Evidence map›Paper›PMID 26554443›Full record

ArticleMolecular endocrinology (Baltimore, Md.)2016

Misfolding Ectodomain Mutations of the Lutropin Receptor Increase Efficacy of Hormone Stimulation.

E Charmandari, R Guan, M Zhang, L G Silveira, Q R Fan, G P Chrousos, A C Sertedaki, A C Latronico, D L Segaloff

Erratum issuedOpen access · bronzeAbstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular endocrinology (Baltimore, Md.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
0.3field-weighted citation impact, top 37% 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

4 citing papers in PubMed, 7 citations in OpenAlex.

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

Corrections and comments

5 · Who and what money

Authors and funding

9 authors at 5 institutions in 3 countries.

E CharmandariDivision of Endocrinology, Metabolism and Diabetes (E.C., G.P.C., A.C.S.), First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, and Division of Endocrinology and Metabolism (E.C., G.P.C., A.C.S.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Department of Pharmacology (Q.R.F.), Columbia University Medical Center, New York, New York 10032; Unidade de Endocrinologia do Desenvolvimento (L.G.S., A.C.L.), Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Department of Molecular Physiology and Biophysics (M.Z., R.G., D.L.S.), The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
R GuanDivision of Endocrinology, Metabolism and Diabetes (E.C., G.P.C., A.C.S.), First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, and Division of Endocrinology and Metabolism (E.C., G.P.C., A.C.S.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Department of Pharmacology (Q.R.F.), Columbia University Medical Center, New York, New York 10032; Unidade de Endocrinologia do Desenvolvimento (L.G.S., A.C.L.), Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Department of Molecular Physiology and Biophysics (M.Z., R.G., D.L.S.), The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
M ZhangDivision of Endocrinology, Metabolism and Diabetes (E.C., G.P.C., A.C.S.), First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, and Division of Endocrinology and Metabolism (E.C., G.P.C., A.C.S.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Department of Pharmacology (Q.R.F.), Columbia University Medical Center, New York, New York 10032; Unidade de Endocrinologia do Desenvolvimento (L.G.S., A.C.L.), Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Department of Molecular Physiology and Biophysics (M.Z., R.G., D.L.S.), The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
L G SilveiraDivision of Endocrinology, Metabolism and Diabetes (E.C., G.P.C., A.C.S.), First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, and Division of Endocrinology and Metabolism (E.C., G.P.C., A.C.S.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Department of Pharmacology (Q.R.F.), Columbia University Medical Center, New York, New York 10032; Unidade de Endocrinologia do Desenvolvimento (L.G.S., A.C.L.), Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Department of Molecular Physiology and Biophysics (M.Z., R.G., D.L.S.), The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
Q R FanDivision of Endocrinology, Metabolism and Diabetes (E.C., G.P.C., A.C.S.), First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, and Division of Endocrinology and Metabolism (E.C., G.P.C., A.C.S.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Department of Pharmacology (Q.R.F.), Columbia University Medical Center, New York, New York 10032; Unidade de Endocrinologia do Desenvolvimento (L.G.S., A.C.L.), Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Department of Molecular Physiology and Biophysics (M.Z., R.G., D.L.S.), The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
G P ChrousosDivision of Endocrinology, Metabolism and Diabetes (E.C., G.P.C., A.C.S.), First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, and Division of Endocrinology and Metabolism (E.C., G.P.C., A.C.S.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Department of Pharmacology (Q.R.F.), Columbia University Medical Center, New York, New York 10032; Unidade de Endocrinologia do Desenvolvimento (L.G.S., A.C.L.), Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Department of Molecular Physiology and Biophysics (M.Z., R.G., D.L.S.), The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
A C SertedakiDivision of Endocrinology, Metabolism and Diabetes (E.C., G.P.C., A.C.S.), First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, and Division of Endocrinology and Metabolism (E.C., G.P.C., A.C.S.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Department of Pharmacology (Q.R.F.), Columbia University Medical Center, New York, New York 10032; Unidade de Endocrinologia do Desenvolvimento (L.G.S., A.C.L.), Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Department of Molecular Physiology and Biophysics (M.Z., R.G., D.L.S.), The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
A C LatronicoDivision of Endocrinology, Metabolism and Diabetes (E.C., G.P.C., A.C.S.), First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, and Division of Endocrinology and Metabolism (E.C., G.P.C., A.C.S.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Department of Pharmacology (Q.R.F.), Columbia University Medical Center, New York, New York 10032; Unidade de Endocrinologia do Desenvolvimento (L.G.S., A.C.L.), Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Department of Molecular Physiology and Biophysics (M.Z., R.G., D.L.S.), The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
D L SegaloffDivision of Endocrinology, Metabolism and Diabetes (E.C., G.P.C., A.C.S.), First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, and Division of Endocrinology and Metabolism (E.C., G.P.C., A.C.S.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Department of Pharmacology (Q.R.F.), Columbia University Medical Center, New York, New York 10032; Unidade de Endocrinologia do Desenvolvimento (L.G.S., A.C.L.), Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Department of Molecular Physiology and Biophysics (M.Z., R.G., D.L.S.), The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
University of Iowa · USHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo · BRNational and Kapodistrian University of Athens · GRBiomedical Research Foundation of the Academy of Athens · GRColumbia University Irving Medical Center · US

Funding

Viral VectorP30CA086862 · NCI · UNIVERSITY OF IOWA · PI Douglas Robert Spitz · 2000 to 2026
$70.0M
Structure and Function of the LH, FSH, and TSH ReceptorsR37HD022196 · NICHD · UNIVERSITY OF IOWA · PI SEGALOFF, DEBORAH · 2003 to 2012
$4.4M
STRUCTURE AND REGULATION OF THE LH/CG RECEPTORR01HD022196 · NICHD · UNIVERSITY OF IOWA · PI SEGALOFF, DEBORAH · 1986 to 2002
$1.0M
NCI NIH HHS P30 CA086862NICHD NIH HHS R01 HD022196NICHD NIH HHS R37 HD022196
6 · The paper itself

Abstract

We demonstrate 2 novel mutations of the LHCGR, each homozygous, in a 46,XY patient with severe Leydig cell hypoplasia. One is a mutation in the signal peptide (p.Gln18_Leu19ins9; referred to here as SP) that results in an alteration of the coding sequence of the N terminus of the mature mutant receptor. The other mutation (p.G71R) is also within the ectodomain. Similar to many other inactivating mutations, the cell surface expression of recombinant human LHR(SP,G71R) is greatly reduced due to intracellular retention. However, we made the unusual discovery that the intrinsic efficacy for agonist-stimulated cAMP in the reduced numbers of receptors on the cell surface was greatly increased relative to the same low number of cell surface wild-type receptor. Remarkably, this appears to be a general attribute of misfolding mutations in the ectodomains, but not serpentine domains, of the gonadotropin receptors. These findings suggest that there must be a common, shared mechanism by which disparate mutations in the ectodomain that cause misfolding and therefore reduced cell surface expression concomitantly confer increased agonist efficacy to those receptor mutants on the cell surface. Our data further suggest that, due to their increased agonist efficacy, extremely small changes in cell surface expression of misfolded ectodomain mutants cause larger than expected alterations in the cellular response to agonist. Therefore, for inactivating LHCGR mutations causing ectodomain misfolding, the numbers of cell surface mutant receptors on fetal Leydig cells of 46,XY individuals exert a more exquisite effect on the relative severity of the clinical phenotypes than already appreciated.

Indexed as

MutationAdolescentFemaleHumansLeydig CellsMaleProtein FoldingPuberty, DelayedReceptors, LHSignal TransductionReceptors, LH

Identifiers

PMID26554443
PMCPMC4695626
OpenAlexW2178744117

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.