Characterization of four Latin American families confirms previous findings and reveals novel features of acid-labile subunit deficiency

Characterization of four Latin American families confirms previous findings and reveals novel features of acid-labile subunit deficiency

Author Scaglia, Paula A. Google Scholar
Keselman, Ana C. Google Scholar
Braslavsky, Debora Google Scholar
Martucci, Lucia C. Google Scholar
Karabatas, Liliana M. Google Scholar
Domene, Sabina Google Scholar
Gutierrez, Mariana L. Google Scholar
Ballerini, Maria G. Google Scholar
Ropelato, Maria G. Google Scholar
Spinola-Castro, Angela Autor UNIFESP Google Scholar
Siviero-Miachon, Adriana A. Autor UNIFESP Google Scholar
Tartuci, Juliana Saito Autor UNIFESP Google Scholar
Rodriguez Azrak, Maria Sol Google Scholar
Rey, Rodolfo A. Google Scholar
Jasper, Hector G. Google Scholar
Bergada, Ignacio Google Scholar
Domene, Horacio M. Google Scholar
Abstract Objective: Acid-labile subunit deficiency (ACLSD), caused by inactivating mutations in both IGFALS gene alleles, is characterized by marked reduction in IGF-I and IGFBP-3 levels associated with mild growth retardation. The aim of this study was to expand the known phenotype and genetic characteristics of ACLSD by reporting data from four index cases and their families. Design: Auxological data, biochemical and genetic studies were performed in four children diagnosed with ACLSD and all available relatives. Methods: Serum levels of IGF-I, IGFBP-3, acid-labile subunit (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 Chinese hamster ovarian (CHO) cells. ALS protein was detected in patients' sera and CHO cells conditioned media and lysates by Western immunoblot (WIB). Results: Four index cases and four relatives were diagnosed with ACLSD. The following variants were found: p.Glu35Glyfs*17, p. Glu35Lysfs* 87, p. Leu213Phe, p. Asn276Ser, p. Leu409Phe, p. Ala475Val and p. Ser490Trp. ACLSD patients presented low IGF-I and low or undetectable levels of IGFBP-3 and ALS. Seven out of 8 patients did not form ivTCF. Conclusions: This study confirms previous findings in ACLSD, such as the low IGF-I and a more severe reduction in IGFBP-3 levels, and a gene dosage effect observed in heterozygous carriers (HC). In addition, father-to-son transmission (father compound heterozygous and mother HC), 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.
Keywords acid-labile subunit deficiency
IGFALS
IGF-I
short stature
Language English
Sponsor Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCYT) (Argentina)
FONCYT
SANDOZ International GmbH, Business Unit Biopharmaceuticals
Grant number ANPCYT: PICT 2010 No 1916
FONCYT: PICT 2013 No 142
Date 2017
Published in Clinical Endocrinology. Hoboken, v. 87, n. 3, p. 300-311, 2017.
ISSN 0300-0664 (Sherpa/Romeo, impact factor)
Publisher Wiley
Extent 300-311
Origin http://dx.doi.org/10.1111/cen.13361
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000409271100012
URI http://repositorio.unifesp.br/handle/11600/51323

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