Characterization of Four Latin-American Families Confirms Previous Findings and Reveals Novel Features of Acid-labile Subunit (ALS) Deficiency

SCAGLIA, PAULA A.; KESELMAN, ANA C.; BRASLAVSKY, DÉBORA; MARTUCCI, LUCÍA C.; KARABATAS, LILIANA M.; DOMENÉ, SABINA; GUTIÉRREZ, MARIANA L.; BALLERINI, MARÍA G.; ROPELATO, MARÍA G.; SPINOLA-CASTRO, ANGELA; SIVIERO-MIACHON, ADRIANA A.; TARTUCI, JULIANA SAITO; RODRÍGUEZ AZRAK, SOL; REY, RODOLFO A.; JASPER, HÉCTOR G.; BERGADÁ, IGNACIO; DOMENÉ, HORACIO M.

CLINICAL ENDOCRINOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2017

0300-0664

Objective: ALS deficiency (ALS-D), caused by inactivating mutations in both IGFALS gene alleles, is characterized by marked reduction of IGF1 and IGFBP3 levels associated to mild growth retardation. The aim of this study was to expand the known phenotype and genetic characteristics of ALS-D by reporting data from four index cases and their families.Design: Auxological data, biochemical and genetic studies were performed in four children diagnosed with ALS-D and all available relatives. Methods: Serum levels of IGF1, IGFBP3, ALS, and in vitro ternary complex formation (ivTCF) were determined. After sequencing the IGFALS gene, pathogenicity of novel identified variants was evaluated by in vitro expression in transfected CHO cells . ALS protein was detected in patients´ sera and CHO cells conditioned media and lysates by Western immunoblot. Results: Four index cases and four relatives were diagnosed with ALS-D. The following variants were found: p.Glu35Glyfs*17, p.Glu35Lysfs*87, p.Leu213Phe, p.Asn276Ser, p.Leu409Phe, p.Ala475Val, and p.Ser490Trp. ALS-D patients presented low IGF1 and undetectable levels of IGFBP3 and ALS. Seven out of 8 patients did not form ivTCF. Conclusions: This study confirms previous findings in ALS-D, such as the low IGF1 and a more severe reduction in IGFBP3 levels, and a gene-dosage effect observed in heterozygous carriers. In addition, father to son transmission (father compound heterozygous and mother heterozygous carrier), preservation of male fertility, and marginal ALS expression with potential involvement in preserved responsiveness to rhGH treatment, are all novel aspects, not previously reported in this condition.