A Novel Class of Pseudoautosomal Region 1 Deletions Downstream of SHOX Is Associated with Léri-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.

PAR1 deletions downstream ofSHOX are the most frequent defect in a Spanish cohort of Léri-Weill dyschondrosteosis (LWD) probands

“…Codon numbering is shown below the amino acids, the initiation codon is referred to as codon +1. Benito-Sanz et al, 2005), this is the first study analyzing the frequency of the three known classes of mutations in a cohort of LWD patients. Using a dense panel of microsatellite markers and SNPs, we carried out a systematic screening of the PAR1 region, including the SHOX gene and the downstream PAR1 region, in a cohort of 26 Spanish LWD probands.…”

“…The deletions are located 30-250 kb downstream from SHOX (Benito-Sanz et al, 2005). A 29 kb common minimally DOI: 10.1002/humu.9456 deleted region was determined from the deletion characterization in 12 LWD patients, suggesting the presence of an enhancer of SHOX transcription within this interval (Benito-Sanz et al, 2005). In this regard, Fukami et al, 2006, identified an 800bp region within this minimal deleted interval which displays enhancer activity to the SHOX promoter (exon 2) in the SHOX stable transfected U20S human osteosarcoma cell line.…”

Identification of the first PAR1 deletion encompassing upstream SHOX enhancers in a family with idiopathic short stature

“…In all cases, the presence of alterations in the SHOX or the downstream enhancer region had been previously excluded by MLPA or microsatellite analysis and by dHPLC or high-resolution melting analysis and DNA sequencing. 3,11,12 A panel of 340 normal individuals, obtained from the Spanish DNA bank (University of Salamanca, Salamanca, Spain), with heights within the normal range for the Spanish population for age and gender (À2 o SDS o +2), was also screened.…”

“…Heterozygous mutations in SHOX or the downstream enhancer elements have been associated with B60% of Léri-Weill dyschondrosteosis (LWD, MIM 127300) and 5-15% of idiopathic short stature (ISS, MIM 300582) cases. [3][4][5] LWD is a skeletal dysplasia, characterized by disproportionate short stature, mesomelic limb shortening and the Madelung deformity. ISS is a condition defined as a height below À2 SDS in the absence of known specific causative disorders.…”

Cryptic intragenic deletion of the SHOX gene in a family with Léri-Weill dyschondrosteosis detected by Multiplex Ligation-Dependent Probe Amplification (MLPA)

“…CA repeat is an intragenic marker identifi ed in the 5' untranslated region of exon I. DYS290 and DXYS10093 are intragenic markers. DXYS10096 is 3' fl anking the gene, located at an important region apparently implicated in etiopathogenesis of LWD (12). DXYS234 is located downstream of SHOX approximately 2 cM from the Xp telomere (Figure 3).…”