Disease relevance of SHOX

• Here, we report large-scale deletions (in seven families) and a nonsense mutation (in one family) of SHOX in patients with DCS and show that Langer mesomelic dwarfism results from homozygous mutations at the DCS locus [1].
• SHOX haploinsufficiency has been implicated in three human growth disorders: Turner syndrome, idiopathic short stature, and Leri-Weill dyschondrosteosis [2].
• The boy manifested, due to nullisomy of this region, short stature (SHOX), chondrodysplasia punctata (ARSE), and mental retardation (putative mental retardation gene MRX 49) [3].
• BACKGROUND: SHOX haplo-insufficiency is considered the molecular basis of short stature in patients with Turner's syndrome, and gives rise to the short stature with mesomelic dysplasia and Madelung deformity of patients with Leri-Weill syndrome [4].
• This observation confirms the importance of FISH in the investigation of chromosomal abnormalities, and further delineates the phenotype of SHOX deleted patients [5].

Psychiatry related information on SHOX

• The SS boys' self-perceptions of domain-specific competencies and global self-worth were comparable to a normative comparison group with the exception that older subjects (13 years or older) described their athletic abilities more positively and their work competence more negatively [6].
• The SS boys were described by parents as being significantly less socially competent and showing more behavioral and emotional problems than a normative sample selected for mental health [6].
• BDHI mean total scores and suspiciousness and negativism subscales scores were significantly higher in SS individuals, in comparison with LL subjects, among heroin addicts [7].

High impact information on SHOX

• To determine whether at high resolution this autosomal pattern also applies to PAR1, we have examined linkage disequilibrium over an interval of 43 kb around the gene SHOX [8].
• Crossover clustering and rapid decay of linkage disequilibrium in the Xp/Yp pseudoautosomal gene SHOX [8].
• A point mutation leading to a premature stop in exon 4 of SHOX was identified in one LWD family [9].
• Our data suggest an involvement of SHOX in idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients [10].
• We have isolated a homeobox-containing gene (SHOX) from this region, which has at least two alternatively spliced forms, encoding proteins with different patterns of expression [10].

Chemical compound and disease context of SHOX

• The results, in conjunction with the adult height data in 47,XXX, 46,XX gonadal dysgenesis, 47,XXY, 46,XY gonadal dysgenesis, and 46,X, idic(Xq-), suggest that the tall stature of this female is caused by the combined effects of SHOX duplication on the der(X) chromosome and gonadal estrogen deficiency [11].

Biological context of SHOX

• 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 [9].
• The results provide further support for the idea that clinical features in X chromosome aberrations are primarily explained by haploinsufficiency of SHOX and the lymphogenic gene and by the extent of chromosome imbalance in mitotic cells and pairing failure in meiotic cells [12].
• The deletion size of each patient was determined by fluorescence in situ hybridization and microsatellite analyses for 38 Xp loci including SHOX, which was deleted in groups 1-3 and preserved in group 4 [12].
• However, the only known disease gene within the pseudoautosomal regions is the SHORT STATURE HOMEBOX (SHOX) gene, functional loss of which is causally related to various short stature conditions and disturbed bone development [13].
• Deletion of the SHOX region on the human sex chromosomes has been shown to result in idiopathic short stature and proposed to play a role in the short stature associated with Turner syndrome [14].

Anatomical context of SHOX

• Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are found in 40-70% of HCH cases [15].
• Recent analyses have furthermore revealed that the phosphorylation-sensitive function of SHOX is directly involved in chondrocyte differentiation and maturation [13].
• To enhance our understanding of the underlying mechanism of action, we have established a cell culture model consisting of four stably transfected cell lines and analysed the functional properties of the SHOX protein on a molecular level [16].
• Results show that the SHOX-encoded protein is located exclusively within the nucleus of a variety of cell lines, including U2Os, HEK293, COS7 and NIH 3T3 cells [16].
• The SHOX expression pattern in the limb and first and second pharyngeal arches not only explains SHOX -related short stature phenotypes, but also for the first time provides evidence for the involvement of this gene in the development of additional Turner stigmata [17].

Associations of SHOX with chemical compounds

• Growth hormone and gonadotropin-releasing hormone analog therapy in haploinsufficiency of SHOX [18].
• Furthermore, the similarity in the growth pattern between this female and patients with estrogen resistance or aromatase deficiency implies that the association of an extra copy of SHOX with gonadal estrogen deficiency may represent the further clinical entity for tall stature resulting from continued growth in late teens or into adulthood [11].
• Here, we report that SHOX is phosphorylated exclusively on serine residues in vivo [19].
• This C to T transition is predicted to cause an arginine to cysteine amino acid change in a highly conserved region of the recognition helix of the homeodomain, which may reduce the stability of the interaction between the SHOX protein and its target DNA [20].
• Sterol and very long chain fatty acid profiles, FISH analysis for SHOX gene deletions, blood lymphocyte karyotype, and phytanic acid levels were normal in those tested, and no mutations in arylsulfatase D and E genes were detected [21].

Other interactions of SHOX

• In this study, we performed mutational analysis of the coding region of the SHOX gene in five DCO and 18 HCH patients, all of whom tested negative for the known HCH-associated FGFR3 mutations [15].
• The final karyotype was 46,Y,der(X)t(X; Y)(p22.3; q11.2).ish der(X) (DXZ1+, KAL+, STS-, SHOX-) mat [22].
• Deficiencies or mutations in the human pseudoautosomal SHOX gene are associated with a series of short-stature conditions, including Turner syndrome, Leri-Weill dyschondrosteosis, and Langer mesomelic dysplasia [23].
• Fluorescence in situ hybridization and microsatellite analyses for 19 loci/regions on the X chromosome demonstrated that the del(Xp) chromosome was missing SHOX and had the breakpoint between DMD and CYBB [24].
• Further studies are necessary to investigate genotype/phenotype correlation in cases with translocations or microdeletions on Xp22.3, including the ARSE and the SHOX gene loci [25].

Analytical, diagnostic and therapeutic context of SHOX

• We studied the expression of SHOX protein, by immunohistochemistry, in human fetal and childhood growth plates and mRNA by in situ hybridization in childhood normal and Leri Weil growth plate [26].
• Methods SHOX gene deletion was evaluated by fluorescence in situ hybridization (FISH), Southern blotting and segregation study of polymorphic marker [27].
• The case also highlights the importance of karyotyping for differentiating LWD and TS, especially in patients with findings such as premature ovarian failure or aortic abnormalities not associated with isolated SHOX haploinsufficiency [28].
• DNA extraction and PCR amplification of the intragenic SHOX microsatellite, at the 5'-untranslated region [4].
• Site-directed mutagenesis demonstrated that serine 106 is the major SHOX phosphorylation site [19].

References