title: A novel class of Pseudoautosomal region 1 deletions downstream of SHOX is associated with Leri-Weill dyschondrosteosis.
abstract: Leri-Weill dyschondrosteosis (LWD) is a pseudoautosomal dominant disorder characterized by disproportionate short stature and a characteristic curving of the radius, known as the "Madelung deformity." SHOX mutations resulting in SHOX haploinsufficiency have been found in LWD and in a variable proportion of patients with idiopathic short stature (ISS), whereas homozygous loss of SHOX results in the more severe Langer mesomelic dysplasia (LMD). Defects in SHOX have been identified in approximately 60% of LWD cases, whereas, in the remaining approximately 40%, the molecular basis is unknown. This suggests either genetic heterogeneity or the presence of mutations in unanalyzed regions of SHOX, such as the upstream, intragenic, or downstream regulatory sequences. Therefore, the pseudoautosomal region 1 (PAR1) of 80 patients with LWD, in whom SHOX deletions and mutations had been excluded, was screened for deletions by use of a new panel of microsatellite markers. We identified 12 patients with LWD who presented with a novel class of PAR1 deletions that did not include SHOX. The deletions were of variable size and mapped at least approximately 30-530 kb downstream of SHOX. In our cohort, this type of deletion accounted for 15% of cases. In all cases, the deletions cosegregated with the phenotype. No apparent phenotypic differences were observed between patients with SHOX deletions and those with this new class of PAR1 deletions. Thus, we present here the identification of a second PAR1 region implicated in the etiopathogenesis of LWD. Our findings suggest the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development. Deletion analysis of this newly identified region should be included in the mutation screening of patients with LWD, LMD, and ISS.
authors.affiliation: Department of Endocrinology, Hospital Infantil Universitario Nino Jesus, Universidad Autonoma de Madrid, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Benito-Sanz
authors.forename: N Simon
authors.initials: NS
authors.lastname: Thomas
authors.forename: Céline
authors.initials: C
authors.lastname: Huber
authors.forename: Celine
authors.initials: C
authors.lastname: Huber
authors.forename: Darya
authors.initials: D
authors.lastname: Gorbenko del Blanco
authors.forename: Darya Gorbenko
authors.initials: DG
authors.lastname: Del Blanco
authors.forename: Miriam
authors.initials: M
authors.lastname: Aza-Carmona
authors.forename: John A
authors.initials: JA
authors.lastname: Crolla
authors.forename: Vivienne
authors.initials: V
authors.lastname: Maloney
authors.forename: Gudrun
authors.initials: G
authors.lastname: Rappold
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.forename: Jesus
authors.initials: J
authors.lastname: Argente
authors.forename: Angel
authors.initials: A
authors.lastname: Campos-Barros
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D015331:Cohort Studies; D017931:DNA Primers; D005260:Female; D017353:Gene Deletion; D018740:Genetic Heterogeneity; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D010009:Osteochondrodysplasias / Q000235:genetics*; D010375:Pedigree; D011884:Radius / Q000002:abnormalities; D000074122:Short Stature Homeobox Protein; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D014157:Transcription Factors