Mutations in the human TBX4 gene cause small patella syndrome

Am J Hum Genet. 2004 Jun;74(6):1239-48. doi: 10.1086/421331. Epub 2004 Apr 21.


Small patella syndrome (SPS) is an autosomal-dominant skeletal dysplasia characterized by patellar aplasia or hypoplasia and by anomalies of the pelvis and feet, including disrupted ossification of the ischia and inferior pubic rami. We identified an SPS critical region of 5.6 cM on chromosome 17q22 by haplotype analysis. Putative loss-of-function mutations were found in a positional gene encoding T-box protein 4 (TBX4) in six families with SPS. TBX4 encodes a transcription factor with a strongly conserved DNA-binding T-box domain that is known to play a crucial role in lower limb development in chickens and mice. The present identification of heterozygous TBX4 mutations in SPS patients, together with the similar skeletal phenotype of animals lacking Tbx4, establish the importance of TBX4 in the developmental pathways of the lower limbs and the pelvis in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Bone Diseases, Developmental / genetics*
  • Chromosomes, Human, Pair 17 / genetics
  • Female
  • Haplotypes / genetics
  • Heterozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation / genetics*
  • Patella / abnormalities*
  • Pedigree
  • Pelvic Bones / abnormalities
  • Protein Conformation
  • Protein Folding
  • Sequence Homology, Amino Acid
  • Syndrome
  • T-Box Domain Proteins / deficiency
  • T-Box Domain Proteins / genetics*


  • T-Box Domain Proteins
  • TBX4 protein, human

Associated data

  • GENBANK/AF188703
  • GENBANK/U28049