The SHOX gene, also known as the pseudoautosomal homeobox-containing osteogenic gene (PHOG), is another gene with a high deletion frequency, yet the underlying mechanisms remain unclear (52,53). The gene is located within the pseudoautosomal region of the X chromosome short arm (PARI), approx 500 kb proximal from the telomere. It consists of seven exons spanning approx 40 kb, and encodes a member of the paired-like homeodomain protein family that acts as a transcriptional activator in osteogenic cells and plays an important role in limb development (54).
SHOX mutations have been found in three disorders: idiopathic short stature (SS; MIM 604271), Leri-Weill dyschondrosteosis (LWD; MIM127300), and Langer mesomelic dysplasia (MIM 249700) (55). In addition, SHOX haploinsufficiency is responsible for the skeletal anomaly in Turner syndrome patients. Approximately 2-7% of individuals with idiopathic SS and 60-100% of LWD patients have SHOX mutations (56-59). The rare and more severe Langer mesomelic dysplasia has homozygous or compound heterozygous mutations of the SHOX gene (56). A striking feature of SHOX mutations is that there is considerable phenotypic heterogeneity among the patients, and no correlation exists between the type and position of a mutation within the gene and the resulting phenotype. Complete gene deletion or the same point mutations could result in SS or LWD, and there is a significant inter- and intrafamilial variation in the severity of the phenotype, indicating the involvement of modifiers (58).
Deletions involving the entire SHOX gene account for a vast majority (>70%) of SHOX mutations regardless of the clinical manifestation. Most of the deletions were detected by FISH, however, and the extents of the deletions have not been determined. For those that have been characterized, they were both terminal and interstitial deletions, and their sizes ranged from 150 kb to more than 9 Mb (52,56,58). Deletions that extend beyond the PARI boundary are associated with contiguous gene syndromes, to be described in the next section. The high frequency of SHOX deletion has been attributed to the prevalence of repetitive sequences within the PAR1 region, although none of the deletion breakpoints have been isolated and sequenced (60).
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