Clinical and molecular evaluation of SHOX/PAR1 duplications in Léri–Weill Dyschondrosteosis (LWD) and idiopathic short stature (ISS)

Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Madrid, Spain
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 02/2011; 96(2):E404-12. DOI: 10.1210/jc.2010-1689
Source: PubMed


Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and the Madelung deformity of the forearm. SHOX mutations and pseudoautosomal region 1 deletions encompassing SHOX or its enhancers have been identified in approximately 60% of LWD and approximately 15% of idiopathic short stature (ISS) individuals. Recently SHOX duplications have been described in LWD/ISS but also in individuals with other clinical manifestations, thus questioning their pathogenicity.
The objective of the study was to investigate the pathogenicity of SHOX duplications in LWD and ISS.
Multiplex ligation-dependent probe amplification is routinely used in our unit to analyze for SHOX/pseudoautosomal region 1 copy number changes in LWD/ISS referrals. Quantitative PCR, microsatellite marker, and fluorescence in situ hybridization analysis were undertaken to confirm all identified duplications.
During the routine analysis of 122 LWD and 613 ISS referrals, a total of four complete and 10 partial SHOX duplications or multiple copy number (n > 3) as well as one duplication of the SHOX 5' flanking region were identified in nine LWD and six ISS cases. Partial SHOX duplications appeared to have a more deleterious effect on skeletal dysplasia and height gain than complete SHOX duplications. Importantly, no increase in SHOX copy number was identified in 340 individuals with normal stature or 104 overgrowth referrals.
MLPA analysis of SHOX/PAR1 led to the identification of partial and complete SHOX duplications or multiple copies associated with LWD or ISS, suggesting that they may represent an additional class of mutations implicated in the molecular etiology of these clinical entities.

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Available from: Karen E Heath, Jul 02, 2015
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    • "Family histories were also documented, including parental heights. In all cases, the presence alterations in SHOX or its enhancers had been previously excluded [4], [7]–[9], [32], [33]. The control cohort consisted of 95 Spanish individuals with normal heights (Spanish DNA Bank, University of Salamanca). "
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    ABSTRACT: SHOX and SHOX2 transcription factors are highly homologous, with even identical homeodomains. Genetic alterations in SHOX result in two skeletal dysplasias; Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), while no human genetic disease has been linked to date with SHOX2. SHOX2 is, though, involved in skeletal development, as shown by different knockout mice models. Due to the high homology between SHOX and SHOX2, and their functional redundancy during heart development, we postulated that SHOX2 might have the same transcriptional targets and cofactors as SHOX in limb development. We selected two SHOX transcription targets regulated by different mechanisms: 1) the natriuretic peptide precursor B gene (NPPB) involved in the endochondral ossification signalling and directly activated by SHOX; and 2) Aggrecan (ACAN), a major component of cartilage extracellular matrix, regulated by the cooperation of SHOX with the SOX trio (SOX5, SOX6 and SOX9) via the protein interaction between SOX5/SOX6 and SHOX. Using the luciferase assay we have demonstrated that SHOX2, like SHOX, regulates NPPB directly whilst activates ACAN via its cooperation with the SOX trio. Subsequently, we have identified and characterized the protein domains implicated in the SHOX2 dimerization and also its protein interaction with SOX5/SOX6 and SHOX using the yeast-two hybrid and co-immunoprecipitation assays. Immunohistochemistry of human fetal growth plates from different time points demonstrated that SHOX2 is coexpressed with SHOX and the members of the SOX trio. Despite these findings, no mutation was identified in SHOX2 in a cohort of 83 LWD patients with no known molecular defect, suggesting that SHOX2 alterations do not cause LWD. In conclusion, our work has identified the first cofactors and two new transcription targets of SHOX2 in limb development, and we hypothesize a time- and tissue-specific functional redundancy between SHOX and SHOX2.
    PLoS ONE 01/2014; 9(1):e83104. DOI:10.1371/journal.pone.0083104 · 3.23 Impact Factor
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    • "Such heterogeneity prompted us to investigate other genetic mutations in the causation of the HCH phenotype. Mutations in the SHOX gene have been associated with other related syndromes of short stature including idiopathic short stature, Leri–Weill syndrome dyschondrosteosis, and Turner syndrome [Benito-Sanz et al., 2011], though this possibility of the SHOX gene mutations being associated with a HCH phenotype has not been stressed. On the other hand, FGFR1 and 2 mutations were previously reported in patients with other skeletal dysplasias like craniosynostosis [Grigelioniene et al., 2000]. "
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    ABSTRACT: We applied a comprehensive set of clinical and radiological criteria for the diagnosis of hypochondroplasia (HCH) in 160 patients with short stature 58 of whom were diagnosed to have HCH. Taking into account the genotypic and phenotypic variations in HCH, we conducted a study with these 58 patients and tested them for mutations in the fibroblast growth factor receptor 3 (FGFR3) and the short stature homeobox (SHOX) gene. We characterized the phenotypes by clinical and radiologic findings. In the patients with HCH, 19 were included in Group I (FGFR3 mutations-mutations of definite significance), and 39 were in Group II (6 SHOX mutations and 33 negative for disease-causing FGFR3 mutations). The clinical findings were similar in two groups regardless of the presence or absence of mutations. More than 95% of the patients had mesomelic proportions. In Group I, the radiological findings of mesomelia of upper and lower limbs and, L1/L4 ratio in anterior-posterior and lateral view were more typical than in Group II. This study proposes comprehensive clinico-radiological criteria for the diagnosis of HCH, which would help in detecting the true incidence of this underdiagnosed condition. The presence of SHOX mutations suggest genotypic-phenotypic overlap between HCH and Leri-Weill dyschondrosteosis, though further investigation is needed to effectively elucidate the importance of these mutations. Also, the 56.9% of HCH patients with negative mutations for FGFR3 suggests that there are other undiscovered gene mutations associated with this phenotypic entity. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 10/2012; 158A(10):2456-62. DOI:10.1002/ajmg.a.35564 · 2.16 Impact Factor
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    • "Mutations and deletions in SHOX have been reported to cause short stature in patients with idiopathic short stature (ISS, OMIM #300582), Turner syndrome [16,17], dyschondrosteosis (Leri-Weill syndrome, LWD, OMIM #127300) [18] and its more severe form Langer mesomelic dysplasia (OMIM #249700) [19]. Recently, some patients with ISS and LWD have been reported to carry duplications of SHOX/PAR1 region [20]. "
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    ABSTRACT: Müllerian aplasia (MA) characterized by congenital loss of functional uterus and vagina is one of the most difficult disorders of female reproductive health. Despite of growing interest in this research field, the cause of the disorder for the majority of patients is still unknown. A recent report of partial SHOX duplications in five patients with MA has motivated us to further evaluate their role in the disorder. Therefore we have studied SHOX copy number variations (CNVs) in a cohort of 101 Finnish patients with MA and in 115 healthy controls. We used multiplex ligation-dependent probe amplification (MLPA) to study SHOX CNVs. All patients showed normal amplification of SHOX. Several aberrations, duplications and deletions, were found downstream of the gene in five patients and seven controls, but these were all copy number polymorphisms. Our study in an extensive cohort of patients with MA does not support a role for SHOX CNVs in the aetiology of the disorder. Further studies in the field are important for both patients looking for answers as well as for the scientific community for better understanding the regulation of the female reproductive duct development.
    Orphanet Journal of Rare Diseases 08/2011; 6(1):53. DOI:10.1186/1750-1172-6-53 · 3.36 Impact Factor
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