Heterozygous IGFALS gene variants in idiopathic short stature and normal children: Impact on height and the IGF system

HORACIO M. DOMENÉ; PAULA A. SCAGLIA; ALICIA S. MARTÍNEZ; ANA C. KESELMAN; LILIANA M. KARABATAS; VIVIANA R. PIPMAN; SONIA V. BENGOLEA; MARÍA C. GUIDA; MARÍA G. ROPELATO; MARÍA G. BALLERINI; EVA M. LESCANO; MIGUEL A. BLANCO; JUAN J. HEINRICH; RODOLFO A. REY; HÉCTOR G. JASPER

Hormone Research in Paediatrics

Karger

Lugar: Basilea; Año: 2013 vol. 80 p. 413 - 423

1663-2818

Background: Heterozygous carriers for IGFALS gene mutations are frequently shorter than their wild-type relatives, suggesting that IGFALS haploinsufficiency could result in short stature. We characterized IGFALS gene variants in ISS and normal children, determining their impact on height and the IGF system. Patients and Methods: In 188 normal and 79 ISS children levels of IGF-I, IGFBP-3, ALS, ternary complex formation and IGFALS gene sequence were determined. Results: Nine non-synonymous or frameshift IGFALS variants: E35Gfs*17, G83S, L97F, R277H, P287L, A330D, R493H, A546V, and R548W, were found in 10 ISS and 6 variants in 7 normal children: G170S, V239M, N276S, R277H, G506R, and R548W. Carriers ISS children presented lower IGFBP-3 and ALS levels than non carriers. ISS children carriers for pathogenic IGFALS gene variants were shorter and presented lower levels of IGF-I, IGFBP-3, and ALS compared to carriers for benign variants. Subjects carrying pathogenic variants were shorter and presented lower IGF-I, IGFBP-3 and ALS levels than non-carriers relatives. Target adjusted height was lower in carriers for IGFALS gene variants than in non-carrier siblings. Conclusions: These findings suggest that heterozygous IGFALS gene variants could be responsible for the short stature in a subset of ISS children with diminished levels of IGF-I, IGFBP-3, and ALS.