Associate Professor Cheryl Shoubridge
|Org Unit||Paediatrics and Reproductive Health|
|Telephone||+61 8 8313 2355|
Intellectual Disability Research
Identification of genes and understanding of molecular mechanisms leading to intellectual disabilities, autisms and some epilepsies represents a challenge of significant medical importance. Our research seeks to further our understanding of human brain function through the identification of genes and characterisation of their naturally occurring mutations implicated in various disorders of the brain.
Led by A/Prof Cheryl Shoubridge, the Molecular Neurogenetics laboratory focuses on identifying the molecular mechanisms and functional impact of mutations in genes causing X-linked intellectual disability (XLID). This research team is currently funded by two NHMRC project grants and a ARC Future Fellowship.
The key areas of research include:
- Utilize primary neuronal cell culture models to investigate the functional impact of patient mutations in genes involved in X-linked Intellectual disability, in particular the ARX and IQSEC2 genes.
- Animal models to investigate functional impact of the two most frequent expanded polyalanine tract mutations in the ARX gene.
- Establish the molecular mechanisms of disease associated with a range of expanded polyalanine tract mutations in ARX to begin to understand how these mutations underpin the intellectual disability with and without a broad spectrum of associated clinical symptoms in affected patients, including epilepsy.
- Investigate how phosphorylation may regulate the function of the ARX homeodomain transcription factor.
- Screen ARX and IQSEC2 in various patient and control groups.
- A/Prof Cheryl Shoubridge, PhD
ARC Future Fellow
Phone (08) 8161 8105
- Dr Kristie Rogers, Postdoctoral Researcher
- Dr Matilda Jackson, Postdoctoral Researcher
- Oliver Dearsley, Research Assistant
- Karagh Loring, Research Assistant
- Tessa Mattiske
Project title: ‘The impact of expanded polyalanine tract mutations in ARX on the transcriptome during brain development’
- Laura Redpath
Project title: "An unbiased interrogation of motif selection by the Aristaless-related homeodomain transcription factor, ARX"
Improving the pehnotypic severity of intellectual disability and seizures caused by expanded polyalanine tract mutations in the ARX homeobox transcription factor (NHMRC Proejct Grant 2016-2019).
Investigating how mutations in IQSEC2 cause intellectual disability and severe early onset seizures in children using a mouse modelling the knock out of Iqsec2 (Channel 7 Children's Research Foundation 2016).
How do mutations in ARX contribute to intellectual disability? (NHMRC Project Grant 2014-2016)
Understanding the molecular mechanisms of intellectual disability (ARC Future Fellowship 2013-2016).
Publications for the last 5 years
Polling S, Ormsby AR, Wood RJ, Lee K, Shoubridge C, Hughes JN, Thomas PQ, Griffing MDWD, Hill AF, Bowden Q, Bocking T & Hatters DM. Polyalanine expansions drive a shift into alpha helical clusters without amyloid fibril formation. Nature Structural and Molecular Biology. Dec; 22 (12) : 1008-15, doi: 10.1038/nsmb.3127.
Ishibashi M, Manning E, Shoubridge C, Krecsmarik M, Hawkins Ta, Giacomotto J, Zhao T, Mueller T, Bader PI, Cheung SW, Stankiewicz P, Bain NL, Hackett A, Reddy CCS, Mechaly AS, Peers B, Wilson SW, Lenhard B, Bally-Cuif L, Gecz J, Becker TS, Rinkwitz S. Copy number variants in patients with intellectual disbaility affect the regulation of ARX transcription factor gene. Human Genetics. Nov; 134 (11-12): 1163-82, doi: 10.1007/500439-015-1594-x.
Moey C, Topper S, Karn M, Knight Jhnson A, Das S, Vidaurre J and Shoubridge C. 2015. Re-initations of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX. European Journal of Human Genetics. Aug 26. doi: 10.1038/ejhg.2015.176.
Tan C, Shard C, Ranieri E, Hynes K, Pham D, LEach D, Buchanan G, Corbett M, Shoubridge C, Kumar R, Douglas E, Nguyen LS, McMahon J, Sadleir L, Specchio N, Marini C, Guerrini R, Steensbjerre Moller R, Depienne C, Han E, Thomas PQ, Berkovic SF, Scheffer IE, Gecz J. 2015. Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiecny. Human Molecular Genetics, Jun 29. pii: ddv245.
Moey C, Hinze SJ, Brueton L, Morton J, Kamien B, Barnett CP, Brunetti-Pierri N, Nicholl J, Gecz J and Shoubridge C. Xp11.1 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders. European Journal of Human Genetics, Jun 10. doi: 10.1038/ejhg.2015.123.
Marques I, Sa MJ, Soares G, Mota MC, Carvalho C, Aguiar LM, Amado M, Delgado CM, Calado A, Dias P, Berta Sousa A, Fortuna A, Santos R, Howell KB, Ryan MM, Leventer RJ, Leventer RJ, Sachdev R, Catford R, Friend K, Mattiska TR, Shoubridge C and Jorge P. 2015. Unravelling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach. MGGM, Jan 2015.
Lee K, Mattiske T, Kitamura K, Gecz J and Shoubridge C. 2014. Reduced polyalanine-expanded Arx mutant protein in developing mouse subpallium alters Lmo1 transcriptional regulation. Human Molecular Genetics, Feb 15;23(4):1084-94
Mattiske TR, Tan MH, Gecz J and Shoubridge C. 2013. Challenges of “Sticky” Co-immunoprecipitationL Polyalanine Tract Protein-Protein Interactions. Methods in Molecular Biology, 1017:121, PMID 23719912.
Tan MH, Gecz J and Shoubridge C. 2013. PCR Amplification and Sequence Analysis of GC-rich Sequences: Aristaless-Related Homeobox Example. Methods in Molecualr Biology, 1017:105, PMID 23719911.
Poeta L, Fusco F, Drongitis D, Shoubridge C, Manganelli G, Filosa S, Paciolla M, Courtney M, Collombat P, Brigida Lioi M, Gecz J, Ursini M.V and Miano MG. 2013. A new regulatory path associated with X-Linked Intellectual Disability and Epilepsy links the histone demethylase KDM5C to the Polyalanine expansions in the transcription factor ARX. American Journal of Human Genetics, 92(1):114.
Huang L, Jolly L, Willis-Owen S, Gardner A, Kumar R, Douglad E, Shoubridge C, Wieczorek D, Tzschach A, Cohen M, Hackett A, Field M, Froyen G, Hu H, Haas SA, Ropers HHM, Kalscheuer V, Corbett M, Gecz J. 2012. Non-coding, regulatory mutation implicates chromatin-associated gene HCEC1 in non-syndromic intellectual disability. American Journal of Human Genetics, Oct; 91(4):694-702.
Shoubridge C, Gardenier A, Schwartz CE, Hackett A, Field M and Gecz J. 2012. Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation. European Journal of Human Genetics, Apr 11; doi:10.1038/ejhg.2012.61.
Shoubridge C, Tan MH, Seiboth G and Gecz J. 2012. Missense mutations in the homeodomain of ARX abolish binding to DNA and cause a loss of transcriptional repression activity. Human Molecular Genetics, Apr 1;21(7): 1639-47.
Nguyen LS, Jolly L, Shoubridge C, CHan W, Huang L, Laumonnier F, Raynaud M, Hackett A, Field M, Rodriguez J, Srivastava AK, Lee Y, Addington AM, Rapoport JL, Suren S, Hahn C, Gamble J, Wilkinson MF, Corbett M and Gecz J. 2012. Genome-wide consequences of compromised RNA surveillance and its relevance for normal brain function. Molecular Psychiatry, Nov; 17 (11):1103-15.
Fullston T, Finnis M, Hackett A, Hodgson B, Brueton L, Baynam G, Norman A, Reish O, Shoubridge C, Gecz J. 2011. Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene. Clinical Genetics, Apr 15. doi: 10.1111/j.1399-0004.2011.01685.x.
To link to this page, please use the following URL: http://www.adelaide.edu.au/directory/cheryl.shoubridge