Genomic organization of the genes Gtf2ird1, Gtf2i, and Ncf1 at the mouse chromosome 5 region syntenic to the human chromosome 7q11.23 Williams syndrome critical region. Genomics 79: 137–143.

Bayes M, Magano LF, Rivera N, Flores R and Perez Jurado LA (2003) Mutational mechanisms of Williams–Beuren syndrome deletions. American Journal of Human Genetics 73: 131–151.

Beunders G, van de Kamp JM, Veenhoven RH et al. (2010) A triplication of the Williams–Beuren syndrome region in a patient with mental retardation, a severe expressive language delay, behavioural problems and dysmorphisms. Journal of Medical Genetics 47: 271–275.

Broder K, Reinhardt E, Ahern J et al. (1999) Elevated ambulatory blood pressure in 20 subjects with Williams syndrome American Journal of Medical Genetics 83: 356–360.

Cairo S, Merla G, Urbinati F, Ballabio A and Reymond A (2001) WBSCR14, a gene mapping to the Williams–Beuren syndrome deleted region, is a new member of the Mlx transcription factor network. Human Molecular Genetics 10: 617–627.

Cherniske EM, Carpenter TO, Klaiman C et al. (2004) Multisystem study of 20 older adults with Williams syndrome American Journal of Medical Genetics Part A 131: 255–264.

Chidambaram M, Radha V and Mohan V (2010) Replication of recently described type 2 diabetes gene variants in a South Indian population. Metabolism 59: 1760–1766.

Chimge NO, Makeyev AV, Ruddle FH and Bayarsaihan D (2008) Identification of the TFII‐I family target genes in the vertebrate genome. Proceedings of the National Academy of Sciences of the USA 105: 9006–9010.

Dai L, Bellugi U, Chen XN et al. (2009) Is it Williams syndrome? GTF2IRD1 implicated in visual‐spatial construction and GTF2I in sociability revealed by high resolution arrays. American Journal of Medical Genetics A 149A: 302–314.

Del Campo M, Antonell A, Magano LF et al. (2006) Hemizygosity at the NCF1 gene in patients with Williams‐Beuren syndrome decreases their risk of hypertension. American Journal of Human Genetics 78: 533–542.

Eaton BA and Davis GW (2005) LIM Kinase1 controls synaptic stability downstream of the type II BMP receptor. Neuron 47: 695–708.

Enkhmandakh B, Makeyev AV, Erdenechimeg L et al. (2009) Essential functions of the Williams–Beuren syndrome‐associated TFII‐I genes in embryonic development. Proceedings of the National Academy of Sciences of the USA 106: 181–186.

Ewart AK, Jin W, Atkinson D, Morris CA and Keating MT (1994) Supravalvular aortic stenosis associated with a deletion disrupting the elastin gene. Journal of Clinical Investigation 93: 1071–1077.

Ewart AK, Morris CA, Ensing GJ et al. (1993) A human vascular disorder, supravalvular aortic stenosis, maps to chromosome 7. Proceedings of the National Academy of Sciences of the USA 90: 3226–3230.

Ferrero GB, Howald C, Micale L et al. (2009) An atypical 7q11.23 deletion in a normal IQ Williams–Beuren syndrome patient. European Journal of Human Genetics 18: 33–38.

Fleury C, Neverova M, Collins S et al. (1997) Uncoupling protein‐2: a novel gene linked to obesity and hyperinsulinemia. Nature Genetics 15: 269–272.

Frangiskakis JM, Ewart AK, Morris CA et al. (1996) LIM‐kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 86: 59–69.

Fujiwara T, Mishima T, Kofuji T et al. (2006) Analysis of knock‐out mice to determine the role of HPC‐1/syntaxin 1A in expressing synaptic plasticity. Journal of Neuroscience 26: 5767–5776.

Giordano U, Turchetta A, Giannotti A et al. (2001) Exercise testing and 24‐hour ambulatory blood pressure monitoring in children with Williams syndrome. Pediatric Cardiology 22: 509–511.

Henrichsen CN, Csardi G, Zabot MT et al. (2011) Using transcription modules to identify expression clusters perturbed in Williams–Beuren syndrome. PLoS Computational Biology 7(1): e1001054.

Hobart HH, Morris CA, Mervis CB et al. (2010) Inversion of the Williams syndrome region is a common polymorphism found more frequently in parents of children with Williams syndrome. American Journal of Medical Genetics Part C: Seminar on Medical Genetics 154C: 220–228.

Hoshino J, Aruga J, Ishiguro A and Mikoshiba K (2003) Dorz1, a novel gene expressed in differentiating cerebellar granule neurons, is down‐regulated in Zic1‐deficient mouse. Brain Research. Molecular Brain Research 120: 57–64.

Huang YH, Bao Y, Peng W et al. (2009) Claudin‐3 gene silencing with siRNA suppresses ovarian tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America 106: 3426–3430.

Iizuka K, Bruick RK, Liang G, Horton JD and Uyeda K (2004) Deficiency of carbohydrate response element‐binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proceedings of the National Academy of Sciences of the USA 101: 7281–7286.

Inoue K and Lupski JR (2002) Molecular mechanisms for genomic disorders. Annual Review of Genomics and Human Genetics 3: 199–242.

Kabashima T, Kawaguchi T, Wadzinski BE and Uyeda K (2003) Xylulose 5‐phosphate mediates glucose‐induced lipogenesis by xylulose 5‐phosphate‐activated protein phosphatase in rat liver. Proceedings of the National Academy of Sciences of the United States of America 100: 5107–5112.

Kerzendorfer C and O'Driscoll M (2009) Human DNA damage response and repair deficiency syndromes: linking genomic instability and cell cycle checkpoint proficiency. DNA Repair 8: 1139–1152.

Kitagawa H, Fujiki R, Yoshimura K et al. (2003) The chromatin‐remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell 113: 905–917.

Kitagawa M, Kudo Y, Iizuka S et al. (2006) Effect of F‐spondin on cementoblastic differentiation of human periodontal ligament cells. Biochemical and Biophysical Research Communications 349: 1050–1056.

Kooner JS, Chambers JC, Aguilar‐Salinas CA et al. (2008) Genome‐wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nature Genetics 40: 149–151.

Kriek M, White SJ, Szuhai K et al. (2006) Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams–Beuren duplications. European Journal of Human Genetics 14: 180–189.

Lam PP, Leung YM, Sheu L et al. (2005) Transgenic mouse overexpressing syntaxin‐1A as a diabetes model. Diabetes 54: 2744–2754.

Li MV, Chen W, Poungvarin N, Imamura M and Chan L (2008) Glucose‐mediated transactivation of carbohydrate response element‐binding protein requires cooperative actions from Mondo conserved regions and essential trans‐acting factor 14‐3‐3. Molecular Endocrinology 22: 1658–1672.

Low SK, Zembutsu H, Takahashi A et al. (2011) Impact of LIMK1, MMP2 and TNF‐alpha variations for intracranial aneurysm in Japanese population. Journal of Human Genetics 56: 211–216.

Makeyev AV, Erdenechimeg L, Mungunsukh O et al. (2004) GTF2IRD2 is located in the Williams–Beuren syndrome critical region 7q11.23 and encodes a protein with two TFII‐I‐like helix–loop–helix repeats. Proceedings of the National Academy of Sciences of the USA 101: 11052–11057.

Manetti F (2011) LIM kinases are attractive targets with many macromolecular partners and only a few small molecule regulators. Medical care Research and Review [Epub ahead of print].

Matsumoto N, Kitani R and Kalinec F (2011) Linking LIMK1 deficiency to hyperacusis and progressive hearing loss in individuals with Williams syndrome. Communicative & Integrative Biology 4: 208–210.

Meng Y, Zhang Y, Tregoubov V et al. (2002) Abnormal spine morphology and enhanced LTP in LIMK‐1 knockout mice. Neuron 35: 121–133.

Merla G, Howald C, Antonarakis SE and Reymond A (2004) The subcellular localization of the ChoRE‐binding protein, encoded by the Williams–Beuren syndrome critical region gene 14, is regulated by 14‐3‐3. Human Molecular Genetics 13: 1505–1514.

Merla G, Howald C, Henrichsen CN et al. (2006) Submicroscopic deletion in patients with Williams–Beuren syndrome influences expression levels of the nonhemizygous flanking genes. American Journal of Human Genetics 79: 332–341.

Meroni G, Cairo S, Merla G et al. (2000) Mlx, a new Max‐like bHLHZip family member: the center stage of a novel transcription factors regulatory pathway? Oncogene 19: 3266–3277.

Micale L, Turturo MG, Fusco C et al. (2010) Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis. European Journal of Human Genetics 18: 317–323.

Nagata K, Ohashi K, Yang N and Mizuno K (1999) The N‐terminal LIM domain negatively regulates the kinase activity of LIM‐kinase 1. Biochemical Journal 343(part 1): 99–105.

Nakayama K, Yanagisawa Y, Ogawa A et al. (2011) High prevalence of an anti‐hypertriglyceridemic variant of the MLXIPL gene in Central Asia. Journal of Human Genetics. [Epub ahead of print].

Neel JV (1962) Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? American Journal of Human Genetics 14: 353–362.

Olson TM, Michels VV, Urban Z et al. (1995) A 30 kb deletion within the elastin gene results in familial supravalvular aortic stenosis. Human Molecular Genetics 4: 1677–1679.

Osborne LR, Li M, Pober B et al. (2001) A 1.5 million‐base pair inversion polymorphism in families with Williams–Beuren syndrome. Nature Genetics 29: 321–325.

Oya H, Yokoyama A, Yamaoka I et al. (2009) Phosphorylation of Williams syndrome transcription factor by MAPK induces a switching between two distinct chromatin remodeling complexes. Journal of Biological Chemistry 284: 32472–32482.

Pober BR, Wang E, Caprio S et al. (2010) High prevalence of diabetes and pre‐diabetes in adults with Williams syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 154C: 291–298.

Roy AL (2007) Signal‐induced functions of the transcription factor TFII‐I. Biochemical and Biophysical Acta 1769: 613–621.

Schratt GM, Tuebing F, Nigh EA et al. (2006) A brain‐specific microRNA regulates dendritic spine development. Nature 439: 283–289.

Somerville MJ, Mervis CB, Young EJ et al. (2005) Severe expressive‐language delay related to duplication of the Williams–Beuren locus. New England Journal of Medicine 353: 1694–1701.

Stetler RA, Cao G, Gao Y et al. (2008) Hsp27 protects against ischemic brain injury via attenuation of a novel stress–response cascade upstream of mitochondrial cell death signaling. Journal of Neuroscience 28: 13038–13055.

Stromme P, Bjornstad PG and Ramstad K (2002) Prevalence estimation of Williams syndrome. Journal of Child Neurology 17: 269–271.

Tassabehji M (2003) Williams–Beuren syndrome: a challenge for genotype–phenotype correlations. Human Molecular Genetics 12(Spec No. 2): R229–237.

Urban Z, Zhang J, Davis EC et al. (2001) Supravalvular aortic stenosis: genetic and molecular dissection of a complex mutation in the elastin gene. Human Genetics 109: 512–520.

Uyeda K, Yamashita H and Kawaguchi T (2002) Carbohydrate responsive element‐binding protein (ChREBP): a key regulator of glucose metabolism and fat storage. Biochemical Pharmacology 63: 2075–2080.

Valero MC, de Luis O, Cruces J and Perez Jurado LA (2000) Fine‐scale comparative mapping of the human 7q11.23 region and the orthologous region on mouse chromosome 5G: the low‐copy repeats that flank the Williams–Beuren syndrome deletion arose at breakpoint sites of an evolutionary inversion(s). Genomics 69: 1–13.

Vintermist A, Bohm S, Sadeghifar F et al. (2011) The chromatin remodelling complex B‐WICH changes the chromatin structure and recruits histone acetyl‐transferases to active rRNA genes. PLoS One 6(4): e19184.

Yamada Y, Metoki N, Yoshida H et al. (2008) Genetic factors for ischemic and hemorrhagic stroke in Japanese individuals. Stroke 39: 2211–2218.

Yoshimura K, Kitagawa H, Fujiki R et al. (2009) Distinct function of 2 chromatin remodeling complexes that share a common subunit, Williams syndrome transcription factor (WSTF). Proceedings of the National Academy of Sciences of the USA 106: 9280–9285.

Zhao C and Pleasure SJ (2005) Frizzled9 protein is regionally expressed in the developing medial cortical wall and the cells derived from this region. Brain Research. Developmental Brain Research 157: 93–97.

Zhu M, Koonpaew S, Liu Y et al. (2006) Negative regulation of T cell activation and autoimmunity by the transmembrane adaptor protein LAB. Immunity 25: 757–768.

Further Reading

Lupski JR (1998) Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends in Genetics 14: 417–422.

Stankiewicz P and Lupski JR (2002) Genome architecture, rearrangements and genomic disorders. Trends in Genetics 18: 74–82.

Schubert C (2009) The genomic basis of the Williams–Beuren syndrome. Cellular and Molecular Life Sciences 66: 1178–1197.

Pober BR (2010) Williams–Beuren syndrome. New England Journal of Medicine 362: 239–252.

Merla G, Brunetti‐Pierri N, Micale L and Fusco C (2010) Copy number variants at Williams–Beuren syndrome 7q11.23 region. Human Genetics 128(1): 3–26.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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. http://www.els.net [doi: 10.1002/9780470015902.a0022436]