Characterization of four Latin American families confirms previous findings and reveals novel features of acid-labile subunit 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, MARÍA SOL; REY, RODOLFO A.; JASPER, HÉCTOR G.; BERGADÁ, IGNACIO; DOMENÉ, HORACIO M.

CLINICAL ENDOCRINOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2017 vol. 87 p. 300 - 311

0300-0664

Objective: Acid-labilesubunit deficiency (ACLSD), caused by inactivating mutations inboth IGFALS gene alleles, is characterized by marked reduction in IGF-Iand IGFBP-3levels associated with mild growth retardation. The aim of this study was to expandthe known phenotype and genetic characteristics of ACLSD by reporting data fromfour index cases and their families.Design: Auxological data, biochemical and genetic studies were performed in four childrendiagnosed with ACLSD and all available relatives.Methods: Serum levels of IGF-I,IGFBP-3,acid-labilesubunit (ALS), and in vitro ternarycomplex formation (ivTCF) were determined. After sequencing the IGFALS gene, pathogenicityof novel identified variants was evaluated by in vitro expression in transfectedChinese 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 followingvariants were found: p.Glu35Glyfs*17, p.Glu35Lysfs*87, p.Leu213Phe,p.Asn276Ser, p.Leu409Phe, p.Ala475Val and p.Ser490Trp. ACLSD patients presentedlow IGF-Iand low or undetectable levels of IGFBP-3and ALS. Seven out of 8 patientsdid not form ivTCF.Conclusions: This study confirms previous findings in ACLSD, such as the low IGF-Iand a more severe reduction in IGFBP-3levels, and a gene dosage effect observed inheterozygous carriers (HC). In addition, father-to-sontransmission (father compoundheterozygous and mother HC), preservation of male fertility, and marginal ALS expressionwith potential involvement in preserved responsiveness to rhGH treatment, areall novel aspects, not previously reported in this condition.