title: Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips.
abstract: 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.
authors.affiliation: Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Hellemans
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
authors.forename: Andres
authors.initials: A
authors.lastname: Giedion
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Peter
authors.initials: P
authors.lastname: Kramer
authors.forename: Frits
authors.initials: F
authors.lastname: Beemer
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D004627:Embryonic Induction / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D005819:Genetic Markers; D006130:Growth Disorders / Q000235:genetics*; D006228:Hand Deformities, Congenital / Q000235:genetics*; D053823:Hedgehog Proteins; D006621:Hip Joint / Q000002:abnormalities*; D006801:Humans; D008126:Lod Score; D008297:Male; D008322:Mammals; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D053823:Hedgehog Proteins; D015534:Trans-Activators