A nonsense mutation in cGMP-dependent type II protein kinase (PRKG2) causes dwarfism in American Angus cattle

James E. Koltes, Bishnu P. Mishra, Dinesh Kumar, Ranjit S. Kataria, Liviu R. Totir, Rohan L. Fernando, Rowland Cobbold, David Steffen, Wouter Coppieters, Michel Georges, James M. Reecy

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Historically, dwarfism was the major genetic defect in U.S. beef cattle. Aggressive culling and sire testing were used to minimize its prevalence; however, neither of these practices can eliminate a recessive genetic defect. We assembled a 4-generation pedigree to identify the mutation underlying dwarfism in American Angus cattle. An adaptation of the Elston-Steward algorithm was used to overcome small pedigree size and missing genotypes. The dwarfism locus was fine-mapped to BTA6 between markers AFR227 and BM4311. Four candidate genes were sequenced, revealing a nonsense mutation in exon 15 of cGMP-dependant type II protein kinase (PRKG2). This C/T transition introduced a stop codon (R678X) that truncated 85 C-terminal amino acids, including a large portion of the kinase domain. Of the 75 mutations discovered in this region, only this mutation was 100% concordant with the recessive pattern of inheritance in affected and carrier individuals (log of odds score = 6.63). Previous research has shown that PRKG2 regulates SRY (sex-determining region Y) box 9 (SOX9)-mediated transcription of collagen 2 (COL2). We evaluated the ability of wild-type (WT) or R678X PRKG2 to regulate COL2 expression in cell culture. Real-time PCR results confirmed that COL2 is overexpressed in cells that overexpressed R678X PRKG2 as compared with WT PRKG2. Furthermore, COL2 and COL10 mRNA expression was increased in dwarf cattle compared with unaffected cattle. These experiments indicate that the R678X mutation is functional, resulting in a loss of PRKG2 regulation of COL2 and COL10 mRNA expression. Therefore, we present PRKG2 R678X as a causative mutation for dwarfism cattle.

Original languageEnglish (US)
Pages (from-to)19250-19255
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number46
DOIs
StatePublished - Nov 17 2009

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Cyclic GMP-Dependent Protein Kinase Type II
Dwarfism
Nonsense Codon
Collagen
Mutation
Pedigree
Inheritance Patterns
Messenger RNA
Terminator Codon
Protein Kinases
Real-Time Polymerase Chain Reaction
Exons
Phosphotransferases
Cell Culture Techniques
Genotype
Amino Acids
Research
Genes

Keywords

  • Achondroplasic dwarfism
  • BTA6
  • Recessive genetic disease
  • cGKII

ASJC Scopus subject areas

  • General

Cite this

A nonsense mutation in cGMP-dependent type II protein kinase (PRKG2) causes dwarfism in American Angus cattle. / Koltes, James E.; Mishra, Bishnu P.; Kumar, Dinesh; Kataria, Ranjit S.; Totir, Liviu R.; Fernando, Rohan L.; Cobbold, Rowland; Steffen, David; Coppieters, Wouter; Georges, Michel; Reecy, James M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 46, 17.11.2009, p. 19250-19255.

Research output: Contribution to journalArticle

Koltes, JE, Mishra, BP, Kumar, D, Kataria, RS, Totir, LR, Fernando, RL, Cobbold, R, Steffen, D, Coppieters, W, Georges, M & Reecy, JM 2009, 'A nonsense mutation in cGMP-dependent type II protein kinase (PRKG2) causes dwarfism in American Angus cattle', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 46, pp. 19250-19255. https://doi.org/10.1073/pnas.0904513106
Koltes, James E. ; Mishra, Bishnu P. ; Kumar, Dinesh ; Kataria, Ranjit S. ; Totir, Liviu R. ; Fernando, Rohan L. ; Cobbold, Rowland ; Steffen, David ; Coppieters, Wouter ; Georges, Michel ; Reecy, James M. / A nonsense mutation in cGMP-dependent type II protein kinase (PRKG2) causes dwarfism in American Angus cattle. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 46. pp. 19250-19255.
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