A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production

• DOI: 10.1210/en.2015-2058
• Publication Date: 2016-03-16T20:20:53Z
• Authors: Michal Marzec; Colin P. Hawkes; Davide Eletto; Sarah Boyle; Ron Rosenfeld; Vivian Hwa; Jan M. Wit; Hermine A. van Du...; Wilma Oostdijk; Monique Losekoot; Oluf Pedersen; Bu Beng Yeap; Leon Flicker; Nir Barzilai; Gil Atzmon; Adda Grimberg; Yair Argon
• Keywords: 0303 health sciences; 03 medical and health sciences; Gene Frequency; Somatomedins; DNA Mutational Analysis; Mutation; Humans; Membrane Proteins; HSP70 Heat-Shock Proteins; Polymorphism, Single Nucleotide; Alleles; 3. Good health

Abstract IGFs are critical for normal intrauterine and childhood growth sustaining health throughout life. We showed previously that the production of IGF-1 IGF-2 requires interaction with chaperone glucose-regulated protein 94 (GRP94) amount secreted is proportional to GRP94 activity. Therefore, we tested hypothesis functional polymorphisms human affect IGF thereby health. describe a hypomorphic variant GRP94, P300L, whose heterozygous carriers have 9% lower circulating concentration. P300L was found first in child primary deficiency later shown be noncommon single-nucleotide polymorphism frequencies 1%–4% various populations. When grp94−/− cell-based complementation assay, supported only approximately 58% secretion relative wild-type GRP94. Furthermore, recombinant impaired nucleotide binding These vitro data strongly support causal relationship between decreased concentration IGF-1, as observed P300L. Thus, mutations its activity represent novel genetic mechanism limits biosynthesis, quite distinct from known genes GH/IGF signaling network.