Research
A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C
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* Corresponding author: Andreas W Kuss kuss_a@molgen.mpg.de
1 Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
2 Department of Animal Breeding and Biotechnology, University of Hohenheim, Stuttgart, Germany
3 Department of Molecular Pathology, SA Pathology and Women's and Children's Hospital, Adelaide, South Australia, Australia
4 Genetische Poliklinik, Klinikum der Universität Heidelberg, Heidelberg, Germany
5 Division of Clinical Genetics, Innsbruck Medical University, Innsbruck, Austria
6 Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
7 Development and Disease Group, Max Planck Institute for Molecular Genetics, Berlin, Germany
8 CHRU de Tours, Service de Génétique, 37000 Tours; INSERM U930, 37000 Tours, France
9 Genetic Services of Western Australia, King Edward Memorial Hospital for Women, Perth, Western Australia, Australia
10 The GOLD Service, Hunter Genetics, Waratah, New South Wales, Australia
11 Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium
12 Institut Cochin de Génétique Moléculaire, Centre National de la Recherche Scientifique (CNRS), Paris, France
13 Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
14 Department of Paediatrics, University of Adelaide, Adelaide, Australia
PathoGenetics 2010, 3:2 doi:10.1186/1755-8417-3-2
Published: 2 February 2010Abstract
Background
Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone. In addition the majority of patients are non-syndromic in that they do not present with clinically recognisable features. This makes it difficult to determine the molecular cause of this disorder on the basis of the phenotype alone. Mutations in KDM5C (previously named SMCX or JARID1C), a gene that encodes a transcriptional regulator with histone demethylase activity specific for dimethylated and trimethylated H3K4, are a comparatively frequent cause of non-syndromic X-linked mental retardation (NS-XLMR). Specific transcriptional targets of KDM5C, however, are still unknown and the effects of KDM5C deficiency on gene expression have not yet been investigated.
Results
By whole-mount in situ hybridisation we showed that the mouse homologue of KDM5C is expressed in multiple tissues during mouse development.
We present the results of gene expression profiling performed on lymphoblastoid cell lines as well as blood from patients with mutations in KDM5C. Using whole genome expression arrays and quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) experiments, we identified several genes, including CMKOR1, KDM5B and KIAA0469 that were consistently deregulated in both tissues.
Conclusions
Our findings shed light on the pathological mechanisms underlying mental retardation and have implications for future diagnostics of this heterogeneous disorder.