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

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Michal Marzec, Colin P Hawkes, Davide Eletto, Sarah Boyle, Ron G Rosenfeld, Vivian Hwa, Jan M Wit, Hermine A van Duyvenvoorde, Wilma Oostdijk, Monique Losekoot, Oluf Pedersen, Bu Beng Yeap, Leon Flicker, Nir Barzilai, Gil Atzmon, Adda Grimberg, Yair Argon

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

Original languageEnglish
JournalEndocrinology
Volume157
Issue number5
Pages (from-to)1914-1928
Number of pages15
ISSN0013-7227
DOIs
Publication statusPublished - May 2016

ID: 178744864