neurogenetics

, Volume 11, Issue 2, pp 251–255 | Cite as

A novel mutation in the DLG3 gene encoding the synapse-associated protein 102 (SAP102) causes non-syndromic mental retardation

  • Ginevra Zanni
  • Hilde van Esch
  • Anissa Bensalem
  • Yoann Saillour
  • Karine Poirier
  • Laetitia Castelnau
  • Hans Hilger Ropers
  • Arjan P. M. de Brouwer
  • Fréderic Laumonnier
  • Jean-Pierre Fryns
  • Jamel Chelly
SHORT COMMUNICATION

Abstract

We have identified a novel splice site mutation (IVS6-1G > A) in the disc-large homolog 3 (DLG3) gene, encoding the synapse-associated protein 102 (SAP102) in one out of 300 families with moderate to severe non-syndromic mental retardation. SAP102 is a member of the neuronal membrane-associated guanylate kinase protein subfamily comprising SAP97, postsynaptic density (PSD)95, and PSD93, which interacts with methyl-d-aspartate receptor and associated protein complexes at the postsynaptic density of excitatory synapses. DLG3 is the first mental retardation gene directly linked to glutamate receptor signalling and trafficking, increasingly recognised as a central mechanism in the regulation of synaptic formation and plasticity in brain and cognitive development.

Keywords

Synapse-associated protein 102 (SAP102) X-linked mental retardation (XLMR) Disc-large homolog 3 (DLG3) Methyl-d-aspartate receptor (NMDAR) Membrane-associated guanylate kinase protein (MAGUK) 

References

  1. 1.
    American Association on Mental Retardation (2002) Mental retardation: definition, classification, and systems of supports, 10th edn. American association on mental retardation, Washington D CGoogle Scholar
  2. 2.
    Mandel JL, Chelly J (2004) Monogenic X-linked mental retardation: is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations. Eur J Hum Genet 12:689–693CrossRefPubMedGoogle Scholar
  3. 3.
    Tarpey P, Parnau J, Blow M, Woffendin H, Bignell G, Cox C, Cox J, Davies H, Edkins S, Holden S, Korny A, Mallya U, Moon J, O'Meara S, Parker A, Stephens P, Stevens C, Teague J, Donnelly A, Mangelsdorf M, Mulley J, Partington M, Turner G, Stevenson R, Schwartz C, Young I, Easton D, Bobrow M, Futreal PA, Stratton MR, Gecz J, Wooster R, Raymond FL (2004) Mutations in the DLG3 gene cause non-syndromic X-linked mental retardation. Am J Hum Genet 75:318–324CrossRefPubMedGoogle Scholar
  4. 4.
    de Brouwer AP, Yntema HG, Kleefstra T, Lugtenberg D, Oudakker AR, de Vries BB, van Bokhoven H, Van Esch H, Frints SG, Froyen G, Fryns JP, Raynaud M, Moizard MP, Ronce N, Bensalem A, Moraine C, Poirier K, Castelnau L, Saillour Y, Bienvenu T, Beldjord C, des Portes V, Chelly J, Turner G, Fullston T, Gecz J, Kuss AW, Tzschach A, Jensen LR, Lenzner S, Kalscheuer VM, Ropers HH, Hamel BC (2007) Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium. Hum Mutat 28:207–208CrossRefPubMedGoogle Scholar
  5. 5.
    Donohoe E (2005) Denaturing high-performance liquid chromatography using the WAVE DNA fragment analysis system. Methods Mol Med 108:173–187PubMedGoogle Scholar
  6. 6.
    Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW (1992) Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 51:1229–1239PubMedGoogle Scholar
  7. 7.
    Fujita A, Kurachi Y (2000) SAP family proteins. Biochem Biophys Res Commun 269:1–6CrossRefPubMedGoogle Scholar
  8. 8.
    Laumonnier F, Cuthbert PC, Grant SG (2007) The role of neuronal complexes in human X-linked brain diseases. Am J Hum Genet 80:205–220CrossRefPubMedGoogle Scholar
  9. 9.
    Sans N, Petralia RS, Wang YX, Blahos J 2nd, Hell JW, Wenthold RJ (2000) A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J Neurosci 20:1260–1271PubMedGoogle Scholar
  10. 10.
    Kim E, Sheng M (2004) PDZ domain proteins of synapses. Nat Rev Neurosci 5:771–781CrossRefPubMedGoogle Scholar
  11. 11.
    Lau CG, Zukin RS. (2007). NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8:413–26. Erratum in: Nat Rev Neurosci 8(7):568.Google Scholar
  12. 12.
    Elias GM, Elias LA, Apostolides PF, Kriegstein AR, Nicoll RA (2008) Differential trafficking of AMPA and NMDA receptors by SAP102 and PSD-95 underlies synapse development. Proc Natl Acad Sci U S A 30(105):20953–20958CrossRefGoogle Scholar
  13. 13.
    Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, Dobrzeniecka S, Côté M, Perreault-Linck E, Carmant L, D'Anjou G, Fombonne E, Addington AM, Rapoport JL, Delisi LE, Krebs MO, Mouaffak F, Joober R, Mottron L, Drapeau P, Marineau C, Lafrenière RG, Lacaille JC, Rouleau GA, Michaud JL (2009) Synapse to disease group. Mutations in SYNGAP1 in autosomal non-syndromic mental retardation. N Engl J Med 360:599–605CrossRefPubMedGoogle Scholar
  14. 14.
    Chelly J, Khelfaoui M, Francis F, Chérif B, Bienvenu T (2006) Genetics and pathophysiology of mental retardation. Eur J Hum Genet 14:701–713CrossRefPubMedGoogle Scholar
  15. 15.
    Humeau Y, Gambino F, Chelly J, Vitale N (2009) X-linked mental retardation: focus on synaptic function and plasticity. J Neurochem 109:1–14CrossRefPubMedGoogle Scholar
  16. 16.
    Boda B, Alberi S, Nikonenko I, Node-Langlois R, Jourdain P, Moosmayer M, Parisi-Jourdain L, Muller D (2004) The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. J Neurosci 24:10816–10825CrossRefPubMedGoogle Scholar
  17. 17.
    Khelfaoui M, Denis C, van Galen E, de Bock F, Schmitt A, Houbron C, Morice E, Giros B, Ramakers G, Fagni L, Chelly J, Nosten-Bertrand M, Billuart P (2007) Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity. J Neurosci 27:9439–9450CrossRefPubMedGoogle Scholar
  18. 18.
    Bassell GJ, Warren ST (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60:201–214CrossRefPubMedGoogle Scholar
  19. 19.
    Elias GM, Nicoll RA (2007) Synaptic trafficking of glutamate receptors by MAGUK scaffolding proteins. Trends Cell Biol 17:343–352CrossRefPubMedGoogle Scholar
  20. 20.
    Cuthbert PC, Stanford LE, Coba MP, Ainge JA, Fink AE, Opazo P, Delgado JY, Komiyama NH, O'Dell TJ, Grant SG (2007) Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies. J Neurosci 27:2673–2682CrossRefPubMedGoogle Scholar
  21. 21.
    McCullumsmith RE, Kristiansen LV, Beneyto M, Scarr E, Dean B, Meador-Woodruff JH (2007) Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder. Brain Res 1127:108–118CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Ginevra Zanni
    • 1
    • 3
  • Hilde van Esch
    • 2
  • Anissa Bensalem
    • 4
  • Yoann Saillour
    • 1
  • Karine Poirier
    • 1
  • Laetitia Castelnau
    • 1
  • Hans Hilger Ropers
    • 5
  • Arjan P. M. de Brouwer
    • 6
  • Fréderic Laumonnier
    • 4
  • Jean-Pierre Fryns
    • 2
  • Jamel Chelly
    • 1
  1. 1.Institut CochinUniversité Paris Descartes, INSERM, CNRS UMR 8104, CHU CochinParisFrance
  2. 2.Centre for Human GeneticsUniversity Hospitals LeuvenLeuvenBelgium
  3. 3.Unit of Molecular MedicineBambino Gesù Childrens’ HospitalRomeItaly
  4. 4.INSERM U930 ERL3106, Université Francois-Rebelais, Centre Hospitalier Régional UniversitaireToursFrance
  5. 5.Max Planck Institute for Molecular GeneticsBerlinGermany
  6. 6.Department of Human GeneticsRadboud University Nijmegen medical CentreNijmegenThe Netherlands

Personalised recommendations