Gene-Dosage Effect of Igfals Gene Mutations on the IGF System

SCAGLIA, PAULA; MARTUCCI, LUCIA; KARABATAS, LILIANA; KESELMAN, ANA; SPINOLA-CASTRO, ANGELA MARIA; BRASLAVSKY, DEBORA; BALLERINI, MARIA GABRIELA; ROPELATO, MARIA GABRIELA; MARTINEZ, ALICIA; BENGOLEA, SONIA; PITMAN, VIVIANA; DOMENE, SABINA; BERGADA, IGNACIO; REY, RODOLFO; DOMENE, HORACIO; JASPER, HECTOR

San Diego

Congreso; 16th International Congress of Endocrinology & the Endocrine Society 96th Annual Meeting & Expo; 2014

Background: First degree relatives of complete ALS deficient patients (ALS-D), heterozygous carriers (HC) for IGFALS mutations present height 1.0 SD lower than wild type (WT) relatives (1), associated with IGF-I, IGFBP-3 and ALS levels intermediate between ALS-D (2 alleles affected) and WT relatives. In addition, children with idiopathic short stature (ISS) HC carriers for IGFALS mutations present reduced levels of IGF-I, IGFBP-3 and ALS (2). These findings are suggestive of a gene-dosage effect of IGFALS mutations on both height and components of the circulating IGF system. Aim: To test whether there is a gene-dosage effect by exploring the impact of IGFALS mutations on height and the IGF system within families of ALS-D patients. Subjects and Methods: We recruited 9 ALS-D (ages 2.8 to 19.6 years), 18 HC (8 siblings and 10 parents; 5.2 to 48.0 years) and 8 WT relatives (6 siblings and 2 parents; 4.4 to 42.0 years). IGF-I and IGFBP-3 serum levels were determined by CLIA, and ALS by ELISA. ALS and IGFBP-3 were also evaluated by Western Immunoblot (WIB) and IGFBPs by Western ligand-blot (WLB). All subjects were genotyped for the IGFALS gene by sequencing PCR amplified fragments. SDS for IGF-I, IGFBP-3 and ALS serum levels in children were calculated from local age-matched control groups (3). Wilcoxon signed rank and Kruskal-Wallis tests were used for statistical analysis. Results: When compared to the normal population, median SDS for height and levels of IGF-I, IGFBP-3 and ALS were significantly lower for both ALS-D and HC, while WT relatives did not differ from normal, as evaluated by Wilcoxon signed rank test. Results are expressed as median SDS (interquartile range), p-value. Height: ALS-D -1.91 (-2.59 to -1.46), p=0.0020, HC -0.80 (-1.51 to 0.11), p=0.0161, WT 0.08 (-0.53 to 0.87), p=0.2734. IGF-I: ALS-D -5.68 (-7.00 to ?5.46), p=0.0020, HC -0.55 (-0.92 to -0.19), p=0.0013, WT 0.08 (-0.41 to 0.35), p=0.4727. IGFBP-3: ALS-D -7.00 (all -7.00 except one -5.30), p=0.0020, HC -1.84 (-2.09 to -1.30), p=0.0002, WT -0.62 (-1.33 to 0.99), p=0.3711. ALS: ALS-D -7.00 (all -7.00 except one -3.57), p=0.0020, HC -2.16 (-2.96 to -1.80), p=0.0001, WT 0.64 (-0.47 to 1.16), p=0.2305. Kruskal-Wallis analysis showed significant differences among the 3 groups (p=0.0011 for height, p<0.0001 for IGF-I, IGFBP-3 and ALS levels). In ALS-D patients, all parameters were significantly lower than WT (p<0.001) and HC (height p<0.05, IGF-I and IGFBP-3 p<0.001, ALS p<0.01) but in HC only ALS levels were significantly lower than WT relatives (p<0.05). WLB results showed a generalized reduction of all IGFBPs in ALS-D patients and variable levels of IGFBPs in HC children. Conclusions: A significant gene dosage-effect was observed for ALS levels among ALS-D, HC and WT subjects, while the effect on height and IGF-I and IGFBP-3 levels was less evident.