| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Editorial |
Department of Pediatrics Johns Hopkins University Baltimore, Maryland 21287
Address all correspondence and requests for reprints to: Sally Radovick, M.D., Division of Pediatric Endocrinology, 600 North Wolfe Street, Park 211, Baltimore, Maryland 21287. E-mail: sradovick{at}jhmi.edu.
Identified genes that are linked to growth and stature can be broadly divided into two categories: 1) genes that are involved in the hypothalamic-pituitary-GH-IGF-I axis (GH-IGF axis), and 2) genes expressed at the skeletal growth plate. The central role of the GH-IGF system to normal growth is well established; however, the effects of this system on the skeletal growth plate at a molecular level are unknown. Olney et al. (1) in this issue describe a heterozygous gene mutation associated with short stature and provide data suggesting that this gene is a point of interaction between the GH-IGF axis and molecular mechanisms present in the chondrocyte environment.
Identification of genes involved in the GH-IGF axis has been accomplished by looking for mutations of candidate genes in patients with well-defined abnormalities of the GH-IGF axis. Several hundred cases of GH mutations associated with GH deficiency and growth failure have been identified in the literature (for review see Ref. 2). GHRH gene mutations causing GH deficiency have also been reported (3). Identification of mutations in genes causing combined pituitary hormone deficiency has led to advances in our knowledge of pituitary development and GH transcription activation. HESX-1, PROP1, and PIT-1 are three such genes (4).
Knowledge of the GH-IGF axis has also led to identification of mutations responsible for GH insensitivity associated with abnormal growth, although these mutations have been reported far less commonly than mutations of the GH gene. Mutations in the GH receptor, IGF-I gene, and IGF-I receptor have been identified (2). A mutation of the gene for signal transducer and activator of transcription-5b (STAT 5b), a transcription factor that is stimulated by GH receptor signaling pathways, has also been shown to cause GH insensitivity with low IGF-I levels (5). These mutations support the hypothesis that GH effects on target tissue are mediated through liver-derived IGF-I actions. However, there is evidence that some effects of GH are IGF-I independent or a result of paracrine actions of IGF-I. GH increases insulin resistance in contrast to IGF-I, which is an insulin sensitizer. In addition, mice that have a liver-specific knockout of the IGF-I gene have dramatically decreased circulatory IGF-I levels but normal postnatal growth (6). Molecular mechanisms to explain these observations have not been characterized.
Genes important for the normal function of the skeletal growth plate have also been identified. By studying patients with well-characterized radiological evidence of skeletal dysplasia, more than 40 genes associated with skeletal dysplasias with or without other organ dysfunction have been found (7). These mutations can be broadly divided into mutations that cause defects in extracellular structural proteins, osteocyte metabolism, macromolecule degradation, osteocyte paracrine and autocrine function, and cellular DNA processing. For many of the genes, the pathways in which they are involved are unknown. The diversity of genes that can cause skeletal abnormalities indicates that integration of many complex, uncharacterized pathways is necessary to result in normal bone formation and growth.
Although important genes have been characterized, the particular genetic recipe determining individual stature is not known. Polymorphic variation of genes involved in determination of stature may give rise to the broad range of normal heights. Polymorphic variation of the GH1 gene and promoter has been suggested to contribute to genetic variation in stature (8), and heterozygous mutations in the GH receptor gene have been suggested as a cause of short stature (9). Haploinsufficiency is known to cause short stature because loss of one allele for the SHOX gene contributes to the short stature of Turner syndrome, and SHOX haploinsufficency has also been linked to idiopathic short stature (10).
The work by Olney et al. (1) has provided insight into a possible mechanism of GH interaction with the growth plate and adds NPR2 to the short list of genes that are associated with short stature when present in the heterozygous state. Previous work by Bartels et al. (11) found that homozygous mutations of the transmembrane natriuretic peptide receptor (NPR-B) gene (NPR2) caused acromesomelic dysplasia type Maroteax [AMDM (OMIM 602875)]. The acromesomelic dysplasias as a group are skeletal dysplasias characterized by the abnormal/premature fusion of the growth plate in long bones, resulting in disproportionately shortened forearms, forelegs, hands, and feet. AMDM also has axial skeletal involvement, and, in contrast to the other acromesomelic dysplasias, it is not characterized by fused or missing distal skeletal elements. It has a prevalence of 1 in 1 million. Individuals with this disease do not have systemic disease, and their final height is typically 5 SD below the mean (11). It has long been recognized that parents of children with AMDM are shorter than average (12), and Bartels et al. noted that carriers were 5.7 cm shorter than population-matched controls. A clear correlation could not be concluded because of the diverse population studied. Olney et al. expanded on this observation and investigated 39 family members of one proband with AMDM for heterozygous mutations in the NPR2 gene. The height z-score of the carriers was –1.9, whereas that of the noncarriers was –0.5. The 1.4 SD difference between the two groups was significant (P < 0.0005). Thus the authors concluded that heterozygous mutation of the NPR2 gene could be a cause of idiopathic short stature seen in carriers.
Interestingly, NPR2 is found on chromosome 9, which has been identified by linkage and segregation analysis as a locus for stature (13). Relatively little is known about NPR2 and its product NPR-B. NPR-B is a transmembrane receptor expressed in growth plate chondrocytes. Binding of its ligand, C-type natriuretic peptide (CNP) leads to cGMP production and activation of protein kinase pathways. Studies have shown that CNP stimulates chondrocyte proliferation and cell hypertrophy at the growth plate (14, 15). The CNP knockout mouse is dwarfed, as is the cGMP protein kinase 2 knockout mouse, further implicating the role of NPR-B at the growth plate (16, 17). It is unknown whether CNP is its only ligand.
A very interesting aspect of this study is that the proband has evidence of GH insensitivity, with a low IGF-I, high GH level, and nonresponsiveness to exogenous GH. Although it is tempting to speculate that NPR-B signaling pathways regulate IGF-I, her skeletal dysplasia does not correspond with the normal skeletal proportions and radiographically normal epiphyses typical of individuals with IGF-I deficiency. Additionally, IGF-I levels rose slightly with the IGF-I generation test, suggesting that the classic GH signaling pathways are intact. Possibly the elevated levels of CNP seen in this patient negatively regulate IGF-I. Clearly, if interactions between the GH-IGF and NPR-B pathways exist, then it is via mechanisms that have yet to be explained. More data on individuals with AMDM and individuals heterozygous for mutations of NPR2 will need to be obtained to confirm a relationship between GH-IGF and NPR-B pathways. If verified, further molecular studies are also necessary to elucidate the role of NPR-B in the chondrocyte and its relationship to GH and IGF-I.
Olney et al. (1) present a novel factor that is an element of the genetic formula resulting in stature. The implications of this work extend beyond the laboratory and into clinical practice. Children with idiopathic short stature very often respond to treatment with GH. However, GH therapy for these children is shrouded in ethical and economic controversies. One source for this controversy is our lack of knowledge about the cellular and molecular mechanisms responsible for stature. Advancing our knowledge of the GH-IGF axis and end-organ responsiveness to growth factors at the cellular and molecular level will assist us in predicting the determinants for responsiveness to therapy. This knowledge would allow clinicians to tailor GH treatment and dosing to an individual’s molecular diagnosis.
Footnotes
Abbreviations: AMDM, Acromesomelic dysplasia type Maroteax; CNP, C-type natriuretic peptide; NPR-B, natriuretic peptide receptor.
Received January 20, 2006.
Accepted January 24, 2006.
References
This article has been cited by other articles:
 |
|
 |
|
  R. G Rosenfeld Pharmacogenomics and pharmacoproteomics in the evaluation and management of short stature Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S27 - S31. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
