Heterozygous Mutations in Natriuretic Peptide Receptor-B (<i>NPR2</i>) Gene as a Cause of Short Stature in Patients Initially Classified as Idiopathic Short Stature

Vasques, Gabriela A; Amano, Nobuyuki; Docko, Ana; Funari, Mariana F A; Quedas, Elisangela P S; Nishi, Mirian Yumie; Arnhold, Ivo J.P.; Hasegawa, Tomonobu; Jorge, Alexander A L

doi:10.1210/jc.2013-2142

Cited by 114 publications

(113 citation statements)

References 38 publications

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“…NPR2 variants were absent in our patient group. This is inconsistent with previous studies which identified NPR2 mutations in 1.9-12.7% of ISS cases [21,22]. Since Amano et al identified pathogenic NPR2 mutations only in ~2% of Japanese short stature patients [23], such mutations may be relatively rare in the Japanese population.…”

Section: Phenotypic Characteristics Of Patients With Sequence Variantscontrasting

confidence: 62%

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

et al. 2017

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Abstract. Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.

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Section: Phenotypic Characteristics Of Patients With Sequence Variantscontrasting

confidence: 62%

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

et al. 2017

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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: 92%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

148

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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“…In clinical settings for the treatment of impaired skeletal growth, we could use OSTN and CNP for different purposes. Concerning therapeutic application for specific skeletal dysplasias, OSTN therapy, rather than CNP therapy, may be beneficial for the heterozygous NPR2 defects, because they mainly cause short stature with mild skeletal defects in appendicular bones (12,15). Furthermore, heterozygous NPPC defects, which have recently been identified and are associated with skeletal abnormalities similar to those seen with heterozygous NPR2 defects, could also be a good application for OSTN therapy (16).…”

Section: 4mentioning

confidence: 99%

“…In fact, NPR-B and CNP are both expressed in the cartilaginous growth plate, and homozygous loss-of-function mutations of NPR-B not only in murine models (7,8) but also in the human disorder acromesomelic dysplasia type Maroteaux (9,10) cause impaired skeletal growth. In addition, heterozygous loss-offunction mutations of NPR-B have been reported to cause short stature and mild skeletal defects (11)(12)(13)(14)(15), and recently heterozygous loss-of-function mutations of CNP have also been shown to cause similar skeletal defects to those of NPR-B (16). Furthermore, a recent case series showed that gain-of-function mutations in NPR-B cause a skeletal overgrowth phenotype (17,18), demonstrating the ability of CNP/NPR-B signaling to stimulate bone growth in humans.…”

Section: Introductionmentioning

confidence: 99%

Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance

Kanai¹,

Yasoda²,

Mori³

et al. 2017

Journal of Clinical Investigation

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Heterozygous Mutations in Natriuretic Peptide Receptor-B (NPR2) Gene as a Cause of Short Stature in Patients Initially Classified as Idiopathic Short Stature

Abstract: We identified heterozygous NPR2 mutations in 6% of patients initially classified as ISS. Affected patients have mild and variable degrees of short stature without a distinct phenotype. Heterozygous mutations in NPR2 could be an important cause of nonsyndromic familial short stature.

Cited by 114 publications

References 38 publications

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance

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