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.

A reinvestigation of non-disjunction resulting in 47, XXY males of paternal origin

“…The identification of PAR 1 microdeletions in patients with LWD 16,17 suggests a possible mechanism to explain some cases of paternal sex chromosome non-disjunction. However, we could find no evidence for the presence of any deletions as large as those reported in LWD, although the presence of much smaller deletions could not be excluded.…”

“…CA-SHOX was taken from Shears et al, 17 otherwise all primer sequences and conditions are available from the Genome Data Base (www.gdb.org). Within PAR 2 we used one diallelic polymorphism DXYS225 9 and two CA repeats, DXYS1107 8 and SKK-1.…”

“…Submicroscopic deletions encompassing the SHOX gene within PAR 1 have recently been identified as the causative mutation in 12 families with Leri-Weill dyschondrosteosis (LWD), a dominantly inherited skeletal dysplasia. 16,17 Such deletions would reduce the extent of X/Y homology and could have a similar effect on pairing or recombination. To test the hypothesis that PAR 1 deletions would increase the risk of sex chromosome non-disjunction, we have screened our series of paternal 47, XXYs for PAR 1 microdeletions using a total of seven microsatellites across the region.…”

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

“…SHOX (MIM# 312865) mutations or deletions have been reported in LWD (Belin et al, 1998;Shears et al, 1998). We recently identified the presence of a new class of pseudoautosomal region 1 (PAR1) deletion in LWD that do not include SHOX.…”

Investigação clínica e genética em meninas com baixa estatura idiopática

“…Em 1997, foi seqüenciado o gene SHOX (short stature homeobox containing gene), localizado na região pseudoautossômica dos braços curtos dos cromossomos X (Xp22.3) (figura 1) e Y (Yp11.3) (5,8). Mutações e deleções do gene SHOX vêm sendo descritas em 1 a 2,4% dos portadores de BEI (8)(9)(10)(11)(12) e com grande freqüência em uma forma de displasia óssea, discondrosteose de Leri Weill, em que se associam à baixa estatura, displasia óssea mesomélica e deformidade de Madelung (10,(13)(14)(15)(16)(17)(18).…”