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A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production
Michal Marzec1, Colin P Hawkes1, Davide Eletto1
1Department of Pathology and Laboratory Medicine (M.M., D.E., S.B., Y.A.), The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia,; Division of Endocrinology and Diabetes (C.P.H., A.G.), The Children's Hospital of Philadelphia, and Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Pennsylvania 19104; National Children's Research Centre (C.P.H.), Dublin 12, Ireland; STAT5, LLC (R.R.), Los Altos, California 94022; Department of Pediatrics (R.R., V.H.), Oregon Health and Science University, Portland, Oregon 97239; Departments of Pediatrics (J.-M.W., H.A.v.D., W.O.), Endocrinology and Metabolic Diseases (H.A.v.D.), and Clinical Genetics (H.A.v.D., M.L.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Faculty of Health and Medical Sciences (O.P.), University of Copenhagen, DK-2400 Copenhagen, Denmark; School of Medicine and Pharmacology (B.B.Y.), Western Australia Centre for Health and Ageing (L.F.), Centre for Medical Research (L.F.), and School of Medicine and Pharmacology (L.F.), University of Western Australia, Perth, Western Australia 6872, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fiona Stanley Hospital, Perth, Western Australia 6150, Australia; Department of Human Biology (G.A.), Faculty of Natural Sciences, University of Haifa, Haifa 3498838, Israel; and Departments of Medicine and Genetics (N.B., G.A.), Albert Einstein College of Medicine, Bronx, New York 10461.
Abstract:
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.
