Marzec, M., Hawkes, C. P., Eletto, D., Boyle, S., Rosenfeld, R. G., Hwa, V., Wit, J. M., van Duyvenvoorde, H. A., Oostdijk, W., Losekoot, M., Pedersen, O., Yeap, B. B., Flicker, L., Barzilai, N., Atzmon, G., Grimberg, A., & Argon, Y. (2016). A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production. Endocrinology, 157(5), 1914-1928. https://doi.org/10.1210/en.2015-2058
A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production. /
Marzec, Michal; Hawkes, Colin P; Eletto, Davide et al.
I:
Endocrinology, Bind 157, Nr. 5, 05.2016, s. 1914-1928.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
Marzec, M, Hawkes, CP, Eletto, D, Boyle, S, Rosenfeld, RG, Hwa, V, Wit, JM, van Duyvenvoorde, HA, Oostdijk, W, Losekoot, M, Pedersen, O, Yeap, BB, Flicker, L, Barzilai, N, Atzmon, G, Grimberg, A & Argon, Y 2016, 'A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production', Endocrinology, bind 157, nr. 5, s. 1914-1928. https://doi.org/10.1210/en.2015-2058
Marzec M, Hawkes CP, Eletto D, Boyle S, Rosenfeld RG, Hwa V et al. A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production. Endocrinology. 2016 maj;157(5):1914-1928. doi: 10.1210/en.2015-2058
Marzec, Michal ; Hawkes, Colin P ; Eletto, Davide et al. / A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production. I: Endocrinology. 2016 ; Bind 157, Nr. 5. s. 1914-1928.
@article{23cbb069b79147cd81f7f2648c21e154,
title = "A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production",
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.",
author = "Michal Marzec and Hawkes, {Colin P} and Davide Eletto and Sarah Boyle and Rosenfeld, {Ron G} and Vivian Hwa and Wit, {Jan M} and {van Duyvenvoorde}, {Hermine A} and Wilma Oostdijk and Monique Losekoot and Oluf Pedersen and Yeap, {Bu Beng} and Leon Flicker and Nir Barzilai and Gil Atzmon and Adda Grimberg and Yair Argon",
year = "2016",
month = may,
doi = "10.1210/en.2015-2058",
language = "English",
volume = "157",
pages = "1914--1928",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "Oxford University Press",
number = "5",
}
TY - JOUR
T1 - A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production
AU - Marzec, Michal
AU - Hawkes, Colin P
AU - Eletto, Davide
AU - Boyle, Sarah
AU - Rosenfeld, Ron G
AU - Hwa, Vivian
AU - Wit, Jan M
AU - van Duyvenvoorde, Hermine A
AU - Oostdijk, Wilma
AU - Losekoot, Monique
AU - Pedersen, Oluf
AU - Yeap, Bu Beng
AU - Flicker, Leon
AU - Barzilai, Nir
AU - Atzmon, Gil
AU - Grimberg, Adda
AU - Argon, Yair
PY - 2016/5
Y1 - 2016/5
N2 - 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.
AB - 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.
U2 - 10.1210/en.2015-2058
DO - 10.1210/en.2015-2058
M3 - Journal article
C2 - 26982636
SN - 0013-7227
VL - 157
SP - 1914
EP - 1928
JO - Endocrinology
JF - Endocrinology
IS - 5
ER -
