Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot

Audrey R. Ester, Katelyn S. Weymouth, Amber Burt, Carol A. Wise, Allison Scott, Christina A. Gurnett, Matthew B. Dobbs, Susan H. Blanton, Jacqueline T. Hecht

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Clubfoot is a common birth defect that affects 135,000 newborns each year worldwide. It is characterized by equinus deformity of one or both feet and hypoplastic calf muscles. Despite numerous study approaches, the cause(s) remains poorly understood although a multifactorial etiology is generally accepted. We considered the HOXA and HOXD gene clusters and insulin-like growth factor binding protein 3 (IGFBP3) as candidate genes because of their important roles in limb and muscle morphogenesis. Twenty SNPs from the HOXA and HOXD gene clusters and 12 SNPs in IGFBP3 were genotyped in a sample composed of non-Hispanic white and Hispanic multiplex and simplex families (discovery samples) and a second sample of non-Hispanic white simplex trios (validation sample). Four SNPs (rs6668, rs2428431, rs3801776, and rs3779456) in the HOXA cluster demonstrated altered transmission in the discovery sample, but only rs3801776, located in the HOXA basal promoter region, showed altered transmission in both the discovery and validation samples (P=0.004 and 0.028). Interestingly, HOXA9 is expressed in muscle during development. An SNP in IGFBP3, rs13223993, also showed altered transmission (P=0.003) in the discovery sample. Gene-gene interactions were identified between variants in HOXA, HOXD, and IGFBP3 and with previously associated SNPs in mitochondrialmediated apoptotic genes. The most significant interactions were found between CASP3 SNPS and variants in HOXA, HOXD, and IGFBP3. These results suggest a biologic model for clubfoot in which perturbation of HOX and apoptotic genes together affect muscle and limb development, which may cause the downstream failure of limb rotation into a plantar grade position.

Original languageEnglish (US)
Pages (from-to)2745-2752
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume149
Issue number12
DOIs
StatePublished - Dec 2009

Fingerprint

Clubfoot
Insulin-Like Growth Factor Binding Protein 3
Single Nucleotide Polymorphism
Extremities
Muscle Development
Genes
Multigene Family
Equinus Deformity
Muscles
Biological Models
Morphogenesis
Hispanic Americans
Genetic Promoter Regions
Caspase 3
Foot
Newborn Infant

Keywords

  • Association study
  • Clubfoot
  • Complex disease
  • Genotyping
  • HOXA
  • IGFBP3

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot. / Ester, Audrey R.; Weymouth, Katelyn S.; Burt, Amber; Wise, Carol A.; Scott, Allison; Gurnett, Christina A.; Dobbs, Matthew B.; Blanton, Susan H.; Hecht, Jacqueline T.

In: American Journal of Medical Genetics, Part A, Vol. 149, No. 12, 12.2009, p. 2745-2752.

Research output: Contribution to journalArticle

Ester, AR, Weymouth, KS, Burt, A, Wise, CA, Scott, A, Gurnett, CA, Dobbs, MB, Blanton, SH & Hecht, JT 2009, 'Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot', American Journal of Medical Genetics, Part A, vol. 149, no. 12, pp. 2745-2752. https://doi.org/10.1002/ajmg.a.33130
Ester, Audrey R. ; Weymouth, Katelyn S. ; Burt, Amber ; Wise, Carol A. ; Scott, Allison ; Gurnett, Christina A. ; Dobbs, Matthew B. ; Blanton, Susan H. ; Hecht, Jacqueline T. / Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot. In: American Journal of Medical Genetics, Part A. 2009 ; Vol. 149, No. 12. pp. 2745-2752.
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