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Identification of Novel Mutations in Patients with Coffin–Lowry Syndrome by a Denaturing HPLC-Based Assay

¹ Laboratorio di Diagnosi Genetica,² Unità Operativa Complessa di Pediatria e Genetica Medica, and³ Unità Operativa di Neurologia per il Ritardo Mentale, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Oasi Maria SS, Troina, Italy;⁴ Consultorio Genetico APSS, Trento, Italy;⁵ Department of Medical Genetics, Yorkhill Hospitals, Glasgow, Scotland, United Kingdom

^aaddress correspondence to this author at: IRCCS Oasi Maria SS, via Conte Ruggero 73, 94018 Troina, Italy; fax 39-0935-653327, e-mail mfichera@oasi.en.it

The first 300 words of the full text of this article appear below.

Coffin–Lowry syndrome (CLS; MIM #303600) is characterized by learning difficulties and dysmorphic traits in male patients and in some female carriers of the X-chromosome–linked gene mutation. The dysmorphic traits, skeletal abnormalities, and other clinical findings have been described (1). Mutations of the RSK2 gene (also called RPS6KA3, MIM *300075), mapping to Xp22.2, are found in the disease (2). The gene encodes a 740-amino acid protein member of the 90-kDa ribosomal S6 serine/threonine kinase family (3). In humans, the RSK family includes 4 growth factor–regulated members (RSK1 to -4) produced in all examined tissues and regions of the brain (4). The highly conserved feature of all these proteins is the presence of 2 nonidentical kinase catalytic domains. The N-terminal kinase domain (amino acids 68–323 in RSK2) is responsible for phosphotransferase activity toward substrates, whereas the C-terminal kinase domain (amino acids 422–675 in RSK2) is necessary for enzymatic activation of the N-terminal domain. RSKs are activated through direct phosphorylation by the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) in response to insulin and growth factors, oncogenic events, and ultraviolet irradiation. RSKs have been implicated in the stimulation of cell proliferation and differentiation, in the cellular stress response, and in apoptosis (5). To date, only a few RSK2-specific physiologic substrates have been described: the transcription factor CREB, histone H3, STAT3 (6), ATF4(7), and p53(8).

According to the most recent data (http://alsace.u-strasbg.fr/chimbio/diag/coffin/index.html), mutations in the RSK2 gene occur within all 22 exons, except exon 2. Approximately one third of the RSK2 gene mutations are missense changes, the other two thirds lead to premature translation termination. The proportion of de novo mutations is unusually high compared with other X-linked disorders, with most cases (80%) being sporadic (. . . [Full Text of this Article]