title: Genes encoding catalytic subunits of protein kinase A and risk of spina bifida.
abstract: BACKGROUND
  PRKACA and PRKACB are genes encoding the cAMP-dependent protein kinase A (PKA) catalytic subunits alpha and beta, respectively. PKA is known to be involved in embryonic development, as it down-regulates the Hedgehog (Hh) signaling pathway, which is critical to normal pattern formation and morphogenesis. The PKA-deficient mouse model, which has only a single catalytic subunit, provided intriguing evidence demonstrating a relationship between decreased PKA activity and risk for posterior neural tube defects (NTDs) in the thoracic to sacral regions of gene-knockout mice. Unlike most other mutant mouse models of NTDs, the PKA-deficient mice develop spina bifida with 100% penetrance. We hypothesized that sequence variations in human genes encoding the catalytic subunits may alter the PKA activity and similarly increase the risk of spina bifida.
  
  
  METHODS
  We sequenced the coding regions and the exon/intron boundaries of PRKACA and PRKACB. We also examined 3 common single-nucleotide polymorphisms (SNPs) of these 2 genes by allele discrimination.
  
  
  RESULTS
  Five sequence variants in coding region and 2 intronic sequence variants proximal to exons were detected. None of the 3 SNPs examined in the association study appeared to be associated with substantially increased risk for spina bifida.
  
  
  CONCLUSIONS
  Our results did not reveal a strong association between these PKA SNPs and spina bifida risk. Nonetheless, it is important to examine the possible gene-gene interactions between PRKACA and PRKACB when evaluating the risk for NTDs, as well as genes encoding regulatory subunits of PKA. In addition, interactions with other genes such as Sonic Hedgehog (SHH) should also be considered for future investigations.
authors.affiliation: Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Cecile
authors.initials: C
authors.lastname: Laurent
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lammer
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
mesh_terms: D000483:Alleles; D002140:California / Q000453:epidemiology; D016022:Case-Control Studies; D020134:Catalytic Domain / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D014644:Genetic Variation; D006801:Humans; D007438:Introns; D008499:Medical Records; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D011247:Pregnancy; D011256:Pregnancy Outcome; D017434:Protein Structure, Tertiary / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D016135:Spinal Dysraphism / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D021122:Protein Subunits; D017868:Cyclic AMP-Dependent Protein Kinases