Concomitant partial exon skipping by a unique missense mutation of RPS6KA3 causes Coffin-Lowry syndrome

Jonathan D.J. Labonne, Min Ji Chung, Julie R. Jones, Priya Anand, Wolfgang Wenzel, Daniela Iacoboni, Lawrence C Layman, Hyung Goo Kim

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)42-47
Number of pages6
JournalGene
Volume575
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Coffin-Lowry Syndrome
Missense Mutation
Exons
Peptides
Mutation
X Chromosome Inactivation
Mothers
Phenotype
Mutant Proteins
Intellectual Disability
Methylation
Nucleotides
Complementary DNA
Adenosine Triphosphate
Western Blotting
ribosomal protein S6 kinase, 90kDa, polypeptide 3
Tissue Donors
Polymerase Chain Reaction
Genes

Keywords

  • Coffin-Lowry syndrome
  • Kinase domain
  • Protein modeling
  • RSK2

ASJC Scopus subject areas

  • Genetics

Cite this

Labonne, J. D. J., Chung, M. J., Jones, J. R., Anand, P., Wenzel, W., Iacoboni, D., ... Kim, H. G. (2016). Concomitant partial exon skipping by a unique missense mutation of RPS6KA3 causes Coffin-Lowry syndrome. Gene, 575(1), 42-47. https://doi.org/10.1016/j.gene.2015.08.032

Concomitant partial exon skipping by a unique missense mutation of RPS6KA3 causes Coffin-Lowry syndrome. / Labonne, Jonathan D.J.; Chung, Min Ji; Jones, Julie R.; Anand, Priya; Wenzel, Wolfgang; Iacoboni, Daniela; Layman, Lawrence C; Kim, Hyung Goo.

In: Gene, Vol. 575, No. 1, 01.01.2016, p. 42-47.

Research output: Contribution to journalArticle

Labonne, JDJ, Chung, MJ, Jones, JR, Anand, P, Wenzel, W, Iacoboni, D, Layman, LC & Kim, HG 2016, 'Concomitant partial exon skipping by a unique missense mutation of RPS6KA3 causes Coffin-Lowry syndrome', Gene, vol. 575, no. 1, pp. 42-47. https://doi.org/10.1016/j.gene.2015.08.032
Labonne, Jonathan D.J. ; Chung, Min Ji ; Jones, Julie R. ; Anand, Priya ; Wenzel, Wolfgang ; Iacoboni, Daniela ; Layman, Lawrence C ; Kim, Hyung Goo. / Concomitant partial exon skipping by a unique missense mutation of RPS6KA3 causes Coffin-Lowry syndrome. In: Gene. 2016 ; Vol. 575, No. 1. pp. 42-47.
@article{68bfccde1213430b942900bb48587938,
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.",
keywords = "Coffin-Lowry syndrome, Kinase domain, Protein modeling, RSK2",
author = "Labonne, {Jonathan D.J.} and Chung, {Min Ji} and Jones, {Julie R.} and Priya Anand and Wolfgang Wenzel and Daniela Iacoboni and Layman, {Lawrence C} and Kim, {Hyung Goo}",
year = "2016",
month = "1",
day = "1",
doi = "10.1016/j.gene.2015.08.032",
language = "English (US)",
volume = "575",
pages = "42--47",
journal = "Gene",
issn = "0378-1119",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Concomitant partial exon skipping by a unique missense mutation of RPS6KA3 causes Coffin-Lowry syndrome

AU - Labonne, Jonathan D.J.

AU - Chung, Min Ji

AU - Jones, Julie R.

AU - Anand, Priya

AU - Wenzel, Wolfgang

AU - Iacoboni, Daniela

AU - Layman, Lawrence C

AU - Kim, Hyung Goo

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

KW - Coffin-Lowry syndrome

KW - Kinase domain

KW - Protein modeling

KW - RSK2

UR - http://www.scopus.com/inward/record.url?scp=84947867226&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84947867226&partnerID=8YFLogxK

U2 - 10.1016/j.gene.2015.08.032

DO - 10.1016/j.gene.2015.08.032

M3 - Article

VL - 575

SP - 42

EP - 47

JO - Gene

JF - Gene

SN - 0378-1119

IS - 1

ER -