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.
References
American Association on Mental Retardation (2002) Mental retardation: definition, classification, and systems of supports, 10th edn. American association on mental retardation, Washington D C
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 12:689–693
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 75:318–324
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 28:207–208
Donohoe E (2005) Denaturing high-performance liquid chromatography using the WAVE DNA fragment analysis system. Methods Mol Med 108:173–187
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 51:1229–1239
Fujita A, Kurachi Y (2000) SAP family proteins. Biochem Biophys Res Commun 269:1–6
Laumonnier F, Cuthbert PC, Grant SG (2007) The role of neuronal complexes in human X-linked brain diseases. Am J Hum Genet 80:205–220
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 20:1260–1271
Kim E, Sheng M (2004) PDZ domain proteins of synapses. Nat Rev Neurosci 5:771–781
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.
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):20953–20958
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 360:599–605
Chelly J, Khelfaoui M, Francis F, Chérif B, Bienvenu T (2006) Genetics and pathophysiology of mental retardation. Eur J Hum Genet 14:701–713
Humeau Y, Gambino F, Chelly J, Vitale N (2009) X-linked mental retardation: focus on synaptic function and plasticity. J Neurochem 109:1–14
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 24:10816–10825
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 27:9439–9450
Bassell GJ, Warren ST (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60:201–214
Elias GM, Nicoll RA (2007) Synaptic trafficking of glutamate receptors by MAGUK scaffolding proteins. Trends Cell Biol 17:343–352
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 27:2673–2682
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 1127:108–118
Acknowledgements
We thank the patients and their family members and the XLMR European Consortium for their participation in the study. We are grateful to Anna Alisi for graphical advice. This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zanni, G., van Esch, H., Bensalem, A. et al. A novel mutation in the DLG3 gene encoding the synapse-associated protein 102 (SAP102) causes non-syndromic mental retardation. Neurogenetics 11, 251–255 (2010). https://doi.org/10.1007/s10048-009-0224-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-009-0224-y