BNP is a transcriptional target of the short stature homeobox gene SHOX

Marchini, Antonio; Häcker, Beate; Marttila, Tiina; Hesse, V.; Emons, Joyce; Weiß, Birgit; Karperien, Marcel; Rappold, Gudrun

doi:10.1093/hmg/ddm266

Cited by 60 publications

(41 citation statements)

References 30 publications

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“…In osteogenic cell line U2OS as well as in primary oral fibroblasts and primary chondrocytes, SHOX overexpression causes blockage of the cell cycle with proliferation arrest and apoptosis which may indicate that the main effect of SHOX is to promote differentiation and to stop proliferation of the hypertrophic chondrocytes in the epiphyseal growth plate [25]. A search for downstream targets has so far detected brain natriuretic peptide (BNP) as a gene whose expression is stimulated by SHOX [27]. So far, the biological meaning of this finding is unclear.…”

Section: Shox Proteinmentioning

confidence: 99%

Short Stature due to SHOX Deficiency: Genotype, Phenotype, and Therapy

2011

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SHOX deficiency is a frequent cause of short stature. The short stature homeobox-containing gene resides in the telomeric PAR1 region on the short arm of both sex chromosomes and escapes X inactivation. For this review, abstracts of 207 publications presented by PubMed for the search term ‘SHOX’ were screened. Heterozygote SHOX mutations (80% deletions) were detected in 2–15% of individuals with formerly idiopathic short stature, in 50–90% of individuals with Leri-Weill dyschondrosteosis, and in almost 100% of girls with Turner syndrome. Mutational analysis is primarily performed by MLPA analysis followed by gene sequencing if necessary. SHOX is a nuclear protein that binds to DNA and acts as a transcriptional activator. Orthologs are present in many vertebrates but not in rodents. Gene expression starting as early as 33 days postconception in humans is predominant in the mid portion of the buds and in the first and second pharyngeal arches. In the growth plate, hypertrophic chondrocytes express SHOX where it seems to have antiproliferative potency. The penetrance of SHOX deficiency is high, but its clinical expression is very variable becoming more pronounced with age and being more severe in females. Growth failure starts early during the first years of life and the height deficit present at preschool age seems not to deteriorate further. The mean adult height is –2.2 SDS. Auxological analysis of the body proportions (mesomelia), the presence of minor abnormalities, and the search for subtle radiographic signs are important keys to the diagnosis which has to be confirmed by genetic analysis. The growth-promoting effect of GH therapy approved for individuals with SHOX mutations seems to be equal to the effect seen in Turner syndrome.

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Section: Shox Proteinmentioning

confidence: 99%

Short Stature due to SHOX Deficiency: Genotype, Phenotype, and Therapy

2011

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“…Both SHOXa and SHOXb are transcriptionally active but SHOXb lacks the transactivation domain and has been predicted to modulate the function of SHOXa [16]. Serine phosphorylation turns the SHOX protein into an active state facilitating efficient regulation of genes involved in ossification and limb development such as the natriuretic peptide BNP (NPPB) and the fibroblast growth factor receptor FGFR3 [17,18,19]. …”

Section: Introductionmentioning

confidence: 99%

Alu-Mediated Recombination Defect in IGF1R: Haploinsufficiency in a Patient with Short Stature

Harmel¹,

Binder

Barnikol-Oettler³

et al. 2013

Horm Res Paediatr

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Background: The insulin-like growth factor (IGF) receptor (IGF1R) is essential for normal development and growth. IGF1R mutations cause IGF-1 resistance resulting in intrauterine and postnatal growth failure. The phenotypic spectrum related to IGF1R mutations remains to be fully understood. Methods: Auxological and endocrinological data of a patient identified previously were assessed. The patient's fibroblasts were studied to characterize the IGF1R deletion, mRNA fate, protein expression and signalling capabilities. Results: The boy, who carries a heterozygous IGF1R exon 6 deletion caused by Alu element-mediated recombination and a heterozygous SHOX variant (p.Met240Ile), was born appropriate for gestational age but developed proportionate short stature postnatally. IGF-1 levels were low-normal. None of the stigmata associated with SHOX deficiency or sporadically observed in IGF1R mutation carriers were present. Nonsense-mediated mRNA decay led to a substantial decline of IGF1R dosage and IGF-1-dependent receptor autophosphorylation but not impaired downstream signalling. Conclusion: We present the first detailed report of an intragenic IGF1R deletion identified in a patient who, apart from short stature, deviates from all established markers that qualify a growth-retarded child for IGF1R analysis. Although such children will usually escape routine clinical mutation screenings, they can contribute to the understanding of factors and mechanisms that cooperate with the IGF1R.

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“…In this regard, several new disorders which lead to short stature have been described such as SHOX deficiency [1,2] and mutations in brain natriuretic peptide [3]. Secondary growth disorders include systemic illnesses and endocrine abnormalities which may affect the growth hormone (GH)-IGF axis.…”

Section: Introductionmentioning

confidence: 99%

Ghrelin Plasma Levels in Patients with Idiopathic Short Stature

et al. 2010

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Background: Novel molecular insights have suggested that ghrelin may be involved in the pathogenesis of some forms of short stature. Recently, growth hormone secretagogue receptor (GHSR) mutations that segregate with short stature have been reported. Aim: To study plasma ghrelin levels in prepubertal patients with idiopathic short stature (ISS). Methods: Fasting total plasma ghrelin levels (radioimmunoassay) in 41 prepubertal patients with ISS (18 females, age 7.9 ± 0.5 years) compared with 42 age- and sex-matched controls (27 females, age 8.0 ± 0.3 years) with normal height. In a subset of 28 patients, the ghrelin receptor was sequenced. Results: ISS patients exhibited a higher level of ghrelin (1,458 ± 137 vs. 935 ± 55 pg/ml, p < 0.01) and similar IGF-I levels (–0.66 ± 1.29 vs. –0.32 ± 0.78 SDS) compared to controls. Ten patients with ISS had ghrelin levels greater than +2 SDS compared to controls. These patients did not differ in height, BMI or IGF-I SDS compared to ISS patients with ghrelin levels within the normal range. Molecular analysis of GHSR did not show any mutations, but showed some polymorphisms. Conclusion: These results suggest that in ISS patients, short stature does not appear to be frequently caused by abnormalities in ghrelin signaling.

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BNP is a transcriptional target of the short stature homeobox gene SHOX

Cited by 60 publications

References 30 publications

Short Stature due to SHOX Deficiency: Genotype, Phenotype, and Therapy

Short Stature due to SHOX Deficiency: Genotype, Phenotype, and Therapy

Alu-Mediated Recombination Defect in IGF1R: Haploinsufficiency in a Patient with Short Stature

Ghrelin Plasma Levels in Patients with Idiopathic Short Stature

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