Towards identification of molecular mechanisms of short stature

Abstract

Growth evaluations are among the most common referrals to pediatric endocrinologists. Although a number of pathologies, both primary endocrine and non-endocrine, can present with short stature, an estimated 80% of evaluations fail to identify a clear etiology, leaving a default designation of idiopathic short stature (ISS). As a group, several features among children with ISS are suggestive of pathophysiology of the GH–IGF-1 axis, including low serum levels of IGF-1 despite normal GH secretion. Candidate gene analysis of rare cases has demonstrated that severe mutations of genes of the GH–IGF-1 axis can present with a profound height phenotype, leading to speculation that a collection of mild mutations or polymorphisms of these genes can explain poor growth in a larger proportion of patients. Recent genome-wide association studies have identified ~180 genomic loci associated with height that together account for approximately 10% of height variation. With only modest representation of the GH–IGF-1 axis, there is little support for the long-held hypothesis that common genetic variants of the hormone pathway provide the molecular mechanism for poor growth in a substantial proportion of individuals. The height-associated common variants are not observed in the anticipated frequency in the shortest individuals, suggesting rare genetic factors with large effect are more plausible in this group. As we advance towards establishing a molecular mechanism for poor growth in a greater percentage of those currently labeled ISS, we highlight two strategies that will likely be offered with increasing frequency: (1) unbiased genetic technologies including array analysis for copy number variation and whole exome/genome sequencing and (2) epigenetic alterations of key genomic loci. Ultimately data from subsets with similar molecular etiologies may emerge that will allow tailored interventions to achieve the best clinical outcome.

Association of single nucleotide polymorphisms in estrogen receptor 1 gene with the risk of idiopathic short stature

“…ISS is thought to be a polygenic disease, both genetic and environmental factors contribute to its pathogenesis, but genetic factors play a more significant part in the development of ISS [22]. Previous reports have shown that mutations in the genes along the GH-IGF axis and genes that regulate the development of the cartilage growth plate are involved in the development of ISS [4,23,24]. At present, studies are focused on the GH-IGF-1 axis genes, but from GWAS results, most genes and biological pathways associated with height were located in growth plate [21], such as BMP2, SOX8, WNT4, et al To reduce the expensive burden of growth hormone therapy,it's profitable to reveal the etiology of ISS.…”

“…Previous reports have shown that hypothalamic-pituitary-gonadal (HPG) axis and growth hormone-Insulin-like growth factor (IGF) axis is the most vital hormonal axis governing growth [3]. Any level of abnormality of GH-IGF axis may cause short stature [4], such as GHR [5], IGF-1R [6,7], IGFALS [8] were associated with ISS, but fewer studies have investigated the association of HPG axis with the risk of ISS.…”

The clinical and mechanistic intersection of primary atopic disorders and inborn errors of growth and metabolism

“…Following ligation, activation of Janus kinase 1 (JAK1) and 2 (JAK2) leads to subsequent activation of the Signal transducer and activator of transcription 1 (STAT1), 3 (STAT3), and 5 (STAT5). JAK2 and STAT5B have been shown to be indispensable for growth hormone‐mediated induction of IGF‐1, the principle transcriptional target required for growth, and lesions in this axis are associated with short stature . Given the known importance of JAK/STAT signaling in the human immune system and the role of STAT5 in lymphocyte proliferation and regulatory T cell development, one might have anticipated that a number of single gene disorders would be identified in which atopic and growth phenotypes coexist (Figure ).…”

A Quick Guide for Building a Successful Bioinformatics Community

“…Beyond these research-project-focused communities, other common bioinformatics-related activities are carried out in communities including professional/career development (especially training and education) or tool and resource development. Examples of such development-focused communities include interactions between groups of fellows and students (e.g., ISCB Student Council and Regional Student Groups [RSGs] [ 22 ] or the Software Sustainability Institute's [SSI] [ 23 ] Fellowship Program http://www.software.ac.uk/fellowship-programme ), local geographically-focused groups of bioinformaticians (e.g., TorBUG http://www.torbug.org or Heidelberg Unseminars in Bioinformatics [HUB] [ 24 ] http://www.hub-hub.de ), bioinformatics trainers and educators (e.g., GOBLET [ 25 ]), heads of nodes and technical coordinators involved in bioinformatics infrastructure development and capacity building (e.g., ELIXIR http://www.elixir-europe.org or H3ABioNet http://www.h3abionet.org ), and cooperations between software/tool developers and their larger user communities (e.g., Bioconductor [ 9 ] or Galaxy [ 7 , 8 , 26 ]).…”