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 inhumancarriers 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 language | English (US) |
|---|---|
| Pages (from-to) | 1914-1928 |
| Number of pages | 15 |
| Journal | Endocrinology |
| Volume | 157 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2016 |
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ASJC Scopus subject areas
- Endocrinology
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A human variant of glucose-regulated protein 94 that inefficiently supports IGF production. / Marzec, Michal; Hawkes, Colin P.; Eletto, Davide; Boyle, Sarah; Rosenfeld, Ron; Hwa, Vivian; Wit, Jan M.; Van Duyvenvoorde, Hermine A.; Oostdijk, Wilma; Losekoot, Monique; Pedersen, Oluf; Yeap, Bu Beng; Flicker, Leon; Barzilai, Nir; Atzmon, Gil; Grimberg, Adda; Argon, Yair.
In: Endocrinology, Vol. 157, No. 5, 01.05.2016, p. 1914-1928.Research output: Contribution to journal › Article
}
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
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 - 2016/5/1
Y1 - 2016/5/1
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 inhumancarriers 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 inhumancarriers 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.
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U2 - 10.1210/en.2015-2058
DO - 10.1210/en.2015-2058
M3 - Article
VL - 157
SP - 1914
EP - 1928
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 5
ER -