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Vol. 122, No. 2, 2008
Issue release date: December 2008
Section title: Original Article
Cytogenet Genome Res 122:181–187 (2008)
(DOI:10.1159/000172086)

Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism

Xu S. · Han J.C. · Morales A. · Menzie C.M. · Williams K. · Fan Y.-S.
aDepartment of Pediatrics, University Miami, Miami, FL bProgram in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health Human Development, NIH, Bethesda, MD cInternational WAGR Syndrome Association, Manassas, VA (USA)

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Article / Publication Details

First-Page Preview
Abstract of Original Article

Accepted: 9/3/2008
Published online: 12/18/2008

Number of Print Pages: 7
Number of Figures: 3
Number of Tables: 3

ISSN: 1424-8581 (Print)
eISSN: 1424-859X (Online)

For additional information: http://www.karger.com/CGR

Abstract

WAGR (Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation) syndrome is a rare genomic disorder caused by deletion of the 11p14-p12 chromosome region. The majority of WAGR patients have mental retardation and behavioral problems, and more than 20% of the patients also have features of autism. While the Wilms tumor/genitourinary anomalies and aniridia are caused by deletion of WT1 and PAX6 respectively, the genomic cause of mental retardation and autism in WAGR syndrome remains unknown. Using oligonucleotide arrays, we have characterized the 11p14-p12 deletions in 31 patients and identified all the genes involved in each deletion. The deletions had sizes ranging from 4.9 to 23 Mb that encompass 18–62 genes (40 on average). In addition to WT1 and PAX6, all the patients had deletion of PRRG4 (transmembrane gamma-carboxyglutamic acid protein 4). The majority of them had deletion of BDNF (brain-derived neurotrophic factor) and SLC1A2 [solute carrier family 1 (glial high affinity glutamate transporter) member 2]. Deletion of BDNF and SLC1A2 occurred in patients with autism more frequently than in those without autism. Literature review on the functions of the genes suggests that haploinsufficiency of SLC1A2, PRRG4, and BDNF may contribute to mental retardation and behavioral problems. In particular, BDNF may modulate the risk of autism in WAGR patients as suggested by its link with Rett syndrome as a target of MECP2. We observed that all the de novo deletions occurred in the chromosome 11 inherited from the father in the families genotyped, implying a predisposition for de novo mutations occurring in spermatogenesis and possible involvement of imprinting in cognitive impairment in WAGR patients.


Article / Publication Details

First-Page Preview
Abstract of Original Article

Accepted: 9/3/2008
Published online: 12/18/2008

Number of Print Pages: 7
Number of Figures: 3
Number of Tables: 3

ISSN: 1424-8581 (Print)
eISSN: 1424-859X (Online)

For additional information: http://www.karger.com/CGR


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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References

  1. Berton O, McClung CA, DiLeone RJ, Krishnan V, Renthal W, et al: Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868 (2006).
  2. Brown KW, Power F, Moore B, Charles AK, Malik KTA: Frequency and timing of loss of imprinting at 11p13 and 11p15 in Wilms’ tumor development. Mol Cancer Res 6:1114–1123 (2008).
  3. Castermans D, Wilquet V, Steyaert J, Van de Ven W, Fryns JP, Devriendt K: Chromosomal abnormalities in individual with autism: A strategy towards the identification of genes involved in autism. Autism 8:141–161 (2004).
  4. Chen WG, Chang Q, Lin Y, Meissner A, West AE, et al: Derepression of BDNF transcription involves calcium-dependent phosphorylation of MECP2. Science 302:885–889 (2003).
  5. Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, et al: Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science314:140–143 (2006).
  6. Dallosso AR, Hancock AL, Brown KW, Williams AC, Malik K: Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms’ tumours. Hum Mol Genet 13:405–415 (2004).
  7. Davis LK, Meyer KJ, Rudd DS, Librant AL, Epping EA, et al: Pax6 3′ deletion results in aniridia, autism and mental retardation. Hum Genet 123:371–378 (2008).
  8. Del Gaudio D, Fang P, Scaglia F, Ward PA, Craigen WJ, et al: Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet Med 8:784–792 (2006).
  9. Fan Y-S, Jayakar P, Zhu H, Barbouth D, Sacharow S, et al: Detection of pathogenetic gene copy number variations in patients with mental retardation by genomewide oligo array genomic hybridization. Hum Mut 28:1124–1132 (2007).
  10. Fischbach BV, Trout KL, Lewis J, Luis CA, Sika M: WAGR syndrome: A clinical review of 54 cases. Pediatrics 116:984–988 (2005).
  11. Gauthier LR, Charrin BC, Borrell-Pages M, Dompierre JP, Rangone H, et al: Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell118:127–138 (2004).
  12. Hancock AL, Brown KW, Moorwood K, Moon H, Malik K, et al: A CTCF-binding silencer regulates the imprinted genes AWT1 and WT1-AS and exhibits sequential epigenetic defects during Wilms’ tumourigenesis. Hum Mol Genet 16:343–354 (2007).
  13. Huff V: Parental origin of WT1 mutations and mental retardation in WAGR syndrome. Nat Genet 8:13–14 (1994).
  14. Huff V, Meadows A, Riccardi VM, Strong LC, Saunders GF: Parental origin of de novo constitutional deletions of chromosomal band 11p13. Am J Hum Genet 1471:155–160 (1990).
  15. Jacquemont ML, Sanlaville D, Redon R, Raoul O, Cormier-Daire V, et al: Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet 43:843–849 (2006).
  16. Jin J, Bao X, Wang H, Pan H, Zhang Y, Wu X: RNAi-induced down-regulation of Mecp2 expression in the rat brain. Int J Dev Neurosci 26:457–465 (2008).
  17. Jinno Y, Yun K, Nishiwaki K, Kubota T, Ogawa O, et al: Mosaic and polymorphic imprinting of the WT1 gene in humans. Nat Genet 6:305–309 (1994).
  18. Kanai Y, Smith CP, Hediger MA: The elusive transporters with a high affinity for glutamate. Trends Neurosci16:365–370 (1993).
  19. Kulman JD, Harris JE, Xie L, Davie EW: Identification of two novel transmembrane gamma-carboxyglutamic acid proteins expressed broadly in fetal and adult tissues. Proc Natl Acad Sci USA98:1370–1375 (2001).
  20. Marshall CR, Noor A, Vincent JB, Lionel AC, Friedman J, Scherer SW, et al: Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82:477–488 (2008).
  21. Martinowich K, Hattori D, Wu H, Fouse S, He F, et al: DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation. Science 302:890–893 (2003).
  22. Persico AM, Bourgeron TT: Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Neurosci 29:349–358 (2006).
  23. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, et al: Strong association of de novo copy number mutations with autism. Science 16:445–449 (2007).

    External Resources

  24. Shashidharan P, Wittenberg I, Plaitakis A: Molecular cloning of human brain glutamate/aspartate transporter II. Biochim Biophys Acta1191:393–396 (1994).
  25. The Autism Genome Project Consortium: Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39:319–327 (2007).
  26. Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, et al: Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am J Hum Genet 77:442–453 (2005).
  27. Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, et al: Unified genetic theory for sporadic and inherited autism. Proc Natl Aacad Sci USA 104:12831–12836 (2007).
  28. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Hayden MR, et al: Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293:493–498 (2001).