A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation

Large deletions in Xq21 often are associated with contiguous gene syndromes consisting of X-linked deafness type 3 (DFN3), mental retardation (MRX), a nd choroideremia (CHM). The identification of deletions associated with cla ssic CHM or DFN3 facilitated the positional cloning of the underlying genes , REP-I and POU3F4, respectively, and enabled the positioning of the MRX ge ne in between these genes. Here, we report the cloning and characterization of a novel gene, ribosomal SG-kinase 4 (RSK4; HGMW-approved symbol RPS6KA6 ), which maps in the MRX critical region. RSK4 is completely deleted in eig ht patients with the contiguous gene syndrome including MRX, partially dele ted in a patient with DFN3 and present in patients with an Xq21 deletion an d normal intellectual abilities. RSK4 is most abundantly expressed in brain and kidney. The predicted protein of 746 amino acids shows a high level of homology to three previously isolated members of the human RSK family. RSK 2 is involved in Coffin-Lowry syndrome and nonspecific MRX. The localizatio n of RSK4 in the interval that is commonly deleted in mentally retarded mal es together with the high degree of amino acid identity with RSK2 suggests that RSK4 plays a role in normal neuronal development. Further mutation ana lyses in males with X-linked mental retardation must prove that RSK4 is ind eed a novel MRX gene. (C) 1999 Academic Press.