COMBINED STAT5B AND IGFALS HETEROZYGOUS GENETIC VARIANTS IN A PATIENT WITH PARTIAL GROWTH HORMONE INSENSITIVITY

RAMIREZ, LAURA; KESELMAN, ANA CLAUDIA; LANDI, ESTEFANÍA; PENNISI, PATRICIA A; REY, RODOLFO A; GUTIÉRREZ, MARIANA L.; SANGUINETI, NORA; BALLERINI, MARÍA GABRIELA; CASTRO, JULIA F; JASPER, HÉCTOR GUILLERMO; DOMENÉ, HORACIO MARIO; SCAGLIA, PAULA ALEJANDRA; KARABATAS, LILIANA; SABINA DOMENE; VÁZQUEZ, MARTÍN; BERGADÁ, IGNACIO

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2019

Sociedad Argentina de Investigacion Clinica

Abstract/Resumen: Monogenic causes of growth hormoneinsensitivity (GHI) include defects in genes encoding the GHreceptor itself (GHR), the signal transducer and activator oftranscription (STAT5B), the insulin like-growth factor type I(IGF1) and the acid-labile subunit (IGFALS). Affected childrencould be severely growth retarded, although mutations inheterozygous state in some of these genes were associated to amilder clinical phenotype. We aimed to characterize themolecular defect in a patient with short stature and partial GHI.Patient and methods: The boy was born at term adequate forgestational age from non-consanguineous normal-statureparents. At 2.2 years, he presented proportionate short stature(height -2.77 SDS), wide forehead and normal mentaldevelopment. Whole-exome analysis and functionalcharacterization (dual luciferase reporter assays,immunofluorescence and, western immunoblot) were performed.Biochemical and endocrinological evaluation revealed partial GHinsensitivity with normal stimulated GH peak (7.8 ng/ml),undetectable IGF1, and low IGFBP3 levels. Two heterozygousvariants in the GH-signaling pathway were found: a novelheterozygous STAT5B variant (p.K632N) and a hypomorphicIGFALS variant (p.R548W). In vitro studies demonstrated thatmutation p.K632N impairs STAT5b phosphorylation, nucleartranslocation and transcriptional activity. Conclusions: In shortchildren with GHI, genetic testing is recommended. We presentcompelling evidence to support p.K632N as a novel inactivatingSTAT5b variant. The combination of heterozygous IGFALS andSTAT5B variants contributes to the patient?s partial GHIphenotype.