Clinical and Molecular Evaluation of SHOX/PAR1 Duplications in Léri-Weill Dyschondrosteosis (LWD) and Idiopathic Short Stature (ISS)

Benito‐Sanz, Sara; Barroso, Eva; Heine-Suñer, Damián; Hisado-Oliva, Alfonso; Romanelli, Valeria; Rosell, Jordi; Aragonés, Ángel; Caimari, María; Argente, Jesús; Ross, Judith L.; Zinn, Andrew R.; Gracía, Ricardo; Lapunzina, Pablo; Campos-Barros, Ángel; Heath, Karen E.

doi:10.1210/jc.2010-1689

Cited by 64 publications

(84 citation statements)

References 35 publications

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“…Along with others, we have recently reported that a phenotype similar to Leri-Weill syndrome (including short stature) can be associated with SHOX duplication. 11,23,24 In two patients, a heterozygous deletion on chromosome 15 containing the IGF1R gene was identified, a well-established cause of short stature. 11,25,26 In both patients, an additional de novo CNV was present (Table 3).…”

Section: Discussionmentioning

confidence: 99%

Copy number variants in patients with short stature

et al. 2013

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Section: Discussionmentioning

confidence: 99%

Copy number variants in patients with short stature

et al. 2013

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“…In all cases, the presence of alterations in the SHOX or the downstream enhancer region had been previously excluded by MLPA or microsatellite analysis and by dHPLC or high-resolution melting analysis and DNA sequencing. 3,11,12 A panel of 340 normal individuals, obtained from the Spanish DNA bank (University of Salamanca, Salamanca, Spain), with heights within the normal range for the Spanish population for age and gender (À2 o SDS o +2), was also screened.…”

Section: Clinical Patientsmentioning

confidence: 99%

Identification of the first PAR1 deletion encompassing upstream SHOX enhancers in a family with idiopathic short stature

et al. 2011

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Short stature homeobox-containing gene, MIM 312865 (SHOX) is located within the pseudoautosomal region 1 (PAR1) of the sex chromosomes. Mutations in SHOX or its downstream transcriptional regulatory elements represent the underlying molecular defect in B60% of Lé ri-Weill dyschondrosteosis (LWD) and B5-15% of idiopathic short stature (ISS) patients. Recently, three novel enhancer elements have been identified upstream of SHOX but to date, no PAR1 deletions upstream of SHOX have been observed that only encompass these enhancers in LWD or ISS patients. We set out to search for genetic alterations of the upstream SHOX regulatory elements in 63 LWD and 100 ISS patients with no known alteration in SHOX or the downstream enhancer regions using a specifically designed MLPA assay, which covers the PAR1 upstream of SHOX. An upstream SHOX deletion was identified in an ISS proband and her affected father. The deletion was confirmed and delimited by array-CGH, to extend B286 kb. The deletion included two of the upstream SHOX enhancers without affecting SHOX. The 13.3-year-old proband had proportionate short stature with normal GH and IGF-I levels. In conclusion, we have identified the first PAR1 deletion encompassing only the upstream SHOX transcription regulatory elements in a family with ISS. The loss of these elements may result in SHOX haploinsufficiency because of decreased SHOX transcription. Therefore, this upstream region should be included in the routine analysis of PAR1 in patients with LWD, LMD and ISS.

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“…Short stature may also be caused by partial duplication of the SHOX gene and of the regulatory region [18,19]. The rate of patients with identified duplications amounts to 7.3% of those with Lerie-Weill dyschondrosteosis (LWD) and 1% of patients with idiopathic short stature (ISS).…”

Section: The Shox Genementioning

confidence: 99%

Diagnostyka rearanżacji genu SHOX u kobiet 46,XX z idiopatyczną niskorosłością

Mitka

Bednarek²,

Kałużewski³

2015

Endokrynologia Polska

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Introduction: The SHOX gene has been mapped at the pseudoautosomal region 1 (PAR1) of chromosomes X (Xp22.33) and Y (Yp11.32). The loss of SHOX gene functionality is assumed to be responsible for the Leri-Weill syndrome formation and the disproportionate short stature (DSS). The SHOX gene rearrangements constitute the majority of cases of gene functionality loss. Therefore, a practical application of the method, which allows for the diagnostics of the gene rearrangements, becomes a primary issue. With such an assumption, the MLPA technique (multiplex ligation -dependent probe amplification) becomes the method of choice. Material and methods: DNA samples were evaluated in the study by means of the MLPA method. The DNA was isolated from peripheral blood of sixty-three (63) 46,XX patients with short stature. Results: Out of the examined patients, deletions within the SHOX gene were found in five (5) patients, and duplication at the PAR1 regulatory region of the SHOX gene in one (1)

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Clinical and Molecular Evaluation of SHOX/PAR1 Duplications in Léri-Weill Dyschondrosteosis (LWD) and Idiopathic Short Stature (ISS)

Abstract: 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.

Cited by 64 publications

References 35 publications

Copy number variants in patients with short stature

Copy number variants in patients with short stature

Identification of the first PAR1 deletion encompassing upstream SHOX enhancers in a family with idiopathic short stature

Diagnostyka rearanżacji genu SHOX u kobiet 46,XX z idiopatyczną niskorosłością

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