Acromesomelic dysplasia, type maroteaux caused by novel loss‐of‐function mutations of the NPR2 gene: Three case reports

Abstract

The C-type natriuretic peptide (CNP)-natriuretic peptide receptor 2 (NPR2) signaling pathway plays an important role in chondrocyte development. Homozygous loss-of-function mutations of the NPR2 gene cause acromesomelic dysplasia, type Maroteaux (AMDM). The aim of this study was to identify and characterize NPR2 loss-of-function mutations in patients with AMDM. The NPR2 gene was sequenced in three Korean patients with AMDM and functional analysis of the mutated proteins was performed in vitro. Five novel NPR2 mutations were found in the three patients: two compound heterozygous mutations [c.1231T>C (Tyr411His) and c.2761C>T (Arg921X) in Patient 1 and c.1663A>T (Lys555X) and c.1711-1G>C (M571VfsX12) in Patient 3] and a homozygous mutation [c.2762G>A (Arg921Gln) in Patient 2]. Serum NT-proCNP concentration was significantly increased in each patient compared to control subjects. Cells transfected with the expression vector of each mutant except those found in Patient 3 showed a negligible or a markedly low cGMP response after treatment with CNP. HA-tagged wild-type (wt) and HA-mutant NPR2 were expressed at comparable levels: there were two bands of ∼130 and ∼120 kDa in wt and Arg921Gln, a single ∼120 kDa band in Tyr411His, and a single ∼110 kDa in the nonsense mutant. With respect to subcellular localization, Arg921Gln as well as wt-NPR2 reached the cell surface, whereas Tyr411His and Arg921X mutants did not. The Tyr411His and Arg921X NPR2 proteins were co-localized with an endoplasmic reticulum (ER) marker and failed to traffic from the ER to the Golgi apparatus. These results are consistent with deglycosylation experiments. Tyr411His and Arg921X NPR2 are complete loss-of-function mutations, whereas Arg921Gln behaves as a receptor for CNP with limited function.

Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth

“…SDS of both CNP and NTproCNP are markedly raised in these children [50] in the face of a profoundly disproportional short stature and greatly reduced height velocity. Similar findings of elevated values of plasma NTproCNP (Biomedica assay) were reported for 3 boys with AMDM aged 10–13 years [61], although an age-related reference range for the assay was not reported.…”

The Absence of Sensory Axon Bifurcation Affects Nociception and Termination Fields of Afferents in the Spinal Cord

“…Point mutations leading to single amino acid exchanges were found throughout the NPR2 protein including the ligand binding, kinase homology or guanylyl cyclase domain (for a synopsis of human NPR2 mutations see Vasques et al, 2014 ). A number of these NPR2 -missense mutations resulted in retention of the protein in the endoplasmic reticulum and poor targeting of the protein to the plasma membrane (Hume et al, 2009 ; Vasques et al, 2013 ; Amano et al, 2014 ; Wang et al, 2016 ) while others reached the cell surface (Dickey et al, 2016 ). Radiographic images demonstrated abnormal growth plates and short bones in the limbs detectable by two years of age.…”

Luteinizing Hormone Action in Human Oocyte Maturation and Quality: Signaling Pathways, Regulation, and Clinical Impact

“…NPR2 mutant mice are infertile due to premature resumption of meiosis caused by a lack of follicle cell cGMP production which results in oocyte fragmentation and poor embryo development [175,176]. Humans with NPR2 mutations develop acromesomelic dysplasia, Marateaux type (AMDM) [177]. Infertility has not been described in these patients.…”