Digenic Variants in the FGF21 Signaling Pathway Associated with Severe Insulin Resistance and Pseudoacromegaly.

Journal of the Endocrine Society
Stephen I StoneDavid M Ornitz

Abstract

Insulin-mediated pseudoacromegaly (IMPA) is a rare disease of unknown etiology. Here we report a 12-year-old female with acanthosis nigricans, hirsutism, and acromegalic features characteristic of IMPA. The subject was noted to have normal growth hormone secretion, with extremely elevated insulin levels. Studies were undertaken to determine a potential genetic etiology for IMPA. The proband and her family members underwent whole exome sequencing. Functional studies were undertaken to validate the pathogenicity of candidate variant alleles. Whole exome sequencing identified monoallelic, predicted deleterious variants in genes that mediate fibroblast growth factor 21 (FGF21) signaling, FGFR1 and KLB, which were inherited in trans from each parent. FGF21 has multiple metabolic functions but no known role in human insulin resistance syndromes. Analysis of the function of the FGFR1 and KLB variants in vitro showed greatly attenuated ERK phosphorylation in response to FGF21, but not FGF2, suggesting that these variants act synergistically to inhibit endocrine FGF21 signaling but not canonical FGF2 signaling. Therefore, digenic variants in FGFR1 and KLB provide a potential explanation for the subject's severe insulin resistance and ma...Continue Reading

References

Mar 1, 1979·The Journal of Clinical Endocrinology and Metabolism·A J D'ErcoleA Plet
Mar 9, 1989·The New England Journal of Medicine·J E FradkinJ Roth
Jun 1, 1967·American Journal of Clinical Pathology·S Burrows
Jan 1, 1997·QJM : Monthly Journal of the Association of Physicians·S N JacksonR C Trembath
May 13, 1999·Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association·C KauschS Matthaei
May 5, 2001·Genome Research·P C Ng, S Henikoff
May 8, 2002·Nature Reviews. Molecular Cell Biology·Nia J BryantDavid E James
Jul 16, 2002·Nature Genetics·David B SavageAlan J Schafer
Oct 4, 2002·Journal of Medical Genetics·L Van MaldergemS O'Rahilly
Mar 21, 2003·The New England Journal of Medicine·I Sadaf FarooqiStephen O'Rahilly
Mar 26, 2003·Archives of Disease in Childhood·S SrinivasanC F Verge
Jun 6, 2003·The Journal of Clinical Endocrinology and Metabolism·Francesco OrioRoberto Vettor
Mar 1, 1956·American Journal of Clinical Pathology·S M RABSON, E N MENDENHALL
May 20, 2005·The Journal of Clinical Investigation·Alexei KharitonenkovArmen B Shanafelt
Jun 21, 2005·Genome Research·Gregory M CooperArend Sidow
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Mar 3, 2006·The Journal of Clinical Investigation·Robert K SempleStephen O'Rahilly
Jun 13, 2006·Molecular and Cellular Endocrinology·Nelly PitteloudWilliam F Crowley
Aug 22, 2006·Trends in Biochemical Sciences·Ramanujan S Hegde, Harris D Bernstein
Jun 7, 2007·Cell Metabolism·Marc L Reitman
Jul 1, 2008·Cell Metabolism·Takeshi InagakiSteven A Kliewer
Jul 16, 2009·Genome Research·Sung Chun, Justin C Fay
Aug 27, 2009·American Journal of Physiology. Endocrinology and Metabolism·Jing XuMurielle M Véniant
Dec 30, 2009·The Journal of Cell Biology·Chiara FrancavillaUgo Cavallaro
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Jul 6, 2010·Nucleic Acids Research·Kai WangHakon Hakonarson
Aug 5, 2010·Diabetes·Ffolliott M FisherEleftheria Maratos-Flier
Dec 15, 2010·PLoS Computational Biology·Eugene V DavydovSerafim Batzoglou
Jan 5, 2011·Trends in Endocrinology and Metabolism : TEM·Alexei Kharitonenkov, Philip Larsen
Jul 2, 2011·Biological & Pharmaceutical Bulletin·Katsutaka Oishi, Tatsunosuke Tomita
Jul 5, 2011·Hormones : International Journal of Endocrinology and Metabolism·Amir H SamKarim Meeran
Jun 8, 2012·PloS One·Andrew C AdamsAlexei Kharitonenkov
Sep 10, 2013·Cell Metabolism·Gregory GaichDavid E Moller
Apr 1, 2014·Nature Methods·Jana Marie SchwarzDominik Seelow
Apr 9, 2014·Trends in Endocrinology and Metabolism : TEM·Ruth E Gimeno, David E Moller

❮ Previous
Next ❯

Methods Mentioned

BETA
exome sequencing
Enzyme-Linked Immunosorbent
enzyme-linked immunosorbent assay
transfection
AlphaLISA
ELISA

Software Mentioned

MegAlign Pro
gnomAD
Prism

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Hormone Molecular Biology and Clinical Investigation
Albert Pérez-MartíJoana Relat
PloS One
Andrew C AdamsAlexei Kharitonenkov
Nihon rinsho. Japanese journal of clinical medicine
Morichika Konishi, Nobuyuki Itoh
© 2021 Meta ULC. All rights reserved