The human SHOX database has recently been established to provide clinicians and scientists access to a central source of information about all known SHOX mutations associated with short stature phenotypes such as idiopathic short stature, Lèri-Weill dyschondrosteosis, Langer syndrome, and Turner syndrome. So far, the database contains 29 unique intragenic mutations of the SHOX gene. These mutations were detected in a total of 39 patients from different families. Fourteen of these mutations have been found from the SHOX research group at the Institute of Human Genetics in Heidelberg, Germany; 25 mutations are from data reported in the literature. Not included in this database are complete SHOX gene deletions which represent the majority of all detectable SHOX mutations [Rappold et al., 2002]. The database is accessible via the website www.shox.uni-hd.de. It contains general information about the SHOX gene, and allows remote users to search the data and to submit new mutations to the database.
"Details on the database structure and the software are published elsewhere [Fokkema et al., 2005]. The main advantage of the LOVD system compared to the former used MuSTAR software [Brown and McKie, 2000; Niesler et al., 2002] is the platform independence and the use of PHP and MySQL open source software [Fokkema et al., 2005]. The LOVD software is running on an HTTP server. "
[Show abstract][Hide abstract] ABSTRACT: Short stature due to SHOX deficiency represents the most commonly known form of growth failure, with a frequency greater than 1:1,000 in the Caucasian population. As many different mutations can cause SHOX haploinsufficiency, a comprehensive collection of gene variants represents an essential tool to distinguish between functional variants and polymorphisms. We have created a novel and widely extended SHOX database using the "LOVD in a box-solution." This database contains not only a larger amount of mutation data (140 novel mutations were added), but also reports on phenotypic consequences, mode of inheritance, and ethnic origin, as well as on functional consequences of mutations investigated. In addition, the database now includes non-disease-related polymorphisms to enable researchers to evaluate their diagnostic findings. The database (Available at: http://hyg-serv-01.hyg.uni-heidelberg.de/lovd/index.php?select_db=SHOX; Last accessed: 12 April 2007) contains all presently known 199 intragenic mutations (SNPs as well as small deletions and insertions), 126 of which are unique. The remote user is able to search the data and to submit new mutations into the database. Furthermore, it includes general information about the SHOX gene via links to other resources such as MIM, GDB, HGMD, and HAPMAP, as well as websites of Short Stature Associations.
Human Mutation 10/2007; 28(10):933-8. DOI:10.1002/humu.20542 · 5.14 Impact Factor
"RESULTS Accumulation of Missense Mutations in the SHOX Homeodomain In the last years, many patients diagnosed with LWD or ISS were screened for intragenic SHOX mutations. Besides frameshift and nonsense mutations leading to truncated and nonfunctional protein variants, a set of missense mutations was found in exon 3 and 4 comprising the homeodomain [Grigelioniene et al., 2000; Huber et al., 2001; Ogata et al., 2002; Falcinelli et al., 2002; Shears et al., 2002; Niesler et al., 2002] (unpublished results). For our analysis, we focused on nine mutations spread over the three homeodomain helices and the regions in-between (Fig. 1). "
[Show abstract][Hide abstract] ABSTRACT: Haploinsufficiency of the short stature homeobox gene SHOX has been found in patients with idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). In addition to complete gene deletions and nonsense mutations, several missense mutations have been identified in both patient groups, leading to amino acid substitutions in the SHOX protein. The majority of missense mutations were found to accumulate in the region encoding the highly conserved homeodomain of the paired-like type. In this report, we investigated nine different amino acid exchanges in the homeodomain of SHOX patients with ISS and LWD. We were able show that these mutations cause an alteration of the biological function of SHOX by loss of DNA binding, reduced dimerization ability, and/or impaired nuclear translocation. Additionally, one of the mutations (c.458G>T, p.R153L) is defective in transcriptional activation even though it is still able to bind to DNA, dimerize, and translocate to the nucleus. Thus, we demonstrate that single missense mutations in the homeodomain fundamentally impair SHOX key functions, thereby leading to the phenotype observed in patients with LWD and ISS.
Human Mutation 07/2005; 26(1):44-52. DOI:10.1002/humu.20187 · 5.14 Impact Factor
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