A cluster of translocation breakpoints in 2q37 is associated with overexpression of NPPC in patients with a similar overgrowth phenotype
ABSTRACT Overexpression of the C-type natriuretic peptide, encoded by the NPPC gene in 2q37.1, was recently reported in a patient presenting an overgrowth phenotype and a balanced t(2;7)(q37.1;q21.3) translocation. We present clinical, cytogenetic, and molecular data from two additional patients carrying balanced translocations involving the same 2q37.1 chromosome band and chromosomes 8 and 13, respectively. The clinical phenotype of these patients is very similar to the first patient described. In addition to the overgrowth syndrome, there is evidence of generalized cartilage dysplasia. In these two new cases, we found overexpression of NPPC, confirming that this unusual overgrowth phenotype in humans is due to the overexpression of this gene. The involvement of three different chromosomes and a cluster of breakpoints around the NPPC gene suggests that the overexpression of this gene in translocation patients could be due to its separation from a negative regulatory element located on chromosome 2, which would constitute a previously undescribed mutational mechanism.
- SourceAvailable from: Toshimi Michigami
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- "The characteristic clinical and radiological findings make it a specific, discernible clinical disease entity, which can be differentiated from Marfan or other related syndromes. However, it is very similar to a phenotype caused by chromosomal translocation of 2q37 and subsequent CNP overproduction [Bocciardi et al., 2007; Moncla et al., 2007]. Hence, CNP overproduction and its receptor gene gain-of-function mutation may be categorized into a disease entity, that is, overgrowth CNP/NPR2 signalopathy, which should be included in differential diagnosis of the overgrowth syndrome. "
ABSTRACT: The signal pathway of the C-type natriuretic (CNP) and its receptor, natriuretic peptide receptor 2 (NPR2) is involved in the longitudinal growth of long bones. Loss of function mutations at NPR2 cause acromesomelic dysplasia, type Maroteaux, while overproduction of CNP by chromosomal translocation and a gain-of-function mutation at NPR2 have been reported to be responsible for an overgrowth syndrome in three cases and one family, respectively. We identified a four-generation family with an overgrowth syndrome characterized by tall stature, macrodactyly of the great toes, scoliosis, coxa valga and slipped capital femoral epiphysis, similar to those previously reported in association with CNP/NPR2 overactivity. The serum level of amino-terminal proCNP was normal in the proband. A novel missense mutation of NPR2, c.1462G>C (p.Ala488Pro) was found to co-segregate with the phenotype in this family. In vitro transfection assay of the mutant NPR2 revealed overactivity of the mutant receptor at baseline as well as with the ligand. This overgrowth syndrome caused by a gain-of-function mutation at NPR2 should be differentiated from Marfan or related syndromes, and may be categorized along with the overgrowth syndrome caused by overproduction of CNP due to its phenotypical similarity as overgrowth CNP/NPR2 signalopathy. © 2013 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36218 · 2.05 Impact Factor
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- "CNP is especially crucial for skeletal growth spurt that occurs in early life, is expressed in the growth plate cartilage, and works as an autocrine/paracrine regulator . In the study by Moncla et al. , the NPPC gene was not expressed in normal lymphoblasts under normal conditions while it is expressed 6-fold in chondrocytes of his patient P1. We think that “normal” expression of NPPC in our patient 1was due to a mild overexpression of the unique gene copy and it could interpreted as an attempt to functional recovery. "
ABSTRACT: Coordinated bone growth is controlled by numerous mechanisms which are only partially understood because of the involvement of many hormones and local regulators. The C-type Natriuretic Peptide (CNP), encoded by NPPC gene located on chromosome 2q37.1, is a molecule that regulates endochondral ossification of the cartilaginous growth plate and influences longitudinal bone growth. Two independent studies have described three patients with a Marfan-like phenotype presenting a de novo balanced translocation involving the same chromosomal region 2q37.1 and overexpression of NPPC. We report on two partially overlapping interstitial 2q37 deletions identified by array CGH. The two patients showed opposite phenotypes characterized by short stature and skeletal overgrowth, respectively. The patient with short stature presented a 2q37 deletion causing the loss of one copy of the NPPC gene and the truncation of the DIS3L2 gene with normal CNP plasma concentration. The deletion identified in the patient with a Marfan-like phenotype interrupted the DIS3L2 gene without involving the NPPC gene. In addition, a strongly elevated CNP plasma concentration was found in this patient. A possible role of NPPC as causative of the two opposite phenotypes is discussed in this study.PLoS ONE 06/2013; 8(6):e66048. DOI:10.1371/journal.pone.0066048 · 3.23 Impact Factor
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- "In addition, it has been found that Sef interacted with FGFR1 and FGFR2 and played its inhibitory function in FGF signaling through its intracellular domain (Tsang et al., 2002; Xiong et al., 2003; Tsang and Dawid, 2004). It has been reported that CNP/guanylatecyclase-B (GC-B) system acts as a physiologically important enhancer of endochondral bone growth in humans through downregulating the MAPK pathway and restores the ECM production (Olney et al., 2006; Bocciardi et al., 2007; Moncla et al., 2007), suggesting that CNP or CNP analogs may be a novel therapeutic method to diseases characterized by impaired skeletal growth. Further studies found that CNP could ameliorate ACH phenotype through inhibiting ERK signaling by cGMP activation via GC-B ligation and at the level of Raf-1 through the activation of cGKII, ultimately increasing matrix synthesis by chondrocytes (Yasoda et al., 2004; Krejci et al., 2005). "
ABSTRACT: Fibroblast growth factor (FGF)/FGF (FGFR) signaling is an important pathway involved in skeletal development. Missense mutations in FGFs and FGFRs were found clinically to cause multiple congenital skeleton diseases including chondrodysplasia, craniosynostosis, syndromes with dysregulated phosphate metabolism. FGFs/FGFRs also have crucial roles in bone fracture repair and bone regeneration. Understanding the molecular mechanisms for the role of FGFs/FGFRs in the regulation of skeletal development, genetic skeletal diseases, and fracture healing will ultimately lead to better treatment of skeleton diseases caused by mutations of FGFs/FGFRs and fracture. This review summarizes the major findings on the role of FGF signaling in skeletal development, genetic skeletal diseases and bone healing, and discusses issues that remain to be resolved in applying FGF signaling-related measures to promote bone healing. This review has also provided a perspective view on future work for exploring the roles and action mechanisms of FGF signaling in skeletal development, genetic skeletal diseases, and fracture healing.Journal of Cellular Physiology 12/2012; 227(12):3731-43. DOI:10.1002/jcp.24083 · 3.87 Impact Factor