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The human gene (SHOX) resides within the pseudoautosomal region of the X and Y chromosomes1–3 and encodes a paired related homeodomain transcription factor. Nominal levels of the SHOX protein have been implicated in bone development and longitudinal body growth, as heterozygous and homozygous loss of SHOX functions result in Léri–Weill dyschondrosteosis (LWD) and Langer dysplasia (LD), respectively.4,5 Apart from mesomelic short stature and a characteristic deformity of the forearm leading to a limited mobility of the wrist (Madelung deformity), some individuals with LWD and LD present with a subset of clinical stigmata frequently observed in females with Turner syndrome, including high arched palate, curvature of radius/ulna/tibia, and short fourth metacarpals.6–8 These clinical features are variable, leading to a significant phenotypic heterogeneity particularly among persons with LWD.9 In addition, SHOX mutations are a major cause of isolated short stature conditions, with an estimated incidence of 2–3% in children presenting with idiopathic growth retardation.10,11 This is higher than the incidence of achondroplasia and growth hormone deficiency together.12,13
The SHOX gene product has been shown to reside within the nucleus of several cell types, and acts as a transcriptional activator of target genes that have yet to be identified.14 This activity is likely to be regulated at different levels, including control of temporal and spatial expression patterns, nuclear translocation, and modification of its transactivating activities. In fact, regulation of SHOX expression was recently shown to involve sequential transcriptional and translational checkpoints, emphasising the importance of fine tuning the amount of functional SHOX protein.15
Here we report a novel missense mutation, 508G>C (A170P), affecting the SHOX homeodomain. This mutation cosegregates with the LWD phenotype in a highly consanguineous Spanish gypsy family. Genotype-phenotype and pedigree analysis revealed that individuals homozygously carrying the …
This work was supported by the Deutsche Forschungsgemeinschaft, Eli Lilly & Co., and the Spanish Ministry of Health, Instituto de Salud Carlos III.
Conflicts of interest: none declared