Role of the Natriuretic Peptide System in Normal Growth and Growth Disorders

Vasques, Gabriela A; Arnhold, Ivo J.P.; Jorge, Alexander A L

doi:10.1159/000365049

Cited by 59 publications

(44 citation statements)

References 51 publications

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“…For instance, in the growth hormone (GH) - insulin-like growth factor 1 (IGF-1) axis, heterozygous carriers of mutations in acid-labile subunit gene ( IGFALS ) 3 and IGF1 gene 1 were shown to be significantly shorter than non-carriers, although generally still within the normal height range. These data support the concept that rare mono-allelic variants with moderate effects on phenotype can be associated with height variability 5 and, as such, can be an etiology for non-syndromic short stature 6, 7 .…”

Section: Introductionsupporting

confidence: 81%

STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability

Scalco

Hwa

Domené

et al. 2015

European Journal of Endocrinology

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Context and objective Growth hormone insensitivity with immune dysfunction caused by signal transducer and activator of transcription 5B (STAT5B) mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations. Methods We genotyped and performed clinical and laboratorial evaluations in 52 relatives of 2 previously described Brazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1,104 adult control individuals from the same region in Brazil and identified 5 additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from 7 families). Data from heterozygous individuals and non-carriers were compared. Results Individuals carrying heterozygous STAT5B c.424_427del mutation were 0.6 SDS shorter than their non-carrier relatives (p= 0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF-1 (p=0.028) and IGFBP-3 (p=0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of −1.4 ± 0.8 when compared with population-matched controls (p < 0.001). Conclusions STAT5B mutations in heterozygous state have a significant negative impact on height (approximately 3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.

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Section: Introductionsupporting

confidence: 81%

STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability

Scalco

Hwa

Domené

et al. 2015

European Journal of Endocrinology

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“…NPR3 helps maintain blood pressure and extracellular fluid volume (46), which are known MR‐regulated pathways (47). Mutations in NPR2 are known to effect muscle growth (48), but NPR3 has not previously been investigated in skeletal muscle. FOS , a regulator of cell proliferation and differentiation in skeletal muscle and other cell types (49), has previously been shown to be up‐regulated by aldosterone and GR overexpression (25, 50).…”

Section: Discussionmentioning

confidence: 99%

Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target

et al. 2015

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Early treatment with heart failure drugs lisinopril and spironolactone improves skeletal muscle pathology in Duchenne muscular dystrophy (DMD) mouse models. The angiotensin converting enzyme inhibitor lisinopril and mineralocorticoid receptor (MR) antagonist spironolactone indirectly and directly target MR. The presence and function of MR in skeletal muscle have not been explored. MR mRNA and protein are present in all tested skeletal muscles from both wild-type mice and DMD mouse models. MR expression is cell autonomous in both undifferentiated myoblasts and differentiated myotubes from mouse and human skeletal muscle cultures. To test for MR function in skeletal muscle, global gene expression analysis was conducted on human myotubes treated with MR agonist (aldosterone; EC 50 1.3 nM) or antagonist (spironolactone; IC 50 1.6 nM), and 53 gene expression differences were identified. Five differences were conserved in quadriceps muscles from dystrophic mice treated with spironolactone plus lisinopril (IC 50 0.1 nM) compared with untreated controls. Genes down-regulated more than 2-fold by MR antagonism included FOS, ANKRD1, and GADD45B, with known roles in skeletal muscle, in addition to NPR3 and SERPINA3, bona fide targets of MR in other tissues. MR is a novel drug target in skeletal muscle and use of clinically safe antagonists may be beneficial for muscle diseases.-Chadwick, J. A., Hauck, J. S., Lowe, J. , Shaw, J. J., Guttridge, D. C., Gomez-Sanchez, C. E., Gomez-Sanchez, E. P., RafaelFortney, J. A. Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target. FASEB J. 29, 4544-4554 (2015). www.fasebj.org

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“…Homozygous inactivating mutations of NPR2 (encoding the main CNP receptor) cause a severe skeletal dysplasia, acromesomelic dysplasia, Maroteaux type (124). Initial observations that relatives heterozygous for NPR2 mutations of patients with acromesomelic dysplasia are shorter than non-carriers (125), were confirmed by recent studies (126,127,128,129). The phenotype of heterozygous NPR2 mutations is similar to that of patients with SHOX haploinsufficiency (Leri-Weill syndrome), with short forearms and lower legs (mesomelia), except for the absence of Madelung deformity (130).…”

Section: Cnp-npr2 Pathwaymentioning

confidence: 94%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

152

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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Role of the Natriuretic Peptide System in Normal Growth and Growth Disorders

Cited by 59 publications

References 51 publications

STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability

STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability

Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

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