Excessive Production of cGMP From Natriuretic Peptide Receptor Gene Mutation Leads To Tall Stature

Me: This is a continuation on the study of how cGMP and NPR2 effects skeletal growth and height. A type of mutation known as p.Val883Met in occurs in Npr2 which encodes the CNP receptor NPR2 (aka natriuretic peptide receptor 2). In a cell culture prepared in a certain way, the DNA with the specfic gene mutation generated intracellular cGMP (cyclic guanosine monophosphate) without the CNP ligand. With the ligand though, the cGMP production was higher in cells with the mutation. the cGMP was seen in the cartilage, which was also seen not only in the cell but also the family that was being analyzed. Blood sampling showed cGMP concentration to be high. The results concluded that the mutation of the NPR2 gene can possibly lead to increased cGMP production in the growth plates leading to larger than normal bone elongation. 

It seems that CNP (c-type natriuretic peptide) plays an influential role in chondrocyte development. When CNP as the ligand binds to the receptor NPR2, the NPR2 seems to act as Guanyl Cyclase which increases cGMP levels in chondrocytes. experimental mice that are bred with the specific mutated gene shows CNP overproduction and excess growth.

Quoted from the abstracts…

“”In human, overproduction of C-type natriuretic peptide (CNP) due to a chromosomal translocation was reported to cause skeletal dysplasia associated with tall stature. cGMP production downstream CNP/NPR2 system regulates the proliferation and differentiation of chondrocytes and determines skeletal growth.””

Since it would appear that only one single mutation of a specific gene can cause tall stature as exhibited within the family, that was the reason why the invention with the Guanyl Cyclase was probably patented. It is a form of gene therapy that has real legitimacy to work since gene therapy can specifically target individual genes using vectors. 

From source link HERE

PLoS One. 2012; 7(8): e42180.
Published online 2012 August 3. doi:  10.1371/journal.pone.0042180
PMCID: PMC3411678

An Overgrowth Disorder Associated with Excessive Production of cGMP Due to a Gain-of-Function Mutation of the Natriuretic Peptide Receptor 2 Gene

Kohji Miura,1 Noriyuki Namba,1 Makoto Fujiwara,1 Yasuhisa Ohata,1 Hidekazu Ishida,1 Taichi Kitaoka,1 Takuo Kubota,1 Haruhiko Hirai,1 Chikahisa Higuchi,2 Noriyuki Tsumaki,3 Hideki Yoshikawa,2 Norio Sakai,1 Toshimi Michigami,4 and Keiichi Ozono1,*

Abstract

We describe a three-generation family with tall stature, scoliosis and macrodactyly of the great toes and a heterozygous p.Val883Met mutation in Npr2, the gene that encodes the CNP receptor NPR2 (natriuretic peptide receptor 2). When expressed in HEK293A cells, the mutant Npr2 cDNA generated intracellular cGMP (cyclic guanosine monophosphate) in the absence of CNP ligand. In the presence of CNP, cGMP production was greater in cells that had been transfected with the mutant Npr2 cDNA compared to wild-type cDNA. Transgenic mice in which the mutant Npr2 was expressed in chondrocytes driven by the promoter and intronic enhancer of the Col11a2 gene exhibited an enhanced production of cGMP in cartilage, leading to a similar phenotype to that observed in the patients. In addition, blood cGMP concentrations were elevated in the patients. These results indicate that p.Val883Met is a constitutive active gain-of-function mutation and elevated levels of cGMP in growth plates lead to the elongation of long bones. Our findings reveal a critical role for NPR2 in skeletal growth in both humans and mice, and may provide a potential target for prevention and treatment of diseases caused by impaired production of cGMP.

Introduction

Several lines of evidence indicate that signaling triggered by CNP plays an important role in chondrocyte development [1], [2]. Upon CNP binding, its cognate receptor natriuretic peptide receptor 2 (NPR2) functions as a guanylyl cyclase to increase cyclic guanosine monophosphate (cGMP) levels in chondrocytes, female reproductive organs, and endothelial cells [3], [4]. Transgenic mice that overproduce CNP exhibit excessive growth, while defects of the CNP or Npr2 gene, leading to impairment of skeletal development [5]–[7]. The increase in cGMP level activates cGMP-dependent protein kinase II and seems to promote the accumulation of extracellular matrix in the growth plate of CNP-transgenic mice [8]. In human, overproduction of C-type natriuretic peptide (CNP) due to a chromosomal translocation was reported to cause skeletal dysplasia associated with tall stature [9]–[10]. In addition, acromesomelic dysplasia, type Maroteaux, characterized by dwarfism and short limbs, is caused by loss-of-function mutations in the Npr2 gene [11]. On the other hand, NPR3, which is thought to act as a clearance receptor, knock-out mice resemble CNP transgenic mice [12].

In this paper, we describe the first family with tall stature and macrodactyly of both great toes caused by a gain-of-function type mutation in the Npr2 gene. The mutant receptor, p.Val883Met, constitutively generates cGMP in vitro. Animal studies using the transgenic mice expressing the mutant NPR2 in chondrocytes demonstrated that skeletal overgrowth was associated with the overproduction of cGMP in cartilage. Our findings provide evidence that cGMP production downstream CNP/NPR2 system regulates the proliferation and differentiation of chondrocytes and determines skeletal growth.

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