title: Heterozygous IGFALS gene variants in idiopathic short stature and normal children: impact on height and the IGF system.
abstract: BACKGROUND
  In acid-labile subunit (ALS)-deficient families, heterozygous carriers of IGFALS gene mutations are frequently shorter than their wild-type relatives, suggesting that IGFALS haploinsufficiency could result in short stature. We have characterized IGFALS gene variants in idiopathic short stature (ISS) and in normal children, determining their impact on height and the IGF system.
  
  
  METHODS
  In 188 normal and 79 ISS children levels of IGF-1, IGFBP-3, ALS, ternary complex formation (TCF) and IGFALS gene sequence were determined.
  
  
  RESULTS
  In sum, 9 nonsynonymous or frameshift IGFALS variants (E35Gfs*17, G83S, L97F, R277H, P287L, A330D, R493H, A546V and R548W) were found in 10 ISS children and 6 variants (G170S, V239M, N276S, R277H, G506R and R548W) were found in 7 normal children. If ISS children were classified according to the ability for TCF enhanced by the addition of rhIGFBP-3 (TCF+), carriers of pathogenic IGFALS gene variants were shorter and presented lower levels of IGF-1, IGFBP-3 and ALS in comparison to carriers of benign variants. In ISS families, subjects carrying pathogenic variants were shorter and presented lower IGF-1, IGFBP-3 and ALS levels than noncarriers.
  
  
  CONCLUSIONS
  These findings suggest that heterozygous IGFALS gene variants could be responsible for short stature in a subset of ISS children with diminished levels of IGF-1, IGFBP-3 and ALS.
authors: Centro de Investigaciones Endocrinológicas 'Dr. César Bergadá' (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños 'Ricardo Gutiérrez', Buenos Aires, Argentina.
authors: Horacio M
authors: HM
authors: Domené
authors: Paula A
authors: PA
authors: Scaglia
authors: Alicia S
authors: AS
authors: Martínez
authors: Ana C
authors: AC
authors: Keselman
authors: Liliana M
authors: LM
authors: Karabatas
authors: Viviana R
authors: VR
authors: Pipman
authors: Sonia V
authors: SV
authors: Bengolea
authors: María C
authors: MC
authors: Guida
authors: María G
authors: MG
authors: Ropelato
authors: María G
authors: MG
authors: Ballerini
authors: Eva M
authors: EM
authors: Lescano
authors: Miguel A
authors: MA
authors: Blanco
authors: Juan J
authors: JJ
authors: Heinrich
authors: Rodolfo A
authors: RA
authors: Rey
authors: Héctor G
authors: HG
authors: Jasper
mesh_terms: D000293:Adolescent; D001827:Body Height; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006023:Glycoproteins / Q000097:blood / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D018972:Insulin-Like Growth Factor Binding Protein 3; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I