eLS || Molecular Genetics of Williams-Beuren Syndrome

Molecular Genetics ofWilliams–BeurenSyndromeGiuseppe Merla, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San

Giovanni Rotondo, Italy

Lucia Micale, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San


Carmela Fusco, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San


Maria Nicla Loviglio, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital,

San Giovanni Rotondo, Italy

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 dupli-

cated, triplicated and inverted in patients with different

and, in some instances, reciprocal phenotypes.

Complementary strategies including mouse models, func-

tional 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. Haploinsuffi-

ciency of several of these genes has beenreported to account

for parts of the overall phenotypes, suggesting their sensi-

tivity 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.

Introduction

Williams–Beuren syndrome (WBS; OMIM#194050, alsoreported as Williams syndrome) is a rare neurodevelop-mental disorder occurring in approximately 1/10 000 livebirths (Stromme et al., 2002), although a precise estimationof the incidence still lacks. Clinical phenotype is widely

heterogeneous in severity and manifestation. WBS indi-viduals display a characteristic pattern of symptomsincluding typical facial dysmorphism, supravalvular aorticstenosis (SVAS), weakness of connective tissue, short stat-ure, mild to moderate mental retardation and a character-istic cognitive profile that includes relative strengths inverbal short-term memory and language, along with severeweakness in visuospatial abilities (Tassabehji, 2003). WBSpatients are hypersensitive to sound, with strong emotionalresponses to music. WBS individuals may suffer from sen-sorineural hearing loss as they get aged. They are also verysociable, loquacious and overfriendly, with a complete lackof fear towards strangers. Other clinical features includeintermittent hypercalcaemia, hypertonia, renal anomalies,dental defects, gastrointestinal problems, urinary tractabnormalities, weakness in daily living skills and motorabilities, and scoliosis/kyphosis. WBS cases are generallysporadic; however, familial cases with an autosomal dom-inant mode of inheritance have been reported. The peculiarset of symptoms and features ofWBS patients arises from a1.5–1.8Mb hemizygous deletion of approximately 30 geneson chromosome7q11.23, a region calledWBScritical region(WBSCR). Larger and smaller atypical deletions have beenalso reported. See also: Williams SyndromeSince 1993, when the genetic cause was discovered

(Ewart et al., 1993), the WBS is diagnosed by fluorescencein situ hybridisation (FISH) using the elastin gene, whichmaps within the WBSCR, as probe. Although FISHremains themostwidely used laboratory test, themoleculardiagnosis can also be established by means of micro-satellite/single nucleotide polymorphism (SNP) genotyp-ing, and more recently by multiplex ligation-dependentprobe amplification (MLPA), real-time quantitative poly-merase chain reaction assay (qPCR), and array compara-tive genomic hybridisation (aCGH).Although has not completely been ascertained howWBS

genes loss leads to the characteristic phenotype, the hap-loinsufficiency of WBS gene products is involved. For

Advanced article

Article Contents

. Introduction

. Genomic Rearrangements and Mutational Mechanisms

in WBS

. Genes Associated to Specific WBS Phenotypes

. Lessons from Single Gene Variants

. Conclusive Remarks

. Abbreviations

Online posting date: 15th January 2012

eLS subject area: Genetics & Disease

How to cite:Merla, Giuseppe; Micale, Lucia; Fusco, Carmela; and Loviglio, Maria

Nicla (January 2012) Molecular Genetics of Williams–BeurenSyndrome. In: eLS. John Wiley & Sons, Ltd: Chichester.

DOI: 10.1002/9780470015902.a0022436

eLS & 2012, John Wiley & Sons, Ltd. www.els.net 1

http://dx.doi.org/10.1038/npg.els.0001908

instance the loss of an elastin allele causes the cardiovascularfeatures ofWBS, while the phenotypic consequences causedby the other genes within the deleted region has not yet beendefinitely assessed and remain still unclear.

The possible correlations between haploinsufficiency ofWBS genes and phenotypic features have been inferredwith complementary strategies including clinical, psycho-logical and molecular analysis of affected individuals withatypical deletions, generation of single-gene knockoutmouse models, functional and biochemical studies onselected genes, and WBS global genes and proteinsexpression profile. Recently, strains of heterozygous miceengineered to carry the full deletion of the region syntenicto theWBS region replicate manyWBS features, includingabnormal social interaction phenotypes.

Genomic Rearrangements andMutational Mechanisms in WBS

The wealth of data arising from global genome analysis hasuncovered a large number of interspersed and tandem seg-mental duplication (SD) over the entire human genome. SDmediates illegitimate recombination that leads to chromo-somal rearrangements resulting in genomic disorders.

The complex genomic structure of the WBSCR at7q11.23 presents a high density of chromosome 7-specificSD. Three large SDs, known also as low-copy repeats(LCRs) (centromeric, medial and telomeric), arranged inthree differentiated high sequence homology blocks of4320 kb in size (from 98% to 99.6% of nucleotidesequence identity), namedA, B andC, flank the single copygene region ofWBS (Valero et al., 2000). The blocks of the

centromeric and medial LCRs are transcriptionally dir-ected in the same orientation, although in different order,whereas the third SD lies more telomeric, with the sameorder as the centromeric LCR but in the opposite tran-scription direction (Figure 1). The single blocks are com-posed mainly of truncated copies of genes, codingpseudogenes, except for some genes, such as POM121,NCF1, GTF2IRD2, NSUN5, TRIM50 and FKBP6, whichare transcriptionally active (Valero et al., 2000). The edgesof the LCR blocks are GC rich (50.1%) and contain anunusually high abundance of repetitive elements consistingprimarily of Alu sequences that may have contributed tothe final generation of these large SDs (Antonell et al.,2005).By a nonallelic homologous recombination (NAHR)

during meiosis, LCRs lead to different deoxyribonucleicacid (DNA) rearrangements: deletion, duplication andinversion. It is likely that some genomic structural features,including LCRs length, degree of homology, distance andreciprocal orientation and the number of subsequentrecombination events facilitate NAHR (Inoue and Lupski,2002). Interchromosomal or interchromatid recombin-ationofmisplaced alignedLCRsblockswith high sequenceidentity and in the same orientation produces a deletionand a reciprocal duplication of the genomic region locatedbetween the repeated regions (Figure 2). Intrachromatidmisalignment of directed repeats results in a deletion and areciprocal circular acentric chromosome (Figure 3). Thehigher sequence homology between centromeric andmedial LCR blocks B (99.6%) compared to the sequencesof centromeric and medial blocks A (98.2%), and theshorter size of centromeric and medial LCR blocks Bcompared to the size of centromeric and medial blocks Afavorites the rearrangement that involves predominantly

Hs 7q11.23

Cc Ac Bc/Bm Am Bt At Ct

Cc Ac/Am Bt At Ct

Deletion of 1.5 Mb

Deletion of 1.8 Mb

TelCen

Single-copy gene region

GTF2IRD

1

FKBP6T1STA

G3L1

DN

AJC

30W

BSCR22

WBSC

R23

GTF2IP1

STAG

3L1FKBPT2

POM

121 H

IP1

GTF2IRD

2

GTF2IRD

2B

POM

121RN

SUN

5CTRIM

74

BAZ

1BBC

L7BTBL2

MLX

IPLVPS37D

STX1A

WBSC

R26

CLD

N3

CLD

N4

WBSC

R27W

BSCR28

ELNLIM

K1

RFC2

CLIP2

GTF2I

NC

F1

PMS2L5

WBSC

R16

PMS2L

NC

F1P1G

TF2ILPO

M121

NSU

N5

TRIM50

FKBP6FZ

D9

ABH

D11

EIF4HLA

T2

STAG

3L2

NC

F1CG

TF2IP2

TRIM73

NSU

N5B

CA

LN1

PMS2L

BmCc Ac Bc Cm Am Bt At Ct

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.

Molecular Genetics of Williams–Beuren Syndrome

eLS & 2012, John Wiley & Sons, Ltd. www.els.net2

the centromeric andmedial blocksB.Haplotype analysis infamilies with an affected child has revealed that inter-chromosomal NAHR is the cause of two-thirds of themicrodeletion, while intrachromosomal NAHR, eitherbetween sister chromatids or within a chromatid, results inone-third of the deletion. See also: Microdeletions andMicroduplications: Mechanism

Fine mapping of the WBS deletion ends has demon-strated that the vast majority of WBS individuals (around89%) presents a common deleted interval of 1.55Mb, whileapproximately 8% of cases present a larger recurrent dele-tion of 1.83Mbbetween centromeric andmedial blocksA; afew individuals (2–3%) display smaller or larger deletions ofthe WBS region whose phenotypic features vary betweenisolated SVAS to the full spectrum of WBS phenotype.

Duplication

Duplications of the WBS region have been reported(Somerville et al., 2005). Patients with duplication of theWBSCR, who therefore carry three copies of all the genes

therein, do not physically or cognitively resemble patientswith WBS. The clinical phenotype associated with recip-rocal WBS microduplication is less distinct and morevariable than inWBS.The facial features are different fromthose ofWBS and the language delay is in direct contrast tothe fluent expressive language displayed by WBS patients.Additional findings associated with the WBSCR dupli-cation are autism, neonatal hypotonia, epilepsy and anincreased incidence of various congenital anomalies. Thissituation is mirrored in other genomic disorders, wheremilder pathological consequences tend to arise from geneduplications if compared to reciprocal deletions outcomes.The frequency of parental transmission in patients

carrying 7q11.23 duplication is high, in contrast to therarity of parental transmission in the WBS deletion. In afew of the reported families, the parent carrying theduplication displayed a mild pattern of WBS-duplicationtypical symptoms, suggesting that mechanisms like geneticand/or environmental interactions, in addition to genedosage effects, are important in determining the pheno-typic outcome of patients with these genetic aberration.

Cc Ac Bc Cm Bm Am Bt At CtBm/Bc Cm

SCGR

NHAR

Duplication

Cc Ac Bc/Bm Am Bt At CtDeletion

Fusion of LCR blocks Bc/Bm

Interchromosomal/Interchromatid non-allelic homologous recombination

Intrachromatid non-allelic homologous recombination

Cc Ac Bc/Bm Am Bt At CtDeletion Acentric chromosome

Cc Ac Bc Cm

Bm Am Bt At Ct

NHAR

Fusion of LCR blocks Bc/Bm

(a)

(b)

+Bm/Bc Cm

Cc Ac Bc Cm Bm Am Bt At Ct

Cc Ac Bc Cm Bm Am Bt At Ct

SCGR

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.





Duplications are a consequence of NAHR, as well as thedeletion (Figure 2). Atypical duplications with smaller andlarger size have been reported (Kriek et al., 2006).

Triplication

The first report of a patient with a triplication of the WBSregion has been described recently (Beunders et al., 2010).The triplicated region does not include FZD9 and FKBP6,two genes that are commonly deleted inWBS patients. Thefact that the triplicated interval occurs not exactly betweenthe low copy repeats suggests that the underlyingmolecularmechanism could be different from NAHR.

The mental deficit and behavioural problems are con-sistentwith, butmore severe than, the phenotypic spectrumreported in 7q11.23 duplication patients, supporting theconclusion that duplications and triplications are patho-genic events and that an increased dosage of the WBSregion is of considerable relevance for the observedphenotypes, likely causing developmental delay associatedwith severe retardation in speech and mild dysmorphicfeatures.

Inversion

Meiotic and mitotic intrachromatid misalignment ofinverted homologous centromeric and telomeric LCRblocks, followed by NAHR may result in a paracentricinversion of the WBS locus (WBSinv-1) (Figure 3). Thisevent, with breakpoints external to the WBS single generegion, does not disrupt any actively expressed genes andcan occur at each of the LCR blocks, thus resulting invariable sized (1.8–2.9Mb) paracentric inversions (Bayeset al., 2003).

The WBSinv-1 has been found in approximately 30% ofthe chromosome-transmitting parents in WBS families, inapproximately 5.8%of the general population, and in a fewindividuals displaying symptoms reminiscent of WBS(Osborne et al., 2001). Inversion is considered a benignpolymorphism; individuals with clinical symptoms andWBSinv-1 show no significant clinical or psychologicaloverlap with classical WBS patients suggesting that previ-ously unidentified copy number variants could contribute tosyndromic features. WBSinv-1 is a predisposing chromo-some rearrangement for unequal meiotic recombination inthe germcells of inversion carriers thus resulting in a 5.4-foldincreased chance of having a child with WBS relative to apersonwhodoesnothave this inversion.As consequence therecurrence risk for a parent heterozygous for a WBS inver-sion is 1/1750 (Hobart et al., 2010).

Genes Associated to Specific WBSPhenotypes

The WBS deletion region encompasses approximately 30transcribed genes. Currently, a large number of studiesbased on knockout mice strategy, correlation betweenclinical and molecular findings in patients with atypicalWBSCR deletion, and functional gene assays, are con-tributing to the elucidation of the contribution that somehemizygous genes have to the various phenotypic features.Here, we present an overview of the state-of-the-art onsome selected WBS genes: BAZ1B that, among othersphenotypes, contributes to the hypercalcaemia in infantswith WBS; MLXIPL that is related to the diabeticphenotype of WBS patients through regulation of glucosemetabolism; three members of TFII-I transcription family

Cc Ac Bc Cm Bm Am Bt At CtSCGR

Intrachromatid misalignment of inverted repeats

Cc Ac Bc Cm

BmAmBtAtCt

Cc Ac Bc/Bt Cm Bm Am CtCm Bc/BtInversion

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.



and LIMK1 that play a major role in developing the cog-nitive features. WBS genes for whom experimental dataimplicate a possible role in the phenotype ofWBS are listedin Table 1.

BAZ1B

Bromodomain adjacent to zinc finger domain 1B(BAZ1B), also known asWilliams syndrome transcriptionfactor (WSTF), is a member of BAZ/WAL (WSTF/Acf1-like) family, a group of proteins that comprise sequential-ordered structural motifs (Figure 4a). BAZ1B associateswith the ISWI protein and the SWI/SNF complexesinvolved in nuclear events, thus forming different chro-matin-remodeling complexes, the MAPK phosphoryl-ation-dependent ‘WSTF including nucleosome assemblycomplex’ (WINAC) (Oya et al., 2009), and the ‘WSTF–ISWI chromatin remodelling complex’ (WICH) (Figure 5a).

Through its transcriptional promoting activity, BAZ1Bparticipates in a number of processes such as chromatinassembly, ribonucleic acid (RNA) polymerase I and IIIregulation and DNA repair. In addition, by functioning asa subunit of the WINAC complex, BAZ1B binds specific-ally to acetylated histones and is itself a histone kinase(Figure 5a) (Vintermist et al., 2011).Studies in Xenopus, mice and human tissue cultures

suggested that the Baz1b heterozygosity might explain anumber of the systemic defects seen in WBS patientsincluding heart disease, growth deficiency, facial appear-ance and infantile hypercalcaemia. Consistent with itspossible role in the heart, Baz1b 2/2 and approximately10%ofBaz1b+/2mice exhibited heart defects resemblingthose found in WBS patients, such as altered structure,atrial and ventricular septal defects, hypertrophy of ven-tricles and doubleoutlet right ventricles (Yoshimura et al.,2009).

Table 1 Phenotypic features of single human genes deleted in Williams–Beuren syndrome

Gene Phenotype References

NCF1 Hypertension Del Campo et al. (2006)

TFII Family WBS cognitive profile Antonell et al. (2005),

Ferrero et al. (2009)Craniofacial features

Behavioural abnormalities

Growth retardation

FZD9 Visuospatial learning/memory Zhao and Pleasure (2005)

Abnormal hippocampal structure

Thymic atrophy

BAZ1B Cardiac malformation Yoshimura et al. (2009),

Barnett and Krebs (2011)Craniofacial abnormalities

Hypercalcemia

MLXIPL Diabetes mellitus Cherniske et al. (2004)

Impaired glucose tolerance

STX1A Hyperglicemia Lam et al. (2005),

Fujiwara et al. (2006)Impaired insulin secretion

Altered synaptic plasticity

CLDN3 and CLDN4 Ovarian tumor growth and metastasis Huang et al. (2009)

ELN Hypertension Broder et al. (1999),

Giordano et al. (2001)Supravalvular aortic stenosis (SVAS) Pulmonaryartery stenosis

Aortic arch hypoplasia

LIMK1 Impaired visuospatial constructive cognition Meng et al. (2002)

Mild deficit in spatial learning and memory

LAT2 Abnormal activation of autoimmune system Zhu et al. (2006)

RFC2 Microcephaly and growth retardation Kerzendorfer and

O’Driscoll (2009)



Moreover, 4 weeks mice carrying a L733R homozygousmutation, altering BAZ1B protein stability, exhibit achanged skull shape that includes a protruding forehead,shorter snout, flattened nasal bone and upward curvatureof the nasal tip (Ashe et al., 2008). These craniofacial fea-tures are strikingly similar to those of WBS patients, sug-gesting that reduced expression of BAZ1B may beresponsible or participate to determination of the peculiarWBS facial characteristics.

Accumulating evidences have revealed that BAZ1Bregulates the expression of enzymes involved in both syn-thesis and catabolism of vitamin D by its direct interactionwith vitamin D receptor (VDR) (Kitagawa et al., 2003).These observations strengthen the hypothesis that thereduced BAZ1B level in WBS patients may transientlycause impaired function in VDR activity, leading toinfantile vitamin D metabolism disregulation and hyper-calcemia in these individuals (Figure 5a).

MLXIPL

The Max-like protein (MLX)-interacting protein-like(MLXIPL) gene (also known asWBSCR14 or CHREBP)

is a member of the basic-helix–loop–helix leucine zipper(bHLHZip) family of transcription factors (Cairo et al.,2001) (Figure 4b). The basic region confers the transcrip-tional activity and the HLH and Zip motifs participate inprotein dimerisation, a prerequisite for DNA binding.MLXIPL heterodimerises with MLX (Meroni et al.,

2000) in a glucose-dependent manner, thus binding andactivating carbohydrate responsive elements (ChoRE),which are located in the promoter of several lipogenic andglucogenic enzyme genes, including LPK, ACC1, FASn,G6pdh, PP1GL, G6Pase (Figure 5b) (Uyeda et al., 2002).The regulation of MLXIPL nucleo-cytoplasmic shut-

tling may be glucose dependent (Uyeda et al., 2002;Kabashima et al., 2003) (Figure 5b) or independent (Li et al.,2008), suggesting that MLXIPL may be a versatile tran-scriptional coactivator playing a pivotal role in coordin-ating signalling events within the transcription machinery.It has been reported thatmRNA levels of all of themajor

lipogenic enzymes genes are significantly lower in Mlxipl2/2 mice fed a high-starch diet than in wild type mice.Consistently, liver triglycerides, total body fat synthesisand glucose intolerance are decreased in Mlxipl2/2 miceas a consequence of the decreased lipogenic enzyme

BAZ1B WAC LH BAZ1 WAKZ PHD BDBAZ2NH2 COOH1441aa

DDT

(a)

COOH700aa

LIM LIM PDZ P/S KD

NES1 NES2NLS

LIMK1

(c)

NES1 NES2

MCR

NLS

GRACE Proline-rich region bHLH/ZIP ZIP -likeNH2

NH2

NH2

NH2

NH2

COOH831aa

MLXIPL

(b)

GTF2IRD1 COOH900aa

LZ 1

HLH

1

HLH

2

HLH

3

HLH

4

HLH

5

NLS(e)

(d)

GTF2I COOH998aa

LZ 1

HLH

1

HLH

2

HLH

3

HLH

4

HLH

5

NLS

HLH

6

GTF2IRD2 COOH900aa

LZ 1

HLH

1

HLH

2 Zing finger

LZ2

NLS(f)

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.



expression (Iizuka et al., 2004). Instead, increased Mlxipltransactivation activity has been demonstrated in genetic-ally obese mice. These data provide compelling evidencefor the physiological role of MLXIPL in the regulation oflypogenic enzyme genes transcription, suggesting that aderegulation ofMLXIPL gene dosage could be responsibleof an alteration in glucose and lipid metabolism. Sinceapproximately 75% of the WBS patients show elevatedglucose levels associated with an impaired glucose toler-ance or silent diabetes (Pober et al., 2010), the hemizygosityof MLXIPL has been proposed to reduce their ability torespond to high-glucose diet, through the activation of theexpression of lipogenic enzymes using glucose precursors(Merla et al., 2004). Notably, another WBS gene, theSyntaxin-1A, should be considered as a good candidate forthe glucose phenotype because of its role in insulin release,and the presence of abnormal glucosemetabolism inmousemodels with aberrantly expressed Stx-1a (Pober et al.,2010).

LIMK1

The LIMKinase 1 (LIMK1) belongs to a phylogeneticallyconserved family of serine/threonine kinases, which havebeen shown to be potent regulators of the actin cyto-skeleton (Nagata et al., 1999; Manetti, 2011) (Figure 4c).The observation that Limk1 is strongly expressed in thebrain has further spurred interest in ascertaining its in vivofunctions, suggesting a possible role in the nervous system(Frangiskakis et al., 1996). Recent findings support thehypothesis that LIMK1 regulates structural developmentof synapses in vivo, through its central role in the regulatorycascade controlling actin dynamics, involving the humanp21-activated kinase Pak and Cofilin, a major actin-depolymerising factor (Figure 5c). However, its linkage withWBS has been challenged for a long time for the divergentresults obtained by independent studies describing theeffects of Limk1 knockout at the neuromuscular junction(NMJ) inmouse andDrosophila animalmodels (Eaton andDavis, 2005;Ang et al., 2006).Amodel that reconciles theseobservations describes that LIMK1 plays a pivotal anddosage sensitive role in both restricting and promotingNMJ growth and synapses stability, strongly supportingthe hypothesis that a consequent disruption in synapsedevelopment may underlie the behavioural and develop-mental symptoms of WBS patients (Eaton and Davis,2005).

LIMK1 is targeted by the brain-specific microRNAmiR-134 (Schratt et al., 2006). It was hypothesised thatupon synaptic stimulation, the release of brain-derivedneurotrophic factor (BDNF) triggers the inactivation ofthe miR-134-associated silencing complex, enhancingLIMK1 protein synthesis that drives the spine growthprocess. Individuals with WBS also manifest hyperacusisand hear defects. Very recently, Matsumoto et al. (2011)showed a previously unknown function for Limk1 in theregulationof themotil responses of cochlear outer hair cells(OHC) and cochlear amplification. These data suggest that

haploinsufficiency of LIMK1 may be responsible for theprogressive hear loss observed in WBS patients.

TFII

General transcription factor 2-I (GTF2I), GTF2I repeatdomain containing protein 1 (GTF2IRD1) and GTF2Irepeat domain containing protein 1 (GTF2IRD2) belongto the TFII-I family of transcription factors, a versatilegroup of proteins with broad functional activities (Bayar-saihan and Ruddle, 2000; Bayarsaihan et al., 2002). TheGTF2IRD1 and GTF2I show a considerable sequencehomology within a repeated domain, known as I-repeats,characterised by the presence ofmultiple helix–loop–helix-like novel motifs, which display sequence-specific DNA-binding properties (Figure 4d–f) (Bayarsaihan et al., 2002).GTF2I acts as a multifunctional transcription factor thatbinds core promoter (Inr) and enhancer (E-box) elements(Roy, 2007). Similarly, GTF2IRD1 modulates genesinvolved in tissue development and differentiation, such asHOXC8, GOOSECOID and TROPONIN ISLOW throughthe binding to highly conserved DNA elements, defined asGTF2IRD1 upstream control elements (GUCEs) (Chimgeet al., 2008). The GTF2IRD2 gene function is not welldefined, even if the presence of several features character-istic of regulatory factors, including two I-repeats, twoleucine zippers and a single Cys-2/His-2 zinc finger, sug-gests that GTF2IRD2 has DNA-binding and protein-binding properties. GTF2I and GTF2IRD1 genes arecommonly deleted in WBS patients, while GTF2IRD2 isdeleted in carriers of the 1.84Mb deletion.Gtf2i and Gtf2ird1, highly expressed during neural devel-

opment and in normal neuronal tissues, are crucial in variousaspects of mouse development, through the regulation of theTGF_RII/Alk1/Smad5 and Vegfr2 signal transduction cas-cades (Figure 5d) (Enkhmandakh et al., 2009). The loss ofeither the Gtf2ird1 or Gtf2i allele was shown to causeembryonic lethality, while Gtf2ird12/2 and Gtf2i2/2embryos appeared to be delayed in development and alsodisplayed brain haemorrhage, vasculogenic, craniofacialand neural tube defects. Furthermore, in a subset of miceheterozygous for these genes bitemporal narrowing, as wellas other growth, skeletal, craniofacial and pigmentationdefects reminiscent of the characteristic facial appearanceand dental problems seen in WBS individuals were found.Among genes whom expression was significantly disturbedby both Gtf2i and Gtf2ird1 knockouts, microarray datarevealed a few candidates with a well-established relevanceto the craniofacial development, such asmouseScand3 andKbtbd (Makeyev et al., 2004). Consistent with these find-ings, the study of individuals carrying atypical deletions ofthe WBSCR has strengthened the idea that GTF2I andGTF2IRD1 may contribute to some of the craniofacialfeatures, the global intellectual deficit and some aspects ofthe cognitive profile, such as visuospatial constructivecognition (VSC) (Ferrero et al., 2009). More specifically,the hemizygosity of the GTF2IRD1 gene has been associ-ated with the WBS facial features and VSC deficits, whilst



(a)

BAZ1B

Chromatin remodeling

OFF

ATP

Glucose

ChoRE

MLXIPL

Regulation of hepatic glycolysis,lipogenesis and gluconeogenesis

Blood glucoseLPKACC1FASNELOVL6G6PDHGYS-2PP1GLG6Pase

E-box E-box

MLX

IPL

MLX

IPL

MLX

MLX

ON

Gene regulation by thevitamin D receptor

Transcriptionfactors

WINAC

BAZ1B

BAZ1B

WICH

Support to DNA replication5′

5′5′5′

5′ 3′

3′

3′

3′ 3′

LIMK1

CofilinPAK

G-actin F-actin

Cell migration

TFII

GTF2RD1

GTF2RD1VEGFR2

TGFBR1

TGFBR2

SMAD5

ALK1

GUCE

GUCE

GTF2I

E-box Inr

HOXC8

Embryo development

Vasculogenesis/angiogenesis

Brain/heart morphogenesis

Craniofacial development

GOOSECOID

TROPONINISLOW

Cell cycle regulation

G1

G2

Neuronal differentation

M SInactive cofilin

miR-134

LIMK1

(ERK, JNK, p38)

PP

P

BAZ1B

Dispensable

SSHCIN

Required

MAPKeffectors

(b)

(d)(c)

Figure 5 Caption on following page.

Mo

lecular

Gen

eticso

fW

illiams–B

euren

Synd

rom

e

eLS

&2012,Jo

hn

Wile

y&

Son

s,Ltd

.w

ww

.els.n

et

8

that of the GTF2I gene is retained to play a crucial role inseveral aspects of embryonic development and the devel-opment of social neurocircuitry, thus providing a strongcontribution in the genesis of the peculiar WBS socialbehaviour (Dai et al., 2009).

Lessons from Single Gene Variants

Single gene variants in WBS patients who exhibit indi-vidual WBS phenotype are helpful to shed light on thepathogenic role of genes within the WBS region. A clearrole for theELNhaploinsufficiency in connective tissue andcardiovascular abnormalities comes from sequence analy-sis studies that identified more than 80 ELN mutations,including single base substitutions, splicing mutations,regulatory mutations and small insertions/deletions(indels) (Ewart et al., 1994; Olson et al., 1995; Urban et al.,2001; Micale et al., 2010) in patients affected by the non-syndromic SVAS.

The phenotypic consequences of the Q241H variant ofMLXIPL have been recently assessed demonstrating a sig-nificant association with decreased concentrations ofplasma triglycerides (Kooner et al., 2008; Nakayama et al.,2011). Given the MLXIPL key role in energy storage, gen-etic variations of the MLXIPL have been suggested to berelevant to physiological adaptations to nutritional stressesthat have occurred during the evolution ofmodern humans,according to the ‘thrifty gene’ concept (Neel, 1962). Inter-estingly, type 2 diabetes mellitus, anotherWBS clinical sign,has been associated with the rs12056034 SNP of BAZ1B inSouth Indian population (Chidambaram et al., 2010).

Low et al. (2011) have recently demonstrated thers6460071 SNP located on LIMK1 gene is significantlyassociated with increased risk of intracranial aneurysm inJapanese population, and that the rs710968 SNP correlateswith an increasing risk of both intracranial aneurysm andintracerebral haemorrhage (Yamada et al., 2008).Of note astrong association has been found for the risk haplotypecomposed of the +502A insertion of ELN, which reducesthe rate of ELN transcription, and the 2187C4T substi-tution in LIMK1, reducing promoter activity, suggesting acombined effect of the SNPs possibly by weakening thevascular wall (Akagawa et al., 2006).

Conclusive Remarks

Despite the genetic advances of the last years,much remainsto be done in order to elucidate the molecular genetics ofWBS. Polymorphisms in the nondeleted allele affectingprotein function or expression level, the effects of the dele-tion on the expression of neighbouring genes, the action ofmodifier genes, including epigenetic alterations, locatedelsewhere in the genome,may contribute to the considerablephenotypic variability observedamongpatients. In linewiththese hypotheses it was recently shown inWBS, andmore ingeneral in genomic disorders, that the causative structuralchromosomal rearrangements affect the relative expressionlevels of normal-copy number neighbouring genes (Merlaet al., 2006) suggesting an underlying complexity that mightinvolve the size of the deletion, the altered structure ofchromatin, a dosage-compensation mechanism, or a com-bination of these factors.By carrying outmicroarray analyses it has been proposed

that a number of WBS phenotypes might arise from thederegulation of a few key gene products, which in concertinfluence regulatory networks, leading to specific traits(Henrichsen et al., 2011). Transcriptomes analysis of skinfibroblasts fromWBS patients have led to the identificationof anumberof transcriptionmodules,whicharederegulatedin WBS patient cells. A significant enrichment in extra-cellular matrix genes, major histocompatibility complex(MHC) genes, as well as genes inwhich the products localiseto the post-synaptic membrane, were identified between thedifferentially expressed genes. Interestingly, the function ofsome of these genes may be relevant to the pathophysiologyof some WBS features, such as metabolic phenotypes(UCP2) (Fleury et al., 1997), dental anomalies (SPON1)(Kitagawa et al., 2006), and neurological features, cognitionor brain development (HSPB2, ABHD14A, GABRE)(Hoshino et al., 2003; Stetler et al., 2008).Further efforts are required to overcome the limitation

of using cell lines from tissues that may be not directlyassociated to the complex WBS phenotypes, such as cog-nitive features or connective tissue anomalies. This limitingexperimental condition could be partially exceed in a veryclose future by generating induced pluripotent stem cells(iPSCs), specialised adult cells that may be reprogrammedgenetically to behave like embryonic stem cells, which have

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.



the potential of differentiating into and generating specificcells and tissues. WBS patient-specific iPSCs represent avaluable tool for the study of human diseases and possiblyfor the development of therapies.

Abbreviations

WBS, Williams–Beuren syndrome; SVAS, supravalvularaortic stenosis; SD, segmental duplications; NAHR, non-allelic homologous recombination; Indels, small inser-tions/deletions

References

Akagawa H, Tajima A, Sakamoto Y et al. (2006) A haplotype

spanning two genes, ELN and LIMK1, decreases their tran-

scripts 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. Devel-

opmental Biology 293: 178–190.

Antonell A, de Luis O, Domingo-Roura X and Perez-Jurado LA

(2005)Evolutionarymechanisms 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 multi-

functional protein in transcription, repair, and replication.

Biochemistry and Cell Biology 89: 12–23.

Bayarsaihan D and Ruddle FH (2000) Isolation and character-

ization of BEN, amember of theTFII-I family ofDNA-binding

proteins containing distinct helix–loop–helix domains. Pro-

ceedings 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 chromo-

some 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.

BroderK,Reinhardt E,Ahern J et al. (1999) Elevated ambulatory

blood pressure in 20 subjects withWilliams syndromeAmerican

Journal of Medical Genetics 83: 356–360.

Cairo S,Merla G, Urbinati F, Ballabio A and Reymond A (2001)

WBSCR14, a gene mapping to theWilliams–Beuren syndrome

deleted region, is a newmember of theMlx transcription factor

network. Human Molecular Genetics 10: 617–627.

Cherniske EM, Carpenter TO, Klaiman C et al. (2004) Multi-

system 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.

ChimgeNO,MakeyevAV,Ruddle FHandBayarsaihanD (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) Hemi-

zygosity at the NCF1 gene in patients with Williams-Beuren

syndrome decreases their risk of hypertension. American Jour-

nal 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-associ-

atedTFII-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.

FerreroGB,HowaldC,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.

FleuryC,NeverovaM,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 con-

structive 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 tran-

scription modules to identify expression clusters perturbed in

Williams–Beuren syndrome.PLoSComputationalBiology 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 childrenwithWilliams syndrome.

American Journal of Medical Genetics Part C: Seminar on

Medical Genetics 154C: 220–228.



Hoshino J, Aruga J, IshiguroA andMikoshibaK (2003) Dorz1, a

novel gene expressed in differentiating cerebellar granule neu-

rons, is down-regulated in Zic1-deficient mouse. Brain

Research. Molecular Brain Research 120: 57–64.

Huang YH, Bao Y, PengW 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 aswell as glycolysis.Proceedings

of theNational Academy of Sciences of theUSA 101: 7281–7286.

Inoue K and Lupski JR (2002) Molecular mechanisms for geno-

mic 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.DNARepair 8:

1139–1152.

KitagawaH, 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.

KitagawaM,KudoY, IizukaS et al. (2006)Effect ofF-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) Gen-

ome-wide scan identifies variation in MLXIPL associated with

plasma triglycerides. Nature Genetics 40: 149–151.

KriekM,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 dupli-

cations. 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 crit-

ical 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 regu-

lators.Medical care Research andReview [Epub ahead of print].

Matsumoto N, Kitani R and Kalinec F (2011) Linking LIMK1

deficiency to hyperacusis and progressive hearing loss in indi-

viduals 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.

MerlaG,Howald C, Antonarakis SE andReymondA (2004) The

subcellular localization of theChoRE-binding protein, encoded

by the Williams–Beuren syndrome critical region gene 14, is

regulated by 14-3-3.HumanMolecular Genetics 13: 1505–1514.

MerlaG,Howald C, Henrichsen CN et al. (2006) Submicroscopic

deletion in patients withWilliams–Beuren syndrome influences

expression levels of the nonhemizygous flanking genes. Ameri-

can 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 tran-

scription 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 LIMdomain 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 Gen-

etics 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.

OyaH,YokoyamaA,Yamaoka I et al. (2009) Phosphorylation of

Williams syndrome transcription factor by MAPK induces a

switching between two distinct chromatin remodeling com-

plexes. 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 Wil-

liams–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 ofmitochondrial 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 muta-

tion 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 Pharma-

cology 63: 2075–2080.

ValeroMC, deLuisO,Cruces J andPerez JuradoLA (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 theWilliams–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 complexB-WICHchanges the chromatin structure

and recruits histone acetyl-transferases to active rRNA genes.

PLoS One 6(4): e19184.

YamadaY,Metoki N, YoshidaH 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 func-

tion 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 andMolecular 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 atWilliams–Beuren syndrome 7q11.23 region.

Human Genetics 128(1): 3–26.



Date post:	08-Dec-2016
Category:	Documents
Upload:	giuseppe
View:	224 times
Download:	9 times

eLS || Molecular Genetics of Williams-Beuren Syndrome

Documents