Evidence map›Paper›PMID 26982636›Full record

ArticleEndocrinology2016

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

Michal Marzec, Colin P Hawkes, Davide Eletto, Sarah Boyle, Ron Rosenfeld, Vivian Hwa, Jan M Wit, Hermine A van Duyvenvoorde, Wilma Oostdijk, Monique Losekoot and 7 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Endocrinology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
2.2field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 18 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Review
  5. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors at 8 institutions in 6 countries.

Michal MarzecDepartment 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.
Colin P HawkesDepartment 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.
Davide ElettoDepartment 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.
Sarah BoyleDepartment 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.
Ron RosenfeldDepartment 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.
Vivian HwaDepartment 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.
Jan M WitDepartment 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.
Hermine A van DuyvenvoordeDepartment 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.
Wilma OostdijkDepartment 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.
Monique LosekootDepartment 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.
Oluf PedersenDepartment 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.
Bu Beng YeapDepartment 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.
Leon FlickerDepartment 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.
Nir BarzilaiDepartment 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.
Gil AtzmonDepartment 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.
Adda GrimbergDepartment 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.
Yair ArgonDepartment 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.
Leiden University Medical Center · NLChildren's Hospital of Philadelphia · USUniversity of Pennsylvania · USAlbert Einstein College of Medicine · USOregon Health & Science University · USFiona Stanley Hospital · AUUniversity of Copenhagen · DKUniversity of Western Australia · AU

Funding

INSTITUTIONAL CLINICAL AND TRANSLATIONAL SCIENCE AWARDUL1RR024134 · NCRR · UNIVERSITY OF PENNSYLVANIA · PI FITZGERALD, GARRET A · 2006 to 2011
$70.4M
Translational Research CoreP30DK020541 · NIDDK · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI STREAMSON C CHUA · 2015 to 2026
$27.7M
Einstein's Nathan Shock Center of Excellence in Basic Biology of AgingP30AG038072 · NIA · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI BARZILAI, NIR J · 2010 to 2024
$10.8M
Regulation of IGF Levels in Development and in AgingR01AG018001 · NIA · UNIVERSITY OF CHICAGO · PI ARGON, YAIR · 2000 to 2016
$5.9M
Dysregulation of Glucose Homeostasis in AgingR37AG018381 · NIA · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI BARZILAI, NIR J · 2010 to 2019
$3.5M
Peripheral Nerve Function Decline in an Aged CohortR01AG028050 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI STROTMEYER, ELSA S. · 2007 to 2015
$3.5M
End of Life in the Very OldR01NR012459 · NINR · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI ALBERT, STEVEN M, LUNNEY, JUNE R · 2011 to 2015
$2.7M
Roles of STAT5b in IGF-I Production and Human GrowthR01HD078592 · NICHD · CINCINNATI CHILDRENS HOSP MED CTR · PI HWA, VIVIAN · 2014 to 2018
$1.7M
Regulation of insulin-like growth factors by the ER chaperone GRP94R01GM077480 · NIGMS · CHILDREN'S HOSP OF PHILADELPHIA · PI ARGON, YAIR · 2010 to 2013
$1.3M
Regulation of IGF-1 by Human GRP94K01AG040153 · NIA · CHILDREN'S HOSP OF PHILADELPHIA · PI MARZEC, MICHAL TOMASZ · 2011 to 2014
$454k
NCRR NIH HHS UL1 RR024134NIA NIH HHS K01 AG040153NIA NIH HHS P30 AG038072NIA NIH HHS R01 AG018001NIA NIH HHS R01 AG028050NIA NIH HHS R37 AG018381NICHD NIH HHS R01 HD078592NIDDK NIH HHS P30 DK020541NIGMS NIH HHS R01 GM077480NINR NIH HHS R01 NR012459
6 · The paper itself

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.

Indexed as

Polymorphism, Single NucleotideAllelesDNA Mutational AnalysisGene FrequencyHSP70 Heat-Shock ProteinsHumansMembrane ProteinsMutationSomatomedinsglucose-regulated proteinsHSP70 Heat-Shock ProteinsMembrane ProteinsSomatomedins

Identifiers

PMID26982636
PMCPMC4870884
OpenAlexW2301200748

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