Abstract
Heterogeneous mutations in the X-linked gene RPS6KA3, encoding the protein kinase RSK2, are responsible for Coffin-Lowry Syndrome. Here we have further studied a male patient with a highly suggestive clinical diagnosis of CLS but in whom no mutation was found by exon sequencing. Western blot analysis revealed a protein much larger than the normal expected size. Sequencing of the RSK2 cDNA, showed the presence of an in-frame tandem duplication of exons 17–20. The mutated RSK2 protein was found to be inactive in an in-vitro kinase assay. This event, which was the result of a homologous unequal recombination between Alu sequences, is the first reported large duplication of the RPS6KA3 gene. Our finding provides further evidence that immunoblot analysis, or a molecular assay capable to detect large genomic mutational events, is essential for patients with a highly suggestive CLS clinical diagnosis but remaining without mutation after exon sequencing.
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References
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Acknowledgments
We are grateful to Verane Sommermeyer for technical assistance. PMP was supported by a fellowship from the Fondation Jérôme Lejeune. The work was supported by grants from the Agence Nationale pour la Recherche, the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche, the Collège de France and the Université Louis Pasteur, Strasbourg.
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439_2007_424_MOESM2_ESM.jpg
Supplementary Figure. B. Fusion of two Alu sequences from introns 16 and 20 led to a chimeric Alu sequence in ACL80. Sequences of intron 20 (with the Alu sequence shown in red), of intron 16 (with the Alu sequence shown in blue) and the sequence of patient ACL80. The box depicts the 8-bp sequence that is identical between introns 16 and 20 and where the recombination occurred (JPG 45 kb)
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Marques Pereira, P., Heron, D. & Hanauer, A. The first large duplication of the RSK2 gene identified in a Coffin-Lowry syndrome patient. Hum Genet 122, 541–543 (2007). https://doi.org/10.1007/s00439-007-0424-1
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DOI: https://doi.org/10.1007/s00439-007-0424-1