Open AccessShort stature and combined immunodeficiency associated with mutations in RGS10
Author(s) -
Iván K. Chinn,
Zhihui Xie,
Eunice C. Chan,
Bianca M. Nagata,
Alexey Koval,
Weisheng Chen,
Fan Zhang,
Sundar Ganesan,
Dia. Hong,
Motoshi Suzuki,
Glenn Nardone,
Ian N. Moore,
Vladimir L. Katanaev,
Andrea Balázs,
Chengyu Liu,
James R. Lupski,
Jordan S. Orange,
Kirk M. Druey
Publication year - 2021
Publication title -
science signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.659
H-Index - 154
eISSN - 1937-9145
pISSN - 1945-0877
DOI - 10.1126/scisignal.abc1940
Subject(s) - biology , short stature , gtpase activating protein , g protein , chemokine receptor , receptor , heterotrimeric g protein , gene , phenotype , genetics , microbiology and biotechnology , endocrinology , chemokine
We report the clinical and molecular phenotype of three siblings from one family, who presented with short stature and immunodeficiency and carried uncharacterized variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). This gene encodes regulator of G protein signaling 10 (RGS10), a member of a large family of GTPase-activating proteins (GAPs) that targets heterotrimeric G proteins to constrain the activity of G protein-coupled receptors, including receptors for chemoattractants. The affected individuals exhibited systemic abnormalities directly related to the RGS10 mutations, including recurrent infections, hypergammaglobulinemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Although the GAP activity of each RGS10 variant was intact, each protein exhibited aberrant patterns of PKA-mediated phosphorylation and increased cytosolic and cell membrane localization and activity compared to the wild-type protein. We propose that the RGS10 p.E163del and p.A171S mutations lead to mislocalization of the RGS10 protein in the cytosol, thereby resulting in attenuated chemokine signaling. This study suggests that RGS10 is critical for both immune competence and normal hormonal metabolism in humans and that rare RGS10 variants may contribute to distinct systemic genetic disorders.