Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome

Schiller, Simone; Spranger, Stephanie; Schechinger, Birgit; Fukami, Maki; Merker, Sabine; Drop, Stenvert L. S.; Tröger, J.; Knoblauch, Hans; Kunze, Jürgen; Seidel, Jörg; Rappold, Gudrun

doi:10.1038/sj.ejhg.5200402

Cited by 142 publications

(140 citation statements)

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“…1 Haploinsufficient loss of the SHOX gene causes short stature and has been correlated with variable skeletal phenotypes frequently observed in Léri-Weill and Turner syndrome patients (2)(3)(4)(5)(6). SHOX-deficient individuals exhibit a considerable phenotypic heterogeneity ranging from mild, barely detectable skeletal malformations to severe dysplasia adversely affecting the life of these patients (7,8). This phenotypic heterogeneity is clinically well documented but not understood on a molecular level.…”

Section: From the Institute Of Human Genetics Ruprecht-karls-universmentioning

confidence: 99%

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Transcriptional and Translational Regulation of the Léri-Weill and Turner Syndrome Homeobox Gene SHOX

Blaschke

Töpfer

Marchini

et al. 2003

Journal of Biological Chemistry

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Regulation of gene expression is particularly important for gene dosage-dependent diseases and the phenomenon of clinical heterogeneity frequently associated with these phenotypes. We here report on the combined transcriptional and translational regulatory mechanisms controlling the expression of the Lé ri-Weill and Turner syndrome gene SHOX. We define an alternative promotor within exon 2 of the SHOX gene by transient transfections of mono-and bicistronic reporter constructs and demonstrate substantial differences in the translation efficiency of the mRNAs transcribed from these alternative promotors by in vitro translation assays and direct mRNA transfections into different cell lines. Although transcripts generated from the intragenic promotor (P 2 ) are translated with high efficiencies, mRNA originating from the upstream promotor (P 1 ) exhibit significant translation inhibitory effects due to seven AUG codons upstream of the main open reading frame (uAUGs). Site-directed mutagenesis of these uAUGs confers full translation efficiency to reporter mRNAs in different cell lines and after injection of Xenopus embryos. In conclusion, our data support a model where functional SHOX protein levels are regulated by a combination of transcriptional and translational control mechanisms.The human pseudoautosomal homeobox gene SHOX has recently been shown to encode a cell type-specific transcription factor involved in cell cycle and growth regulation (1).1 Haploinsufficient loss of the SHOX gene causes short stature and has been correlated with variable skeletal phenotypes frequently observed in Léri-Weill and Turner syndrome patients (2-6). SHOX-deficient individuals exhibit a considerable phenotypic heterogeneity ranging from mild, barely detectable skeletal malformations to severe dysplasia adversely affecting the life of these patients (7,8). This phenotypic heterogeneity is clinically well documented but not understood on a molecular level. Although dominant negative effects of mutated gene products have been discussed (1), phenotypes caused by complete gene deletions argue for a quantitative threshold of functional protein to be necessary for normal development. Along these lines, the understanding of mechanisms regulating the level of functional protein will provide important clues to explain the SHOX-related phenotypes and their inherent phenotypic heterogeneity.Although initially transcriptional regulation has been correlated with a variety of human diseases, it has become increasingly clear that post-transcriptional processing and differential translation represent equally important checkpoints in the tissue-specific and disease-related control of gene expression (9 -11). Among the various elements of mature mRNAs that are known to regulate translational efficiency, several recent investigations have emphasized the role of the 5Ј-untranslated region (UTR) 2 as major determinant controlling the initial steps of protein expression (12, 13). Most eukaryotic mRNAs that exhibit high translational competence present...

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Section: From the Institute Of Human Genetics Ruprecht-karls-universmentioning

confidence: 99%

“…SHOX-deficient individuals exhibit a considerable phenotypic heterogeneity ranging from mild, barely detectable skeletal malformations to severe dysplasia adversely affecting the life of these patients (7,8). This phenotypic heterogeneity is clinically well documented but not understood on a molecular level.…”

mentioning

confidence: 99%

Transcriptional and Translational Regulation of the Léri-Weill and Turner Syndrome Homeobox Gene SHOX

Blaschke

Töpfer

Marchini

et al. 2003

Journal of Biological Chemistry

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“…LWD is an inherited skeletal dysplasia characterized by disproportionate short stature, mesomelic limb shortening and Madelung deformity of the arm. Later studies have found submicroscopic deletions in the SHOX gene in 34% to 81% of affected families and point mutations in the SHOX gene in 19% to 39% of LWD families studied [38][39][40][41][42][43][44][45][46]. Patients with SHOX haploinsufficiency could benefit from early growth hormone treatment, so early screening of children with unexplained short stature has been suggested [47,48].…”

Section: Par1/par2 and Diseasementioning

confidence: 99%

The Human Pseudoautosomal Region (PAR): Origin, Function and Future

Mangs¹,

Morris

2007

197

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Abstract:The pseudoautosomal regions (PAR1 and PAR2) of the human X and Y chromosomes pair and recombine during meiosis. Thus genes in this region are not inherited in a strictly sex-linked fashion. PAR1 is located at the terminal region of the short arms and PAR2 at the tips of the long arms of these chromosomes. To date, 24 genes have been assigned to the PAR1 region. Half of these have a known function. In contrast, so far only 4 genes have been discovered in the PAR2 region. Deletion of the PAR1 region results in failure of pairing and male sterility. The gene SHOX (short stature homeobox-containing) resides in PAR1. SHOX haploinsufficiency contributes to certain features in Turner syndrome as well as the characteristics of Leri-Weill dyschondrosteosis. Only two of the human PAR1 genes have mouse homologues. These do not, however, reside in the mouse PAR1 region but are autosomal. The PAR regions seem to be relics of differential additions, losses, rearrangements and degradation of the X and Y chromosome in different mammalian lineages. Marsupials have three homologues of human PAR1 genes in their autosomes, although, in contrast to mouse, do not have a PAR region at all. The disappearance of PAR from other species seems likely and this region will only be rescued by the addition of genes to both X and Y, as has occurred already in lemmings. The present review summarizes the current understanding of the evolution of PAR and provides up-to-date information about individual genes residing in this region. THE X AND Y CHROMOSOMESThe human sex chromosomes (X and Y) originate from an ancestral homologous chromosome pair, which during mammalian evolution lost homology due to progressive degradation of the Y chromosome [1]. The X-chromosome in placental mammals represents approximately 5% of the haploid genome and the gene content is almost completely conserved amongst species. To ensure dosage compensation, most genes on the X are subject to X inactivation in females. The Y chromosome is much smaller than the X, being only 2-3% of the haploid genome, and is largely composed of repeated sequences. Most genes on the Y have relatives on the X chromosome and these are not subject to X inactivation. The degeneration of the Y chromosome has been researched and reviewed extensively [2][3][4][5][6]. THE PSEUDOAUTOSOMAL REGIONSThe pseudoautosomal regions (PAR1 and PAR2) are short regions of homology between the mammalian X and Y chromosomes. The PAR behave like an autosome and recombine during meiosis. Thus genes in this region are inherited in an autosomal rather than a strictly sex-linked fashion.PAR1 comprises 2.6 Mb of the short-arm tips of both X and Y chromosomes in humans and other great apes [7,8] and is required for pairing of the X and Y chromosomes during male meiosis. All characterized genes within PAR1 escape X inactivation. X-Y pairing in the PAR is thought to serve a critical function in spermatogenesis, at least in humans and mouse [9][10][11]. PAR2 is located at the tips of the long arms and is a much shor...

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“…1,2 Depending on the population analyzed, between 60-90% of LWD cases are caused by haploinsufficiency of the short stature homeobox gene (SHOX), which is situated in the pseudoautosomal region of the human sex chromosomes. [3][4][5] SHOX encodes a homeodomain transcription factor and is strongly expressed in developing limb buds and in fetal and prepubertal growth plates, suggesting a role in bone development. In addition to its function underlying the growth and skeletal deficits of LWD and Langer syndrome, 1,2 SHOX haploinsufficiency is also the primary cause of short stature in Turner Syndrome 6 and in about 5-15% of patients diagnosed clinically as having idiopathic short stature.…”

Section: Introductionmentioning

confidence: 99%

Enhancer elements upstream of the SHOX gene are active in the developing limb

et al. 2009

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Lé ri-Weill Dyschondrosteosis (LWD) is a dominant skeletal disorder characterized by short stature and distinct bone anomalies. SHOX gene mutations and deletions of regulatory elements downstream of SHOX resulting in haploinsufficiency have been found in patients with LWD. SHOX encodes a homeodomain transcription factor and is known to be expressed in the developing limb. We have now analyzed the regulatory significance of the region upstream of the SHOX gene. By comparative genomic analyses, we identified several conserved non-coding elements, which subsequently were tested in an in ovo enhancer assay in both chicken limb bud and cornea, where SHOX is also expressed. In this assay, we found three enhancers to be active in the developing chicken limb, but none were functional in the developing cornea. A screening of 60 LWD patients with an intact SHOX coding and downstream region did not yield any deletion of the upstream enhancer region. Thus, we speculate that SHOX upstream deletions occur at a lower frequency because of the structural organization of this genomic region and/or that SHOX upstream deletions may cause a phenotype that differs from the one observed in LWD.

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Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome

Cited by 142 publications

References 14 publications

Transcriptional and Translational Regulation of the Léri-Weill and Turner Syndrome Homeobox Gene SHOX

Transcriptional and Translational Regulation of the Léri-Weill and Turner Syndrome Homeobox Gene SHOX

The Human Pseudoautosomal Region (PAR): Origin, Function and Future

Enhancer elements upstream of the SHOX gene are active in the developing limb

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