ESPE Abstracts (2016) 86 FC14.6

In vitro and in vivo Evidence for a Growth Inhibitory Role of the Transcription Factor ZBTB38 Throughout Pre- and Post-Natal Life

Sam Parsons, Adam Stevens, Andrew Whatmore, Philip Murray & Peter Clayton

Institute of Human Development, Manchester, UK

Background: Single nucleotide polymorphisms (SNPs) within the promotor and 5’UTR of the transcriptional factor, ZBTB38, are associated with adult height and idiopathic short stature although their precise auxological effects have not previously been described. In addition, the molecular mechanisms through which ZBTB38 affects growth have not been fully elucidated but potential downstream mediators are suggested to include MCM10 or IGF2.

Objectives: 1. To describe the auxology of two independent cohorts of children genotyped for ZBTB38 SNPs rs6764769 (G/A) and rs724016 (A/G) 2. Explore the effects of ZBTB38 expression on childhood growth, cell growth as well as MCM10 and IGF2 transcription.

Methods: The EPIGROW (n=261) and Manchester Growth Study (n=93) were genotyped via sequencing (Next Generation/Sanger sequencing) and detailed auxology collected. ZBTB38 knockdown was achieved in a SiHa cell line via siRNA transfection with transcription of MCM10 and IGF2 assessed by qPCR and cell growth by WST-8 assay. Age related childhood gene expression in PBMCs from normal control children was derived from data from multiple GEO datasets.

Results: Carriage of GG genotype was associated with reduced birth length SDS (both SNPs, P=0.001) and birth weight (g) (rs724016, P=0.01) but there was no effect on childhood BMI, head circumference or response to GH therapy (defined as 1st year ΔHt SDS). ZBTB38 expression in PBMCs was inversely related to growth rate throughout childhood and adolescence. The in vitro ZBTB38 knockdown demonstrated increased cell growth (P=0.001) at 72 hours post-transfection with no change in MCM10 or IGF2 expression.

Conclusion: The knockdown studies link reduced ZBTB38 expression to increased growth independent of IGF2 or MCM10 expression. ZBTB38 expression affects both pre- and post-natal growth and, given the location of the SNPs, it is likely that they mediate their effects via altering ZBTB38 expression.

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