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Neurogenetics Research ProgramIdentification of genes and understanding of molecular mechanisms leading to intellectual disability represents a challenge of significant medical importance. Our focus on syndromic and non-syndromic forms of X-chromosome linked intellectual disability (XLMR) extends the work carried out in the Department on fragile X syndrome. We identified the first gene for non-syndromic intellectual disability (MRX) in 1996 (the FMR2 gene). Several other MRX genes (PAK3, RSK2, alpha PIX and ARX), candidate MRX genes (FHF2, GRIA3, KFL8) as well as genes for syndromic forms of XLMR (MRXS; BFLS, ATRX gene mutation in SFM syndrome, CDKL5 in Rett syndrome) have been identified since. We might be seen primarily as a gene discovery group, however, our focus is gradually shifting towards functional characterisation of the novel MRX/MRXS genes (including animal and cellular models) and their role in molecular processes underpinning human cognitive function. We are also involved in studies of other X-linked disorders. In 1999 we identified the gene for spondyloepiphyseal dysplasia tarda (SEDL; disorder of bone growth), and more recently characterised its function and spectrum of mutations. We have an ongoing collaboration with A/Prof. Jamie Craig from Flinders University , Adelaide on cataract genetics and also tackle the gene discovery for X-linked cutaneous amyloidosis or reticulate pigmentary disorder (XLCA/PRD). Current researchOur main research focus is isolation and further characterisation of genes implicated in various forms of intellectual disability. We have a range of projects addressing various aspects of this work. Some of these include:
Key personnelResearch staffAssociate Professor Jozef Gécz, PhD Dr. Cheryl Shoubridge Dr. Mark Corbett Ms. Joanna Crawford Ms. Olivia McKenzie Ms. Lynne Hobson Postgraduate StudentsDesiree Cloosterman Marie Shaw Tod Fullston Recent publicationsGécz J, Pollard H, Consalez GG, Villard L, Stayton CL, Millasseau P, Khrestchatisky M, Fontes M Cloning and expression of a murine homologue of a human X-linked nuclear protein gene close to PGK1 (Xq13.3). Human Molecular Genetics 3:39-44, 1994. IF=8.59, SCI=31 Gécz J, Gedeon AG, Sutherland GR, Mulley JC Identification of FMR2 : A gene associated with FRAXE mental retardation. Nature Genetics 13:105-108, 1996. IF=26.49, SCI=131 Villard L,Gécz J, Mattei JF, Saugier-Veber P, Munnich A, Lyonnet S, Fontes M XNP Mutation in a large family with Juberg-Marsidi Syndrome. Nature Genetics 12:359-360, 1996. IF=26.49, SCI=38 Merienne K, Jacquot S, Pennetier S, Bankier A, Gécz J, Mandel JL, Mulley JC, Sassone-Corsi P, and Hanauer A A missense mutation in RPS6KA3 ( RSK2 ) responsible for non-specific mental retardation. Nature Genetics 22, 13-14, 1999. IF=26.49, SCI=68 Gedeon AK, Colley A, Jamieson R, Thompson EM, Rogers J, Sillence D. Tiller GE, Mulley JC and Gécz J Identification and expression of the SEDL gene for X-linked spondyloepiphyseal dysplasia tarda (SEDL). Nature Genetics 22, 400-404, 1999. IF=26.49, SCI=33 Gécz J FMR3 is a novel gene associated with FRAXE CpG island and transcriptionally silent in FRAXE non-specific mental retardation . Journal of Medical Genetics 37:782-784, 2000.IF=6.37, SCI=7 Hillman M, and Gécz J Fragile XE associated familial mental retardation protein 2 (FMR2) acts as a potent transcription activator. Journal of Human Genetics 46(5):251-259, 2001. IF=2.28, SCI=7 Gedeon AK, Tiller GE, Le Merrer M, Heuertz S, Tranebjaerg L, Chitayat D, Robertson S, Glass IA, Savarirayan R, Cole WG, Rimoin DL, Kousseff BG, Ohashi H, Zabel B, Munnich A, Gécz J, Mulley JC . The molecular basis of X-linked spondyloepiphyseal dysplasia tarda (SEDL). American Journal of Human Genetics 68:1386–1397, 2001.IF=11.60 , SCI=12 Tiller GE, Hannig VL, Dozier D, Carrel L, Trevarthen KC, Wilcox WR, Mundlos S, Haines JL, Gedeon AK , Gécz J A recurrent RNA splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda (SEDL). American Journal of Human Genetics 68:1398–1407, 2001. IF=11.60, SCI=8 Strømme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SM, Bruyere H, Lutcherath V, Gedeon AK, Wallace RH, Scheffer IE, Turner G, Partington M, Frints SG, Fryns JP, Sutherland GR, Mulley JC, Gécz J Mutations of the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nature Genetics 30: 441-445, 2002. IF=26.49 , SCI=60 Lower KM, Turner G, Kerr BA, Mathews KD, Shaw MA, Gedeon AK, Schelley S, Hoyme HE, White SM, Delatycki MB, Lampe AK, Clayton-Smith J, Stewart H, van Ravenswaay CM, de Vries BB, Cox B, Grompe M, Ross S, Thomas P, Mulley JC , Gécz J Mutations in a novel PHD finger gene, PHF6, cause Börjeson -Forssman-Lehmann syndrome Nature Genetics 32(4):661-5, 2002. IF=26.49, SCI=7 Turner G, Partington M, Kerr B, Mangelsdorf M, Gécz J Variable Expression of Mental Retardation, Autism, Seizures and Dystonic Hand Movements in Two Families with an Identical ARX Gene Mutation . American Journal of Medical Genetics 112(4):405-11, 2002. IF=2.60, SCI=11 Shaw MA, Chiurazzi P, Romain DR, Neri G, Gécz J A novel gene, FAM11A , associated with the FRAXF CpG island is transcriptionally silent in FRAXF full mutation. European Journal of Human Genetics 10:767-72, 2002. IF=3.67, SCI=2 Ropers HH, Hoeltzenbein M, Kalscheuer VM, Yntema H, Hamel B, Fryns JP, Chelly J, Turner G, Gécz J and Moraine C Non-syndromic X-linked mental retardation: where are the missing mutations? Trends in Genetics Jun;19(6):316-320, 2003. IF=12.02, SCI=9 Kalscheuer VM, Freude K, Jensen LR, Gécz J , Hoffmann K, Moser B Haas S, Gurok S, Haesler S, Nierle P, Aranda B, Nshedjan A, Tzschach A, Hartmann N, Roloff TC, Shoichet S, Hagens O, Jiong T, Fryns JP, Nuber U, Hoeltzenbein M, Reinhardt R, Vingron M, Scharff C, Scherthan H, Lenzner S, Schweiger S & Ropers HH. Mutations in the polyglutamine-binding protein 1 gene cause X-linked mental retardation. Nature Genetics 35(4):313-315, 2003. IF=26.49, SCI=3 Burdon KP, McKay JD, Sale MM, Russell-Eggitt IM, Mackey DA, Wirth MG, Elder JE, Nicoll A, Clarke MP, FitzGerald LM, Stankovich JM, Shaw MA, Sharma S, Gajovic S, Gruss P, Ross S, Thomas P, Voss AK, Thomas T, Gécz J, Craig JE. Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation. American Journal of Human Genetics 73(6):1120-30, 2003. IF=11.60, SCI=1 Sarafidou T, Kahl C, Martinez-Garay I, Mangelsdorf M, Gesk S, Baker E, Kokkinaki M, Talley, Maltby EL, French L, Harder L, Hinzmann B, Nobile C, Richkind K, Finnis M, European Collaborative Consortium for the study of ADLTE, Deloukas P, Sutherland GR, Kutsche K, Moschonas NK, Siebert R, Gécz J Folate-sensitive fragile site FRA10A is due to an expansion of a CGG-repeat in a novel gene FRA10AC1, encoding a nuclear protein. Genomics 84(1):69-81, 2004. IF=3.49 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, Gécz J , Wooster R, Raymond FL. Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation. American Journal of Human Genetics 75(2):318-324, 2004. IF=11.60 Freude K, Hoffmann K, Jensen LR, Delatycki MB, des Portes V, Moser B, Hamel B, van Bokhoven H, Moraine C, Fryns JP, Chelly J, Gécz J , Lenzner S, Kalscheuer VM, Ropers HH. Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation. American Journal of Human Genetics 75(2):305-309, 2004. IF=11.60 Weaving LS, Christodoulou J, Williamson SL, Friend KL, McKenzie OLD, Archer H, Evans J, Clarke A, Pelka GJ, Tam PPL, Watson C, Lahooti H, Ellaway CJ, Bennetts B, Leonard H, and Gécz J Mutations of CDKL5 Cause Infantile Spasms, Mental Retardation and a Rett Syndrome-like Phenotype. American Journal of Human Genetics 75:1079-1093, 2004, IF=11.60 IF - impact factor (as published in 2004) SCI - Science Citations (as of 11/2004; excluding self-citations) Invited reviewsGécz J and Mulley, JC Genes for cognitive function: Developments on the X. Genome research 10:157-163, 2000.IF=9.64 ,SCI=25 Gécz J The FMR2 gene, FRAXE and non-specific X-linked mental retardation: clinical and molecular aspects. Annals of Human Genetics 64(2):95-106, 2000. IF=3.10, SCI=25 Lower K, Mangelsdorf M, Gécz J Molecular genetics of mental retardation: A complex picture emerging. Expert Reviews in Molecular Diagnostics 1(2):89-94, 2001. IF not available yet. Marshall Graves JA, Gécz J and Hameister H Evolution of the human X - a smart and sexy chromosome that controls speciation and development . Cytogenetics and Genome Research 99(1-4):141-5, 2002. IF=0.50 Savarirayan R, Thompson E and Gécz J Spondylo-epiphyseal dysplasia tarda (SEDL, MIM #313400). European Journal of Human Genetics 11(9):639-42, 2003. IF=3.67 Gécz J Sutherland GR. Preface. Cytogenetics and Genome Research 100(1-4):5-6, 2003. IF=0.50 Gécz J The molecular basis of intellectual disability: novel genes with naturally occurring mutations causing altered gene expression in the brain. Frontiers in Bioscience Jan 1;9:1-7, 2004. IF=3.60 Weaving LS, Ellaway CJ, Gécz J , Christodoulou J Rett Syndrome: Clinical Review and Genetic Update Journal of Medical Genetics - in press. Invited chaptersGécz J and Gedeon AK SEDL. In: Creighton, T.E (Ed.) Encyclopedia of Molecular Medicine. Willey, 5 Vol. Pp.2875-2876, 2002. Sutherland GR, Gécz J, and Mulley JC Fragile X Syndrome and Other Causes of X-linked Mental Handicap. In: Emery & Rimoin's Principles and Practice of Medical Genetics (4th edition). Churchill Livingstone, 2002. Gécz J and Fish G FRAXE fragile site associated non-specific mental retardation and the FMR2 gene. In: Genetics of Neurobehavioral Disorders. Ed. G. Fish. Humana Press. 2003, p289-306. Gécz J and Savarirayan R Spondyloepiphyseal Dysplasia Tarda. In: Florian Lang (ed): Encyclopedic Reference of Molecular Mechanisms of Disease, 2004. Contact InformationUnit HeadAssociate Professor Jozef Gécz, PhD LocationNeurogenetics Laboratory Mailing AddressNeurogenetics Laboratory Phone/Fax/EmailPh (08) 8161 6339 Fax (08) 8161 7342 Email jozef.gecz@adelaide.edu.au LinksXLMR Update at Greenwood, SC USA AcknowledgementsWe have a range of national and international collaborators who contribute significantly to our research projects. Among these are: Prof. Gill Turner and Dr. Michael Partington, Newcastle, Australia Prof. John Christodoulou, Sydney, Australia A/Prof. Jamie Craig, Adelaide, Australia Drs. Anne Voss and Tim Thomas, Melbourne, Australia Prof. Hilger Ropers and his group, Berlin, Germany Dr. Laurent Villard, Marseille, France Dr. Lucy Raymond, Cambridge, UK Dr. Charles Schwartz, Greenwood, USA Dr. Dan Geschwind, Los Angels, USA This is a research laboratory, which is currently funded predominantly by Australian NH&MRC. Grants include NH&MRC Program Grant (1x), NH&MRC Project grant (1x) and NH&MRC Fellowship (1x). Other current funding bodies: CAN (Cure Autism Now Foundation), USA RSRF (Rett Syndrome Research Foundation), USA
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