Partial growth hormone insensitivity and dysregulatory immune disease associated with de novo germline activating STAT3 mutations

GUTIERREZ M; SCAGLIA P; ANA KESELMAN; MARTUCCI LUCIA; KARABATAS L; DOMENÉ S; MARTÍN, AYELEN; PENNISI PATRICIA A; BLANCO M; SANGUINETI N; BEZRODNIK L; DI GIOVANNI D; CALDIROLA C; ESNAOLA AZCOITI M; GAILLARD MI; DENSON L; ZHANG K; HUSAMI A; YAYAH JONES N; HWA V; REVALE S; VAZQUEZ M; JASPER HG; KUMAR A; DOMENÉ HM

MOLECULAR AND CELLULAR ENDOCRINOLOGY.

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2018

0303-7207

Ger mi nal het erozy gous ac ti vat ing STAT3 mu ta tions rep re sent a novel mono genic de fect as so ci ated withmulti-or gan au toim mune dis ease and, in some cases, se vere growth re tar da tion. By us ing whole-ex ome se -quenc ing, we iden ti fied two novel STAT3 mu ta tions, p.E616del and p.C426R, in two un re lated pe di atric pa -tients with IGF-I de fi ciency and im mune dys reg u la tion. The func tional analy ses showed that both vari antswere gain-of-func tion (GOF), al though they were not con sti tu tively phos pho ry lated. They pre sented dif fer -ences in their de phos pho ry la tion ki net ics and tran scrip tional ac tiv i ties un der in ter leukin-6 stim u la tion. Bothvari ants in creased their tran scrip tional ac tiv i ties in re sponse to growth hor mone (GH) treat ment. Nonethe -less, STAT5b tran scrip tional ac tiv ity was di min ished in the pres ence of STAT3 GOF vari ants, sug gest ing adis rup tive role of STAT3 GOF vari ants in the GH sig nal ing path way. This study high lights the broad clin i calspec trum of pa tients pre sent ing ac ti vat ing STAT3 mu ta tions and ex plores the un der ly ing mol e c u lar path wayre spon si ble for this con di tion, sug gest ing that dif fer ent mu ta tions may drive in creased ac tiv ity by slightlydif fer ent mech a nisms