title: Assessment of pathogenicity of natural IGFALS gene variants by in silico bioinformatics tools and in vitro functional studies.
abstract: Acid-labile subunit (ALS) is essential for stabilization of IGF-I and IGFBP-3 in ternary complexes within the vascular system. ALS deficient (ALS-D) patients and a subset of children with idiopathic short stature (ISS), presenting IGFALS gene variants, show variable degree of growth retardation associated to IGF-I and IGFBP-3 deficiencies. The aim of this study was to evaluate the potential pathogenicity of eleven IGFALS variants identified in ALS-D and ISS children using in silico and in vitro approaches. We were able to classify seven of these variants as pathogenic since they present impaired synthesis (p.Glu35Lysfs*87, p.Glu35Glyfs*17, p.Asn276Ser, p.Leu409Phe, p.Ser490Trp and p.Cys540Arg), or partial impairment of synthesis and lack of secretion (p.Leu213Phe). We also observed significant reduction of secreted protein for variants p.Ala330Asp, Ala475Val and p.Arg548Trp, while still retaining their ability to form ternary complexes. These findings provide an approach to test the pathogenicity of IGFALS gene variants.
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330 - C1425EFD, Buenos Aires, Argentina.
authors.forename: Lucía C
authors.initials: LC
authors.lastname: Martucci
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330 - C1425EFD, Buenos Aires, Argentina.
authors.forename: Mariana L
authors.initials: ML
authors.lastname: Gutiérrez
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330 - C1425EFD, Buenos Aires, Argentina.
authors.forename: Liliana M
authors.initials: LM
authors.lastname: Karabatas
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330 - C1425EFD, Buenos Aires, Argentina.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Scaglia
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330 - C1425EFD, Buenos Aires, Argentina.
authors.forename: Rodolfo A
authors.initials: RA
authors.lastname: Rey
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330 - C1425EFD, Buenos Aires, Argentina.
authors.forename: Horacio M
authors.initials: HM
authors.lastname: Domené
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330 - C1425EFD, Buenos Aires, Argentina.
authors.forename: Héctor G
authors.initials: HG
authors.lastname: Jasper
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330 - C1425EFD, Buenos Aires, Argentina.
authors.forename: Sabina
authors.initials: S
authors.lastname: Domené
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D002648:Child; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D050505:Mutant Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016415:Sequence Alignment; D012984:Software; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D050505:Mutant Proteins; C075944:insulin-like growth factor binding protein, acid labile subunit
keywords: Acid-labile subunit; IGF-I deficiency; IGFALS gene variants; Idiopathic short stature