Williams-Beuren syndrome: a challenge for genotype-phenotype correlations.

Many human chromosomal abnormality syndromes include specific cognitive and behavioural components. Children with Prader-Willi syndrome lack a paternally derived copy of the proximal long arm of chromosome 15, and eat uncontrollably; in Angelman syndrome lack of a maternal contribution of 15q11-q13 results in absence of speech, frequent smiling and episodes of paroxysmal laughter; deletions on 22q11 can be associated with obsessive behaviour and schizophrenia. The neurodevelopmental disorder Williams-Beuren syndrome (WBS), is caused by a microdeletion at 7q11.23 and provides us with one of the most convincing models of a relationship that links genes with human cognition and behaviour. The hypothesis is that deletion of one or a series of genes causes neurodevelopmental abnormalities that manifest as the fractionation of mental abilities typical of WBS. Detailed molecular characterization of the deletion alongside well-defined cognitive profiling in WBS provides a unique opportunity to investigate the neuromolecular basis of complex cognitive behaviour, and develop integrated approaches to study gene function and genotype-phenotype correlations.

[1]  A. Schinzel,et al.  High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions. , 1998, Human molecular genetics.

[2]  S. Desiderio,et al.  BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[3]  B. Morrow,et al.  Genomic disorders on 22q11. , 2002, American journal of human genetics.

[4]  A. Roy.  Biochemistry and biology of the inducible multifunctional transcription factor TFII-I. , 2001, Gene.

[5]  Colleen A. Morris,et al.  The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis , 1993, Cell.

[6]  C. Morris,et al.  A novel human gene FKBP6 is deleted in Williams syndrome. , 1998, Genomics.

[7]  Linda Chang,et al.  Brain biochemistry in Williams syndrome: evidence for a role of the cerebellum in cognition? , 1999, Neurology.

[8]  K. Uğurbil,et al.  Neural correlates of visual form and visual spatial processing , 1999, Human brain mapping.

[9]  R. Roeder,et al.  Cloning of an Inr‐ and E‐box‐binding protein, TFII‐I, that interacts physically and functionally with USF1 , 1997, The EMBO journal.

[10]  U. Francke,et al.  The gene for replication factor C subunit 2 (RFC2) is within the 7q11.23 Williams syndrome deletion. , 1996, American journal of human genetics.

[11]  A Ballabio,et al.  WBSCR14, a gene mapping to the Williams--Beuren syndrome deleted region, is a new member of the Mlx transcription factor network. , 2001, Human molecular genetics.

[12]  J. Weber,et al.  Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. , 2001, American journal of human genetics.

[13]  Alexandre Reymond,et al.  Identification of additional transcripts in the Williams-Beuren syndrome critical region , 2002, Human Genetics.

[14]  P. Enarson,et al.  Function and assembly of nuclear pore complex proteins. , 1999, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[15]  Mark Noble,et al.  LIM-kinase1 Hemizygosity Implicated in Impaired Visuospatial Constructive Cognition , 1996, Cell.

[16]  A. B. Maksymowych,et al.  Cloning and sequence analysis of a cDNA encoding human syntaxin 1A, a polypeptide essential for exocytosis. , 1995, Gene.

[17]  W. Merrick,et al.  Purification and Characterization of a New Eukaryotic Protein Translation Factor , 1998, The Journal of Biological Chemistry.

[18]  C. Deruelle,et al.  Configural and Local Processing of Faces in Children with Williams Syndrome , 1999, Brain and Cognition.

[19]  S. Narumiya,et al.  Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. , 1999, Science.

[20]  Patricia Spallone,et al.  Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome , 1993, Nature Genetics.

[21]  M. C. Caselli,et al.  Language acquisition in special populations: a comparison between Down and Williams syndromes , 2002, Neuropsychologia.

[22]  C. Cytrynbaum,et al.  Elastin: mutational spectrum in supravalvular aortic stenosis , 2000, European Journal of Human Genetics.

[23]  A. Schinzel,et al.  Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome. , 1996, Human molecular genetics.

[24]  S. Scherer,et al.  The BCL7 gene family: deletion of BCL7B in Williams syndrome. , 1998, Gene.

[25]  C. Inglehearn,et al.  Analysis of a human gene homologous to rat ventral prostate.1 protein. , 1997, Genomics.

[26]  Hiromichi Nagasawa,et al.  RETRACTED: The Chromatin-Remodeling Complex WINAC Targets a Nuclear Receptor to Promoters and Is Impaired in Williams Syndrome , 2003, Cell.

[27]  A Mari,et al.  Detection of an atypical 7q11.23 deletion in Williams syndrome patients which does not include the STX1A and FZD3 genes , 1999, Journal of medical genetics.

[28]  F. Ruddle,et al.  Isolation and characterization of BEN, a member of the TFII-I family of DNA-binding proteins containing distinct helix-loop-helix domains. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[29]  A. Karmiloff-Smith,et al.  Using case study comparisons to explore genotype-phenotype correlations in Williams-Beuren syndrome , 2003, Journal of medical genetics.

[30]  Rappold,et al.  Human Molecular Genetics , 1996, Nature Medicine.

[31]  A. Winterpacht,et al.  Partial deletion of the critical 1.5 Mb interval in Williams-Beuren syndrome , 2003, Journal of medical genetics.

[32]  Marleen Verhoye,et al.  Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice , 2002, Nature Genetics.

[33]  R. Nusse,et al.  A novel human homologue of the Drosophila frizzled wnt receptor gene binds wingless protein and is in the Williams syndrome deletion at 7q11.23. , 1997, Human molecular genetics.

[34]  E. Zackai,et al.  Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects , 2001, Journal of medical genetics.

[35]  E. Hardeman,et al.  Identification of a Novel Slow-Muscle-Fiber Enhancer Binding Protein, MusTRD1 , 2000, Molecular and Cellular Biology.

[36]  R. Ross,et al.  THE FINE STRUCTURE OF ELASTIC FIBERS , 1966, The Journal of cell biology.

[37]  M. C. Valero,et al.  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). , 2000, Genomics.

[38]  J. Macdonald,et al.  Abnormal Spine Morphology and Enhanced LTP in LIMK-1 Knockout Mice , 2002, Neuron.

[39]  Stephen W. Scherer,et al.  A 1.5 million–base pair inversion polymorphism in families with Williams-Beuren syndrome , 2001, Nature Genetics.

[40]  P. Scambler,et al.  Tbx1 haploinsufficiency identified by functional scanning of the DiGeorge syndrome region is the cause of aortic arch defects in mice. , 2001 .

[41]  M. Fichera,et al.  How microsatellite analysis can be exploited for subtelomeric chromosomal rearrangement analysis in mental retardation , 2001, Journal of medical genetics.

[42]  M Davies,et al.  Language and Williams syndrome: how intact is "intact"? , 1997, Child development.

[43]  A. Karmiloff-Smith,et al.  Cognitive modularity and genetic disorders. , 1999, Science.

[44]  R. Mecham,et al.  Novel arterial pathology in mice and humans hemizygous for elastin. , 1998, The Journal of clinical investigation.

[45]  A. Karmiloff-Smith.  Development itself is the key to understanding developmental disorders , 1998, Trends in Cognitive Sciences.

[46]  W. Miller,et al.  Divergent human and mouse orthologs of a novel gene (WBSCR15/Wbscr15) reside within the genomic interval commonly deleted in Williams syndrome , 2000, Cytogenetic and Genome Research.

[47]  K. Kuma,et al.  Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif. , 1994, Oncogene.

[48]  Gary H. Glover,et al.  Neural Correlates of Auditory Perception in Williams Syndrome: An fMRI Study , 2003, NeuroImage.

[49]  R. Borgatti,et al.  Unusual cognitive and behavioural profile in a Williams syndrome patient with atypical 7q11.23 deletion , 2003, Journal of medical genetics.

[50]  Ursula Bellugi,et al.  I. The Neurocognitive Profile of Williams Syndrome: A Complex Pattern of Strengths and Weaknesses , 2000, Journal of Cognitive Neuroscience.

[51]  X. Yan,et al.  Characterization and gene structure of a novel retinoblastoma-protein-associated protein similar to the transcription regulator TFII-I. , 2000, The Biochemical journal.

[52]  A. Buonanno,et al.  Molecular Dissection of DNA Sequences and Factors Involved in Slow Muscle-Specific Transcription , 2001, Molecular and Cellular Biology.

[53]  Weijia Zhang,et al.  LAB: A new membrane-associated adaptor molecule in B cell activation , 2003, Nature Immunology.

[54]  Alan C. Evans,et al.  Emotional responses to pleasant and unpleasant music correlate with activity in paralimbic brain regions , 1999, Nature Neuroscience.

[55]  K. Svoboda,et al.  Structure and function of dendritic spines. , 2002, Annual review of physiology.

[56]  Lawrence G. Appelbaum,et al.  III. Electrophysiological Studies of Face Processing in Williams Syndrome , 2000, Journal of Cognitive Neuroscience.

[57]  S. Thorgeirsson,et al.  Integration of a c-myc transgene results in disruption of the mouse Gtf2ird1 gene, the homologue of the human GTF2IRD1 gene hemizygously deleted in Williams-Beuren syndrome. , 2001, Genomics.

[58]  C. I. Zeeuw,et al.  The murine CYLN2 gene: genomic organization, chromosome localization, and comparison to the human gene that is located within the 7q11.23 Williams syndrome critical region. , 1998, Genomics.

[59]  C. Cytrynbaum,et al.  Music Skills and the Expressive Interpretation of Music in Children with Williams-Beuren Syndrome: Pitch, Rhythm, Melodic Imagery, Phrasing, and Musical Affect , 2001, Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence.

[60]  U. Francke,et al.  TBL2, a novel transducin family member in the WBS deletion: characterization of the complete sequence, genomic structure, transcriptional variants and the mouse ortholog , 1999, Cytogenetic and Genome Research.

[61]  U. Bellugi,et al.  Neuropsychological, neurological, and neuroanatomical profile of Williams syndrome. , 2005, American journal of medical genetics. Supplement.

[62]  C. Morris,et al.  A novel human gene, WSTF, is deleted in Williams syndrome. , 1998, Genomics.

[63]  S. Milgram,et al.  Signals from the X: signal transduction and X-linked mental retardation , 2002, International Journal of Developmental Neuroscience.

[64]  D. Ayer,et al.  MondoA, a Novel Basic Helix-Loop-Helix–Leucine Zipper Transcriptional Activator That Constitutes a Positive Branch of a Max-Like Network , 2000, Molecular and Cellular Biology.

[65]  J. Katahira,et al.  Clostridium perfringens Enterotoxin Utilizes Two Structurally Related Membrane Proteins as Functional Receptors in Vivo * , 1997, The Journal of Biological Chemistry.

[66]  C. Morris,et al.  Hypothesis for development of a behavioral phenotype in Williams syndrome. , 2005, American journal of medical genetics. Supplement.

[67]  I. Kondo,et al.  Interstitial deletion of chromosome 7q in a patient with Williams syndrome and infantile spasms , 1998, Journal of Human Genetics.

[68]  A. Deckel.  Hemispheric control of territorial aggression in Anolis carolinensis: effects of mild stress. , 1998, Brain, behavior and evolution.

[69]  Ursula Bellugi,et al.  Williams syndrome: neuronal size and neuronal-packing density in primary visual cortex. , 2002, Archives of neurology.

[70]  A. C. Chinault,et al.  Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome , 1997, Nature Genetics.

[71]  E. Hardeman,et al.  Identification of a Novel Slow-Muscle-Fiber Enhancer Binding Protein, MusTRD1 , 1998, Molecular and Cellular Biology.

[72]  C. I. Zeeuw,et al.  CLIP-115, a Novel Brain-Specific Cytoplasmic Linker Protein, Mediates the Localization of Dendritic Lamellar Bodies , 1997, Neuron.

[73]  M. Bayés,et al.  Mutational mechanisms of Williams-Beuren syndrome deletions. , 2003, American journal of human genetics.

[74]  A. Karmiloff-Smith,et al.  Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. , 1999, American journal of human genetics.

[75]  A. Doll,et al.  Characterization of two novel genes, WBSCR20 and WBSCR22, deleted in Williams-Beuren syndrome , 2002, Cytogenetic and Genome Research.

[76]  Stephan Eliez,et al.  IV. Neuroanatomy of Williams Syndrome: A High-Resolution MRI Study , 2000, Journal of Cognitive Neuroscience.

[77]  Dean Y. Li,et al.  Elastin is an essential determinant of arterial morphogenesis , 1998, Nature.

[78]  D. Young,et al.  FAMILIAL SUPRAVALVULAR AORTIC STENOSIS. , 1964, American journal of diseases of children.

[79]  U. Francke,et al.  A duplicated gene in the breakpoint regions of the 7q11.23 Williams-Beuren syndrome deletion encodes the initiator binding protein TFII-I and BAP-135, a phosphorylation target of BTK. , 1998, Human molecular genetics.

[80]  C A Morris,et al.  Natural history of Williams syndrome: physical characteristics. , 1988, The Journal of pediatrics.

[81]  B. Pober,et al.  Williams Syndrome: An Overview of Medical, Cognitive, and Behavioral Features , 1996 .

[82]  H. Aasheim,et al.  Identification and characterization of TESK2, a novel member of the LIMK/TESK family of protein kinases, predominantly expressed in testis. , 1999, Genomics.

[83]  M. Tassabehji,et al.  A transcription factor involved in skeletal muscle gene expression is deleted in patients with Williams syndrome , 1999, European Journal of Human Genetics.

[84]  U. Francke,et al.  Genes for two autosomal recessive forms of chronic granulomatous disease assigned to 1q25 (NCF2) and 7q11.23 (NCF1). , 1990, American journal of human genetics.

[85]  U. Bellugi,et al.  Cerebellar abnormalities in infants and toddlers with Williams syndrome , 2002, Developmental medicine and child neurology.

[86]  J. Westman,et al.  Infantile spasms in two children with Williams syndrome. , 1997, American journal of medical genetics.

[87]  Carolyn B. Mervis,et al.  COGNITIVE AND BEHAVIORAL GENETICS '99 Visuospatial Construction , 1999 .

[88]  M. Tassabehji,et al.  LIM–kinase deleted in Williams syndrome , 1996, Nature Genetics.

[89]  C. I. Zeeuw,et al.  Functional analysis of CLIP-115 and its binding to microtubules. , 2000, Journal of cell science.

[90]  Karel Svoboda,et al.  Abnormal Development of Dendritic Spines inFMR1 Knock-Out Mice , 2001, The Journal of Neuroscience.

[91]  Virginia Valian,et al.  A study of relative clauses in Williams syndrome , 2002, Journal of Child Language.

[92]  S. Thibodeau,et al.  A 30 kb deletion within the elastin gene results in familial supravalvular aortic stenosis. , 1995, Human molecular genetics.

[93]  Kazuhiro Kikuchi,et al.  Essential Role of Fkbp6 in Male Fertility and Homologous Chromosome Pairing in Meiosis , 2003, Science.

[94]  H. Katoh,et al.  Rho family GTPases as key regulators for neuronal network formation. , 2002, Journal of biochemistry.