title: Concomitant partial exon skipping by a unique missense mutation of RPS6KA3 causes Coffin-Lowry syndrome.
abstract: Coffin-Lowry syndrome (CLS) is an X-linked semi-dominant disorder characterized by diverse phenotypes including intellectual disability, facial and digital anomalies. Loss-of-function mutations in the Ribosomal Protein S6 Kinase Polypeptide 3 (RPS6KA3) gene have been shown to be responsible for CLS. Among the large number of mutations, however, no exonic mutation causing exon skipping has been described. Here, we report a male patient with CLS having a novel mutation at the 3' end of an exon at a splice donor junction. Interestingly, this nucleotide change causes both a novel missense mutation and partial exon skipping leading to a truncated transcript. These two transcripts were identified by cDNA sequencing of RT-PCR products. In the carrier mother, we found only wildtype transcripts suggesting skewed X-inactivation. Methylation studies confirmed X-inactivation was skewed moderately, but not completely, which is consistent with her mild phenotype. Western blot showed that the mutant RSK2 protein in the patient is expressed at similar levels relative to his mother. Protein modeling demonstrated that the missense mutation is damaging and may alter binding to ATP molecules. This is the first report of exon skipping from an exonic mutation of RPS6KA3, demonstrating that a missense mutation and concomitant disruption of normal splicing contribute to the manifestation of CLS.
authors: Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Georgia Regents University, Augusta, GA 30912, USA; Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA.
authors: Jonathan D J
authors: JD
authors: Labonne
authors: Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Georgia Regents University, Augusta, GA 30912, USA; St Mark's School, 25 Marlboro Road, Southborough, MA 01772, USA.
authors: Min Ji
authors: MJ
authors: Chung
authors: Greenwood Genetic Center, Greenwood, SC 29646, USA.
authors: Julie R
authors: JR
authors: Jones
authors: Karlsruhe Institute of Technology (KIT)/University of Karlsruhe (TH), Germany.
authors: Priya
authors: P
authors: Anand
authors: Karlsruhe Institute of Technology (KIT)/University of Karlsruhe (TH), Germany.
authors: Wolfgang
authors: W
authors: Wenzel
authors: Divison of Human Genetics, Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA.
authors: Daniela
authors: D
authors: Iacoboni
authors: Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Georgia Regents University, Augusta, GA 30912, USA; Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA; Neuroscience Program, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors: Lawrence C
authors: LC
authors: Layman
authors: Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Georgia Regents University, Augusta, GA 30912, USA; Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: hkim@gru.edu.
authors: Hyung-Goo
authors: HG
authors: Kim
mesh_terms: D038921:Coffin-Lowry Syndrome / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D022821:RNA Splice Sites; D012326:RNA Splicing; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics* / Q000378:metabolism
chemical_list: D022821:RNA Splice Sites; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3
keywords: Coffin–Lowry syndrome; Kinase domain; Protein modeling; RSK2