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.

Figure 1

Pedigrees of the 12 families with LWD. The blackened symbols indicate individuals affected with LWD (i.e., Madelung deformity is present), whereas the gray symbols indicate those with a classification of ISS, since no Madelung deformity was observed.

Figure 2

Schematic representation of the PAR1 deletion intervals detected using a panel of known and novel microsatellites and SNPs (not to scale). Microsatellites and amplicons incorporating the SNPs listed in tables 4 and 5 are given above and below the scale bar, respectively. Markers in bold indicate novel microsatellites.

Figure 3

FISH analyses of proband 1 and her unaffected sister. A, Two copies of SHOX observed as two signals with cosmid 34F5, which hybridizes to exons 2–6a. B, The deletion observed with cosmid 167H21, which hybridizes to sequences downstream of SHOX. C, Cosmid 261P4, which maps proximally to the deletion, present as two copies. D, Cosmid 167H21, present as two copies in the unaffected sister of proband 1. The red signal indicates the pseudoautosomal cosmid/BAC, and the green signal indicates the control probe DXZ2, which maps to the X centromere.

Figure 4

Schematic representation of the FISH analysis in probands 1, 2, 4, and 7, by use of a series of PAR1 cosmids and BACs (not to scale). Microsatellites present in the respective cosmids or BACs are shown above the scale bar. The deletions (Δ) are represented below the corresponding cosmids or BACs. dim = diminished FISH signal, which indicates that the sequence was partly deleted and partly normal.