Evidence map›Paper›PMID 26911863›Full record

ArticleHuman reproduction (Oxford, England)2016

A novel follicle-stimulating hormone receptor mutation causing primary ovarian failure: a fertility application of whole exome sequencing.

Matthew S Bramble, Ellen H Goldstein, Allen Lipson, Tuck Ngun, Ascia Eskin, Jason E Gosschalk, Lara Roach, Neerja Vashist, Hayk Barseghyan, Eric Lee and 5 more

Open access · bronzeAbstract readCase ReportsValidation Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Human reproduction (Oxford, England), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
39citing papers in PubMed, 1 pooled it
7.0field-weighted citation impact, top 3% 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

39 citing papers in PubMed, 1 synthesis or guideline pooled it, 93 citations in OpenAlex.

  1. Pooled it
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  18. 46,XX DSD: Developmental, Clinical and Genetic Aspects.Diagnostics (Basel, Switzerland) · 2021
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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

15 authors at 4 institutions in 3 countries.

Matthew S BrambleDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Ellen H GoldsteinDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California Los Angeles, 10833 Le Conte Avenue, Room 24-130 CHS, Los Angeles, CA 90095, USA.
Allen LipsonDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Tuck NgunDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Ascia EskinDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Jason E GosschalkDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Lara RoachDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Neerja VashistDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Hayk BarseghyanDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Eric LeeDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Valerie A ArboledaDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Daniel VaimanDepartment of Development, Reproduction, and Cancer, Institut Cochin, U1016 Inserm, University Sorbonne Paris, CNRS UMR8104, Paris, France.
Zafer YukselDepartment of Medical Genetics, Women and Children Hospital, Halkkent Mh. Fatih Sultan Mehmet Boulevard No. 23, Mersin 33240, Turkey.
Marc FellousDepartment of Development, Reproduction, and Cancer, Institut Cochin, U1016 Inserm, University Sorbonne Paris, CNRS UMR8104, Paris, France.
Eric VilainDepartment of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, 695 Charles E Young Drive South, Los Angeles, CA 90095, USA evilain@ucla.edu.
University of California, Los Angeles · USCentre National de la Recherche Scientifique · FRFatih Sultan Mehmet Eğitim Ve Araştırma Hastanesi · TRInserm · FR

Funding

Women's CancersP30CA016042 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Samuel Wheeler French · 1985 to 2026
$134.5M
Virology CoreP30AI028697 · NIAID · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI KITCHEN, SCOTT G · 1991 to 2018
$39.9M
Disorders of Sex Development: Platform for Basic and Translational ResearchR01HD068138 · NICHD · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI SANDBERG, DAVID ERIC, VILAIN, ERIC J. · 2011 to 2015
$4.0M
Neuroendocrinology, Sex Differences, and ReproductionT32HD007228 · NICHD · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARNOLD, ARTHUR P · 1985 to 2015
$3.9M
NCI NIH HHS P30 CA016042NIAID NIH HHS P30 AI028697NICHD NIH HHS 1R01HD068138NICHD NIH HHS 5T32HD007228NICHD NIH HHS R01 HD068138NICHD NIH HHS T32 HD007228
6 · The paper itself

Abstract

study questionCan whole exome sequencing (WES) and in vitro validation studies be used to find the causative genetic etiology in a patient with primary ovarian failure and infertility? SUMMARY ANSWER: A novel follicle-stimulating hormone receptor (FSHR) mutation was found by WES and shown, via in vitro flow cytometry studies, to affect membrane trafficking. WHAT IS KNOWN ALREADY: WES may diagnose up to 25-35% of patients with suspected disorders of sex development (DSD). FSHR mutations are an extremely rare cause of 46, XX gonadal dysgenesis with primary amenorrhea due to hypergonadotropic ovarian failure. STUDY DESIGN, SIZE, DURATION: A WES study was followed by flow cytometry studies of mutant protein function. PARTICIPANTS/MATERIALS, SETTING,

methodsThe study subjects were two Turkish sisters with hypergonadotropic primary amenorrhea, their parents and two unaffected sisters. The affected siblings and both parents were sequenced (trio-WES). Transient transfection of HEK 293T cells was performed with a vector containing wild-type FSHR as well as the novel FSHR variant that was discovered by WES. Cellular localization of FSHR protein as well as FSH-stimulated cyclic AMP (cAMP) production was evaluated using flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: Both affected sisters were homozygous for a previously unreported missense mutation (c.1222G>T, p.Asp408Tyr) in the second transmembrane domain of FSHR. Modeling predicted disrupted secondary structure. Flow cytometry demonstrated an average of 48% reduction in cell-surface signal detection (P < 0.01). The mean fluorescent signal for cAMP (second messenger of FSHR), stimulated by FSH, was reduced by 50% in the mutant-transfected cells (P < 0.01). LIMITATIONS, REASONS FOR CAUTION: This is an in vitro validation. All novel purported genetic variants can be clinically reported only as 'variants of uncertain significance' until more patients with a similar phenotype are discovered with the same variant. WIDER IMPLICATIONS OF THE

findingsWe report the first WES-discovered FSHR mutation, validated by quantitative flow cytometry. WES is a valuable tool for diagnosis of rare genetic diseases, and flow cytometry allows for quantitative characterization of purported variants. WES-assisted diagnosis allows for treatments aimed at the underlying molecular etiology of disease. Future studies should focus on pharmacological and assisted reproductive treatments aimed at the disrupted FSHR, so that patients with FSH resistance can be treated by personalized medicine. STUDY FUNDING/COMPETING INTERESTS: E.V. is partially funded by the DSD Translational Research Network (NICHD 1R01HD068138). M.S.B. is funded by the Neuroendocrinology, Sex Differences and Reproduction training grant (NICHD 5T32HD007228). The authors have no competing interests to disclose.

Indexed as

Models, MolecularMutation, MissenseAdultConsanguinityExomeFemaleGenome-Wide Association StudyHEK293 CellsHomozygoteHumansPrimary Ovarian InsufficiencyProtein Structure, SecondaryProtein TransportReceptors, FSHRecombinant ProteinsSequence Analysis, DNAReceptors, FSHRecombinant Proteinsfollicle-stimulating hormone receptorpremature ovarian failureprimary amenorrhearesistant ovary syndromewhole exome sequencing

Identifiers

PMID26911863
PMCPMC5007606
OpenAlexW2287743229

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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.