Heterozygous IGFALS Gene Variants in Idiopathic Short Stature and Normal Children: Impact on Height and the IGF System

DOMENÉ, H.; SCAGLIA, P.; MARTÍNEZ, A.; KESELMAN, A.; KARABATAS, L.; PIPMAN, V.; BENGOLEA, S.V.; GUIDA, M.C; ROPELATO, M.G.; BALLERINI, M.G.; LESCANO, E.M.; BLANCO, M.A.; HEINRICH, J.J.; REY, R; JASPER, H.

Hormone Research in Paediatrics

Karger

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

1663-2818

Background: In acid-labile subunit (ALS)-deficient families,heterozygous carriers of IGFALS gene mutations are frequentlyshorter than their wild-type relatives, suggestingthat IGFALS haploinsufficiency could result in short stature.We have characterized IGFALS gene variants in idiopathicshort stature (ISS) and in normal children, determining theirimpact on height and the IGF system. Patients and Methods:In 188 normal and 79 ISS children levels of IGF-1, IGFBP-3,ALS, ternary complex formation (TCF) and IGFALS gene sequencewere determined. Results: In sum, 9 nonsynonymousor frameshift IGFALS variants (E35Gfs * 17, G83S, L97F,R277H, P287L, A330D, R493H, A546V and R548W) werefound in 10 ISS children and 6 variants (G170S, V239M,N276S, R277H, G506R and R548W) were found in 7 normalchildren. If ISS children were classified according to the abilityfor TCF enhanced by the addition of rhIGFBP-3 (TCF+), carriers of pathogenic IGFALS gene variants were shorter andpresented lower levels of IGF-1, IGFBP-3 and ALS in comparisonto carriers of benign variants. In ISS families, subjectscarrying pathogenic variants were shorter and presentedlower IGF-1, IGFBP-3 and ALS levels than noncarriers. Conclusions:These findings suggest that heterozygous IGFALSgene variants could be responsible for short stature in a subsetof ISS children with diminished levels of IGF-1, IGFBP-3and ALS.