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

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

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Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium.


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.

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