Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism
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Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ~12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
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Many other genes have been identified in association with developmental defects in GnRH neurons.
“Many other genes have been identified in association with developmental defects in GnRH neurons.”
From Pubertal development and regulation (2016) · cites this paper as [53]
These genes affect GnRH neuronal migration and are associated with hypogonadotropic hypogonadism with anosmia, or Kallmann's syndrome.
“These genes affect GnRH neuronal migration and are associated with hypogonadotropic hypogonadism with anosmia, or Kallmann’s syndrome (table).35,46,47,53,88–90”
From Pubertal development and regulation (2016) · cites this paper as [53]
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Mortensen, O. V. (2013) · Cell Calcium · doi:10.1016/j.ceca.2012.12.004 · Cited by 23 · see citing works
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Tata, B. K., Chung, W. C. J., Brooks, L. R., Kavanaugh, S. I., & Tsai, P. (2012) · Biology of Reproduction · doi:10.1095/biolreprod.111.095992 · Cited by 15 · see citing works
Self-citation
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- Authors
- Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., Raivio, T., Crowley, W. F., Seminara, S. B., Quinton, R., Hughes, V. A., Kumanov, P., Young, J., Yialamas, M. A., Hall, J. E., Van Vliet, G., Chanoine, J.-P., Rubenstein, J., Mohammadi, M., Tsai, P.-S., Sidis, Y., Lage, K., & Pitteloud, N.
- Affiliations
- Harvard University (US)
- University of Colorado Boulder (US)
- New York University (US)
- University of California, San Francisco (US)
- Broad Institute (US)
- Poznan University of Medical Sciences (PL)
- University of Helsinki (FI)
- Newcastle University (GB)
- Medical University of Sofia (BG)
- Bicêtre Hospital (FR)
- Brigham and Women's Hospital (US)
- University of British Columbia (CA)
- Corresponding author
- Pitteloud, Nelly
- ORCID
- Dwyer, Andrew A.
- Sykiotis, Gerasimos P.
- Chung, Wilson
- Feng, Bihua
- Beenken, Andrew
- Pers, Tune H.
- Niedziela, Marek
- Raivio, Taneli
- Crowley, William F.
- Seminara, Stephanie B.
- Quinton, Richard
- Kumanov, Philip
- Young, Jacques
- Hall, Janet E.
- Chanoine, Jean-Pierre
- Rubenstein, John
- Mohammadi, Moosa
- Tsai, Pei-San
- Lage, Kasper
- Pitteloud, Nelly
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 92
- Issue
- 5
- Pages
- 725-743
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3644636
- OpenAlex
- W2025161059
- Cited by
- 267
- References
- 89
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 12 · 2023: 16 · 2022: 19 · 2021: 28 · 2020: 27 · 2019: 25 · 2018: 20 · 2017: 24 · 2016: 15 · 2015: 23 · 2014: 26 · 2013: 7
- FWCI
- 28.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- IRIS (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion, other-oa)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Institutes of Health (2R01DE013686-11, R01HD056264, R01HD15788, U54HD028138)
- National Institute of Neurological Disorders and Stroke (R01 NS34661)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- European Cooperation in Science and Technology (BM1105)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- congenital hypogonadotropic hypogonadism, Kallmann syndrome, FGF17, DUSP6, SPRY4, FLRT3, FGFR1 signaling, protein-protein interaction network, anosmia, hearing loss, oligogenic inheritance, candidate gene identification
- MeSH terms
- Algorithms, Animals, Base Sequence, Female, Fibroblast Growth Factors, Humans, Hypogonadism, Immunohistochemistry, Male, Membrane Glycoproteins, Membrane Proteins, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Sequence Homology, Sequence Analysis, DNA, Receptors, Interleukin, Computational Biology, Genetic Predisposition to Disease, Surface Plasmon Resonance, Inheritance Patterns, Intracellular Signaling Peptides and Proteins, Mice, Dual Specificity Phosphatase 6, Genetic Association Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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