Heterozygous<i>NPR2</i>Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis

Hisado-Oliva, Alfonso; Garre-Vazquez, Ana Isabel; Santaolalla-Caballero, Fabiola; Belinchón, Alberta; Barreda-Bonis, Ana C; Vasques, Gabriela A; Ramirez, Joaquin; Luzuriaga, Cristina; Carlone, Gianni; González‐Casado, Isabel; Benito‐Sanz, Sara; Jorge, Alexander Augusto de Lima; Campos-Barros, Ángel; Heath, Karen E.

doi:10.1210/jc.2015-1612

Cited by 66 publications

(59 citation statements)

References 40 publications

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“…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). Heterozygous NPR2 mutations may explain 2-3% of cases with assumed ISS (129) and probably more if one of the parents has a similar phenotype.…”

Section: Cnp-npr2 Pathwaymentioning

confidence: 83%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

153

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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Section: Cnp-npr2 Pathwaymentioning

confidence: 83%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

153

132

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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%

“…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). Nevertheless, the clinical phenotype of individuals with heterozygous NPR2 defects is reported to be highly variable: some have short stature, whereas others have normal stature but shortened arms (15). Accordingly, it would be hard to generalize which therapy, i.e., OSTN or CNP, is optimal for treating patients with heterozygous NPR2 or possibly NPPC defects, and we might have to choose pertinent therapy for each patient.…”

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%

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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 inactivating mutations in GC-B are also associated with short stature observed in Léri-Weill dyschondrosteosis (20). Conversely, genetic mutations that increase GC-B activity result in skeletal overgrowth (21)(22)(23).…”

mentioning

confidence: 99%

Catalytically Active Guanylyl Cyclase B Requires Endoplasmic Reticulum-mediated Glycosylation, and Mutations That Inhibit This Process Cause Dwarfism

Dickey

Edmund

Otto

et al. 2016

Journal of Biological Chemistry

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C-type natriuretic peptide activation of guanylyl cyclase B (GC-B), also known as natriuretic peptide receptor B or NPR2, stimulates long bone growth, and missense mutations in GC-B cause dwarfism. Four such mutants (L658F, Y708C, R776W, and G959A) bound 125 I-C-type natriuretic peptide on the surface of cells but failed to synthesize cGMP in membrane GC assays. Immunofluorescence microscopy also indicated that the mutant receptors were on the cell surface. All mutant proteins were dephosphorylated and incompletely glycosylated, but dephosphorylation did not explain the inactivation because the mutations inactivated a "constitutively phosphorylated" enzyme. Tunicamycin inhibition of glycosylation in the endoplasmic reticulum or mutation of the Asn-24 glycosylation site decreased GC activity, but neither inhibition of glycosylation in the Golgi by N-acetylglucosaminyltransferase I gene inactivation nor PNGase F deglycosylation of fully processed GC-B reduced GC activity. We conclude that endoplasmic reticulummediated glycosylation is required for the formation of an active catalytic, but not ligand-binding domain, and that mutations that inhibit this process cause dwarfism.

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HeterozygousNPR2Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis

Cited by 66 publications

References 40 publications

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

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

Catalytically Active Guanylyl Cyclase B Requires Endoplasmic Reticulum-mediated Glycosylation, and Mutations That Inhibit This Process Cause Dwarfism

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