{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSHOX is a homeobox‐containing gene that encodes a nuclear transcription factor essential for normal growth and skeletal development. Its dosage is critically important, as haploinsufficiency has been implicated in a spectrum of clinical entities—including idiopathic short stature, Léri–Weill dyschondrosteosis, and even the skeletal features observed in Turner syndrome. SHOX expression is observed early during embryogenesis in limb and craniofacial primordia and in growth plate chondrocytes, where it modulates gene expression programs to control cell cycle arrest, apoptosis, and differentiation. In many studies, SHOX has been shown to act mainly as a transcriptional activator (or repressor depending on the target) of genes involved in cartilage and bone formation. Its activity is tightly regulated by both upstream and downstream cis‐regulatory sequences, and its proper nuclear localization—mediated by a specific nuclear localization signal—is required for its function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic investigations have revealed that SHOX modulates the expression of a host of downstream genes that are critical for skeletal patterning. For instance, SHOX has been implicated in the regulation of growth factor receptors (such as FGFR3) and other targets like BNP and aggrecan – key players in chondrogenesis. It interacts physically and functionally with other transcription factors (e.g. members of the SOX family) and is subject to multiple layers of regulation including alternative promoter usage and translational control. These studies further demonstrate that mutations (including point mutations, deletions and disruptions of enhancer regions) and failures in proper nuclear transport of SHOX protein compromise its transcriptional activity, thereby altering cell cycle progression and leading to abnormal bone maturation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, disruptions of the SHOX gene or its adjacent regulatory domains are among the most frequent genetic causes of short stature and skeletal dysplasias. Detailed molecular analyses – including MLPA, FISH and sequencing – have enabled the identification of not only whole‐gene deletions but also subtle intragenic and enhancer mutations that account for variable phenotypic severity. In addition, emerging animal and in vitro models have provided insight into the interplay between SHOX dosage and regional growth plate homeostasis, offering a rationale for current therapeutic strategies such as growth hormone treatment in affected children. These findings underscore the importance of incorporating analyses of distal and proximal regulatory elements of SHOX in the genetic work‐up of short stature."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "E Rao, R J Blaschke, A Marchini, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SHOX nullizygosity and haploinsufficiency in a Japanese family: implication for the development of Turner skeletal features."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jcem.87.3.8348"}], "href": "https://doi.org/10.1210/jcem.87.3.8348"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11889214"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11889214"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Gudrun A Rappold, Maki Fukami, Beate Niesler, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Horm Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000197874"}], "href": "https://doi.org/10.1159/000197874"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19188742"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19188742"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "J Chen, G Wildhardt, Z Zhong, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Enhancer elements upstream of the SHOX gene are active in the developing limb."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2009.216"}], "href": "https://doi.org/10.1038/ejhg.2009.216"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19997128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19997128"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Cristina Gervasini, Francesca Romana Grati, Faustina Lalatta, et al. 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