The genetics of signal transduction and the outcome of diagnostic tests in growth retardation

Abstract

The effects of 'normal' genetic variability of signal transduction on endocrine function may be more evident during stimulation tests than is observed in basal states, thereby contributing to a greater understanding of the possible role of signal transduction genetics in the pathogenesis of endocrine disorders. In the present study, we have studied the outcome of growth hormone (GH) stimulation testing by insulin in growth-retarded children in relation to the genotype of ACP1 (acid phosphatase locus 1; also referred to as cLMWPTP, cytosolic low molecular weight phosphotyrosine phosphatase). ACP1 is an enzyme, expressed as two distinct isoforms designated F and S, that down-regulates insulin receptor signal transduction and which shows a genetic polymorphism with strong quantitative enzymatic differences among genotypes. In this study, we examined 116 growth-retarded children of which 101 were genotyped for ACP1. We found that the basal level of GH is higher in ACP1 genotypes with low concentrations of the S isoform than in genotypes with high S isoform concentrations (P<0·02). Additionally, during GH stimulation with insulin, the genotypes with low S isoform concentrations were found to perform better (P<0·005) and to react more promptly than the genotypes with high S isoform concentrations (P<0·05). These findings suggest that high S isoform ACP1 activity slows down the effect of insulin, resulting in a retardation of its metabolic effect.

Functional aspects of genetic variability in the GH genomic region

“…We have reconsidered a previous study (Bottini et al 2001) showing an effect of ACP1 genetic variability on the area under the GH secretory curve during provocative tests.…”

“…In a previous note, we have shown that the area under the GH secretory curve is greater in subjects with medium-low ACP1 activity than in those with high activity (Bottini et al 2001). ACP1 is a protein tyrosine phosphatase that is able to dephosphorylate the insulin receptor, thus decreasing the effects of insulin (Bottini et al 2002a).…”

“…The outcome of a GH diagnostic test in relation to GH region genotypes has been evaluated by the analysis of area under the GH secretory curve. We have also considered possible interaction between GH region genotypes and acid phosphatase (ACP1; Bottini et al 2001Bottini et al , 2002a in relation to GH release during provocative tests.…”