The Effect of Heterozygous IGFALS Gene Variants on Height and the IGF System in Normal (N), Idiopathic Short Stature (ISS) and GH Deficient (GHD) Children.

HM DOMENE; PA SCAGLIA; AS MARTINEZ; AC KESELMAN; VR PIPMAN; SV BENGOLEA; LM KARABATAS; MC GUIDA; MG ROPELATO; MG BALLERINI; EM LESCANO; MA BLANCO; JJ HEINRICH; RA REY; HG JASPER

Congreso; 92nd Annual Meeting of The Endocrine Society; 2010

Inactivation of the IGFALS gene results in ALS deficiency, characterized by low levels of IGF-I and IGFBP-3, that remain unchanged after GH treatment (1,2). Heterozygous carriers (HC) for IGFALS gene mutations are frequently shorter than their wild type (WT) relatives (3), suggesting that this gene could be involved in the etiology of short stature in a subset of ISS children. We characterized IGFALS gene mutations in N, ISS and GHD children, determining the impact of these mutations on height and the IGF system.Levels of IGF-I, IGFBP-3, and ALS were measured in 196 N (5.0-16.3 y), 27 GHD (2.0-17.6 y) and 89 ISS children (1.8-16.9 y) and expressed as SDS in relation to controls. The IGFALS gene was sequenced, evaluating the effect of SNPs in silico by mean of PolyPhen analysis (classified as severe and non-severe).Besides two common polymorphisms (D70D and Y462Y), the following genetic variants were found: Genetic variants in the IGFALS gene   Severe nsSNPs Non-severe nsSNPs Synonymous SNPs N N276S; R277H; R548W (2) 4/196=2.0% G170S; V239M; G506R 3/196=1.5% N236N; A267A; L271L (2); L487L (2); T522T (3) 9/196=4.6% ISS E35GfsX16; L97F; R277H; R548W (2) 5/89=5.6% G83S; P287L; A330D; R493H; A546V 5/89=5.6% P73P.L316L; P271L; T522T 3/89=3.4% GHD   R157H 1/27=3.7%   HC-ISS children show lower IGFBP-3 (-1.90±1.46 vs. -0.77±1.24 SDS; p=0.007) and ALS levels (-2.34±1.77 vs. -1.22±1.45 SDS; p=0.02) when compared to WT-ISS children.The study was extended to 15 parents (7 HC) and 14 siblings (2 HC) of HC-ISS children. Auxological, biochemical and genetic data in families of HC-ISS children SDS Severe (n=8) Non-severe (n=12) WT (n=20) One-way ANOVA Height -2.09±1.40a -2.26±0.83a -0.30±0.92 p<0.0001 IGF-I -2.38±1.83a,b -0.99±1.21 -0.46±1.08 p=0.0024 IGFBP-3 -1.90±1.28a -1.14±1.24c 0.18±1.11 p=0.0003 ALS -3.22±1.34a,d -1.07±1.19 -0.66±1.04 p<0.0001 ap<0.001 vs. WT; bp<0.05 vs. non-severe; cp<0.05 vs. WT; dp<0.01 vs. non-severeIn families of ISS children the finding of lower levels of IGF-I, IGFBP-3 and ALS in HC for severe mutations suggests that both gene alleles are required to maintain the circulating IGF system and to fulfill growth potential. Functional characterization of mutant ALS-proteins is required to confirm the involvement of this gene in the etiology of short stature in a subset of ISS children.