Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips

Am J Hum Genet. 2003 Apr;72(4):1040-6. doi: 10.1086/374318. Epub 2003 Mar 11.


Acrocapitofemoral dysplasia is a recently delineated autosomal recessive skeletal dysplasia, characterized clinically by short stature with short limbs and radiographically by cone-shaped epiphyses, mainly in hands and hips. Genomewide homozygosity mapping in two consanguineous families linked the locus to 2q35-q36 with a maximum two-point LOD score of 8.02 at marker D2S2248. Two recombination events defined the minimal critical region between markers D2S2248 and D2S2151 (3.74 cM). Using a candidate-gene approach, we identified two missense mutations in the amino-terminal signaling domain of the gene encoding Indian hedgehog (IHH). Both affected individuals of family 1 are homozygous for a 137C-->T transition (P46L), and the three patients in family 2 are homozygous for a 569T-->C transition (V190A). The two mutant amino acids are strongly conserved and predicted to be located outside the region where brachydactyly type A-1 mutations are clustered.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosome Mapping
  • Chromosomes, Human, Pair 2*
  • Embryonic Induction / genetics
  • Female
  • Genes, Recessive*
  • Genetic Markers
  • Growth Disorders / genetics*
  • Hand Deformities, Congenital / genetics*
  • Hedgehog Proteins
  • Hip Joint / abnormalities*
  • Humans
  • Lod Score
  • Male
  • Mammals
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Trans-Activators / chemistry
  • Trans-Activators / genetics*


  • Genetic Markers
  • Hedgehog Proteins
  • Trans-Activators

Associated data

  • GENBANK/P97812
  • GENBANK/Q02936
  • GENBANK/Q14623
  • GENBANK/Q15465
  • GENBANK/Q61488
  • GENBANK/Q62226
  • GENBANK/Q90419
  • GENBANK/Q91611
  • GENBANK/Q98862
  • OMIM/113100
  • OMIM/142945
  • OMIM/200700