Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation

Am J Hum Genet. 2008 Nov;83(5):616-22. doi: 10.1016/j.ajhg.2008.10.004. Epub 2008 Oct 23.


Clubfoot is one of the most common severe musculoskeletal birth defects, with a worldwide incidence of 1 in 1000 live births. In the present study, we describe a five-generation family with asymmetric right-sided predominant idiopathic clubfoot segregating as an autosomal-dominant condition with incomplete penetrance. Other lower-limb malformations, including patellar hypoplasia, oblique talus, tibial hemimelia, developmental hip dysplasia, and preaxial polydactyly, were also present in some family members. Genome-wide linkage analysis with Affymetrix GeneChip Mapping 10K mapping data from 13 members of this family revealed a multipoint LOD(max) of 3.31 on chromosome 5q31. A single missense mutation (c.388G-->A) was identified in PITX1, a bicoid-related homeodomain transcription factor critical for hindlimb development, and segregated with disease in this family. The PITX1 E130K mutation is located in the highly conserved homeodomain and reduces the ability of PITX1 to transactivate a luciferase reporter. The PITX1 E130K mutation also suppresses wild-type PITX1 activity in a dose-dependent manner, suggesting dominant-negative effects on transcription. The propensity for right-sided involvement in tibial hemimelia and clubfoot suggests that PITX1, or pathways involving PITX1, may be involved in their etiology. Implication of a gene involved in early limb development in clubfoot pathogenesis also suggests additional pathways for future investigations of idiopathic clubfoot etiology in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Case-Control Studies
  • Chromosome Mapping
  • Chromosomes, Human, Pair 5
  • Congenital Abnormalities / genetics*
  • Conserved Sequence
  • Female
  • Gene Frequency
  • Genes, Dominant
  • Genetic Linkage
  • Genetic Markers
  • Haplotypes
  • Heterozygote
  • Humans
  • Lod Score
  • Lower Extremity Deformities, Congenital / diagnostic imaging
  • Lower Extremity Deformities, Congenital / genetics*
  • Lysine / metabolism
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation*
  • Mutation, Missense
  • Paired Box Transcription Factors / genetics*
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Radiography
  • Transcription Factors / genetics


  • Genetic Markers
  • Paired Box Transcription Factors
  • Transcription Factors
  • homeobox protein PITX1
  • Lysine