title: Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis.
abstract: Leri-Weill Dyschondrosteosis (LWD; OMIM 127300) is a dominantly inherited skeletal dysplasia characterized by disproportionate short stature with predominantly mesomelic limb shortening. Expression is variable and consistently more severe in females, who frequently display the Madelung deformity of the forearm (shortening and bowing of the radius with dorsal subluxation of the distal ulna). The rare Langer Mesomelic Dysplasia (LD; OMIM 249700), characterized by severe short stature with hypoplasia/aplasia of the ulna and fibula, has been postulated to be the homozygous form of LWD (refs 4-6). In a six-generation pedigree with LWD, we established linkage to the marker DXYS6814 in the pseudoautosomal region (PAR1) of the X and Y chromosomes (Z max=6.28; theta=0). Linkage analysis of three smaller pedigrees increased the lod score to 8.68 (theta=0). We identified submicroscopic PAR1 deletions encompassing the recently described short stature homeobox-containing gene SHOX (refs 7,8) segregating with the LWD phenotype in 5 families. A point mutation leading to a premature stop in exon 4 of SHOX was identified in one LWD family.
authors.affiliation: Department of Clinical Genetics, Institute of Child Health, London, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Shears
authors.forename: H J
authors.initials: HJ
authors.lastname: Vassal
authors.forename: F R
authors.initials: FR
authors.lastname: Goodman
authors.forename: R W
authors.initials: RW
authors.lastname: Palmer
authors.forename: W
authors.initials: W
authors.lastname: Reardon
authors.forename: A
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: P J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: R M
authors.initials: RM
authors.lastname: Winter
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA; D005260:Female; D008040:Genetic Linkage; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D000074122:Short Stature Homeobox Protein
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D004247:DNA