Abstract
BackgroundMental 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.ResultsBy 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.ConclusionsOur findings shed light on the pathological mechanisms underlying mental retardation and have implications for future diagnostics of this heterogeneous disorder.
Highlights
Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone
Non-syndromic forms seem to be more prevalent and they show a high degree of genetic heterogeneity; defects in >30 genes have been reported in patients with non-syndromic X-linked mental retardation (NS-X-linked mental retardation (XLMR))
We have previously shown that this mutation leads to reduced KDM5C expression [5]
Summary
Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome 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). Sequencing a large number of candidate genes to identify the underlying molecular defects is too costly and time consuming for routine diagnostics, at least with the currently employed methodology [2] Very often this approach will not discriminate between disease-causing mutations and functionally neutral changes. That are suitable for discerning disease-causing mutations are only available for a small minority of the known NS-XLMR genes so far If such tests do not exist, gene expression profiling is an alternative, provided the candidate gene is expressed in accessible cells or tissues. We found that these patients have specific gene expression signatures, which could be used to assess the pathogenic nature of DNA changes in KDM5C
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