title: Brachydactyly type A1 associated with unusual radiological findings and a novel Arg158Cys mutation in the Indian hedgehog (IHH) gene.
abstract: Brachydactyly type A1 (BDA1; MIM 112500) is characterized by shortness or absence of the middle phalanx of the hands and feet. The condition is caused by heterozygous mutations in the Indian hedgehog (IHH) gene or a yet unidentified gene on chromosome 5p13. We investigated six affected members of a large Swedish family segregating autosomal dominant brachymesophalangia. Affected individuals show hypoplasia of the ulnar styloid processes, ulna minus, osteoarthritis, normal length of all distal phalanges and shortening or absence of the middle phalanges. Stationary ossicles or sesamoid bones were observed at the metacarpal heads in all patients. Genetic analysis of the family showed that the IHH-gene was linked to the disease (Z(max) 3.42 at theta 0.00) and sequence analysis of IHH revealed a novel c.472C > T transition in all affected family members. The mutation results in a p.158Arg > Cys substitution located in the highly conserved amino-terminal domain of IHH. This domain is of importance for the interaction between IHH and the Patched receptor. Our combined findings add radiological findings to the BDA1 phenotype and confirm a critical functional domain of IHH.
authors.affiliation: Department of Medical Biosciences, Medical and Clinical genetics, Umeå University, Umeå, Sweden. evalena.stattin@medbio.umu.se
authors.forename: Eva-Lena
authors.initials: EL
authors.lastname: Stattin
authors.forename: Bjarne
authors.initials: B
authors.lastname: Lindén
authors.forename: Torsten
authors.initials: T
authors.lastname: Lönnerholm
authors.forename: Jens
authors.initials: J
authors.lastname: Schuster
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D002889:Chromosomes, Human, Pair 2; D002895:Chromosomes, Human, Pair 5; D003545:Cysteine / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D005819:Genetic Markers; D053823:Hedgehog Proteins / Q000737:chemistry / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D017880:Limb Deformities, Congenital / Q000000981:diagnostic imaging* / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011859:Radiography; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013548:Sweden
chemical_list: D005819:Genetic Markers; D053823:Hedgehog Proteins; C509246:IHH protein, human; D004247:DNA; D003545:Cysteine