Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes
Open accessAbstract
Background Kallmann's syndrome (KS) is a clinically and genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. Mutations in KAL1 causing the X-linked form of KS have been identified in 10% of all KS patients and consistently result in a severe reproductive phenotype. KAL1 gene encodes for anosmin-1, a key protein involved in olfactory and GnRH neuronal migration through a putative interaction with FGFR1. Heterozygous mutations in the FGFR1 gene accompanied by a high frequency of cleft palate and other facial dysmorphisms were recently identified in 8% of a large KS cohort, yet the reproductive phenotype of KS patients harboring FGFR1 mutations has not been described.Results One hundred and fifty probands with KS (130 males and 20 females) were studied to determine the frequency and distribution of FGFR1 mutations and their detailed reproductive phenotypes. Fifteen heterozygous mutations in unrelated probands were identified. Twelve missense mutations (p.R78C, p.V102I, p.D224H, p.G237D, p.R254Q, p.V273M, p.E274G, p.Y339C, p.S346C, p.I538V, p.G703S and p.G703R) were distributed among the first, second and third immunoglobulin-like domains (D1-D3), as well as the tyrosine kinase domain (TKD). The mutations Y339C and S346C are located in exon 8B and code for the isoform FGFR1c. Additionally, two nonsense mutations (p.T585X and p.R622X) were documented in the TKD of the protein. A wide spectrum of reproductive function was observed among KS probands including: (1) a severe phenotype demonstrated by microphallus, cryptorchidism, no pubertal development, undetectable serum gonadotropins and low serum testosterone (T) and inhibin B; (2) partial pubertal development; (3) the fertile eunuch variant of IHH with normal testicular size and active spermatogenesis with a reversal of HH after T therapy. In addition, we found an even wider spectrum of reproductive function within pedigrees carrying an FGFR1 mutation ranging from IHH to delayed puberty to normal reproductive function (anosmia only or asymptomatic carriers). These observations strongly suggest a role for other genes that modify the phenotype of FGFR1 mutations.Conclusion KS patients and family members carrying an FGFR1 mutation present a broad spectrum of pubertal development in contrast to the almost uniform severe clinical phenotype described in KS subjects with a KAL1 mutation. Additionally, this report implicates the isoform FGFR1c in the pathogenesis of KS.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The dimorphic distribution with incomplete penetrance suggests that changes may occur in more than one gene and/or that sex-associated modifying factors may contribute to the phenotype.
“This pattern suggests that changes may occur in more than one gene and/or that sex-associated modifying factors may contribute to the phenotype.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [5]
In some cases, the severity of hypogonadism and the presence of associated phenotypes in a pedigree present in a dimorphic distribution with incomplete penetrance.
“In some cases, the severity of hypogonadism and the presence of associated phenotypes in a pedigree present in a dimorphic distribution with incomplete penetrance.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [5]
The Asp224His substitution in the second immunoglobulin-like domain is believed to prevent ligand-induced or heparin-sulfate-induced FGFR-1 dimerization and signaling.
“An Asp224His substitution, also in the second immunoglobulin-like domain, is believed to prevent ligand-induced or heparin-sulfate-induced FGFR-1 dimerization and signaling.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [5]
Amino acid substitutions in the third immunoglobulin-like domain of FGFR-1, such as Val273Met, Glu274Gly, Tyr339Cys, and Ser346Cys, are predicted to disrupt the Cys277-Cys341 disulfide bond.
“Amino acid substitutions that map to the third immunoglobulin-like domain of FGFR-1, such as Val273Met, Glu274Gly, Tyr339Cys, and Ser346Cys, are predicted to disrupt a characteristic Cys277–Cys341 disulfide bond in this domain.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [5]
Mutations in the tyrosine kinase domain of FGFR-1 are predicted to decrease or inhibit kinase activity by disrupting receptor conformation and/or altering the normal pattern of phosphorylation.
“Mutations in the tyrosine kinase domain of FGFR-1 are predicted to decrease or inhibit kinase activity by disrupting receptor conformation (Ile538Val, Asn724Lys, and Gly703Arg) and/or altering the normal pattern of phosphorylation of the kinase domain (Ala520Thr, Gly703Ser, Pro722Ser, Pro745Ser, and Pro772Ser).”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [5]
Cites
Molecular and Cellular Endocrinology
Rainey, W. E., & Rodgers, R. J. (2004) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2004.10.007 · Cited by 1,309 · see citing works
Schlessinger, J., Plotnikov, A. N., Ibrahimi, O. A., Eliseenkova, A. V., Yeh, B. K., Yayon, A., Linhardt, R. J., & Mohammadi, M. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00073-3 · Cited by 1,199 · see citing works
Self-citationOrigin of luteinizing hormone-releasing hormone neurons
Schwanzel-Fukuda, M., & Pfaff, D. W. (1989) · Nature · doi:10.1038/338161a0 · Cited by 1,116 · see citing works
Recommendations for a nomenclature system for human gene mutations
Antonarakis, S. E., & Nomenclature Working Group (1998) · Human Mutation · doi:10.1002/(sici)1098-1004(1998)11:1 · Cited by 934 · see citing works
Franco, B., Guioli, S., Pragliola, A., Incerti, B., Bardoni, B., Tonlorenzi, R., Carrozzo, R., Maestrini, E., Pieretti, M., Taillon-Miller, P., et al. (1991) · Nature · doi:10.1038/353529a0 · Cited by 846 · see citing works
Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome
Dodé, C., Levilliers, J., Dupont, J., Paepe, A. D., Dû, N. L., Soussi-Yanicostas, N., Coimbra, R., Delmaghani, S., Compain-Nouaille, S., Baverel, F., et al. (2003) · Nature Genetics · doi:10.1038/ng1122 · Cited by 822 · see citing works
Legouis, R., Hardelin, J.-P., Levilliers, J., Claverie, J.-M., Compain, S., Wunderle, V., Millasseau, P., Le Paslier, D., Cohen, D., & Caterina, D. (1991) · Cell · doi:10.1016/0092-8674(91)90193-3 · Cited by 678 · see citing works
A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome
Muenke, M., Schell, U., Hehr, A., Robin, N. H., Losken, H. W., Schinzel, A., Pulleyn, L. J., Rutland, P., Reardon, W., Malcolm, S., et al. (1994) · Nature Genetics · doi:10.1038/ng1194-269 · Cited by 614 · see citing works
Seminara, S. B., Hayes, F. J., & Crowley, W. F. (1998) · Endocrine Reviews · doi:10.1210/edrv.19.5.0344 · Cited by 412 · see citing works
Self-citationStructure of the FGF Receptor Tyrosine Kinase Domain Reveals a Novel Autoinhibitory Mechanism
Mohammadi, M., Schlessinger, J., & Hubbard, S. R. (1996) · Cell · doi:10.1016/s0092-8674(00)80131-2 · Cited by 371 · see citing works
Self-citationHoffman, A. R., & Crowley, W. F. (1982) · New England Journal of Medicine · doi:10.1056/nejm198211113072003 · Cited by 352 · see citing works
Self-citationWray, S., Nieburgs, A., & Elkabes, S. (1989) · Developmental Brain Research · doi:10.1016/0165-3806(89)90295-2 · Cited by 329 · see citing works
Quality Control of mRNA Function
Maquat, L. E., & Carmichael, G. (2001) · Cell · doi:10.1016/s0092-8674(01)00202-1 · Cited by 328 · see citing works
Sex differences in odor identification ability: A cross-cultural analysis
Doty, R. L., Applebaum, S., Zusho, H., & Settle, R. G. (1985) · Neuropsychologia · doi:10.1016/0028-3932(85)90067-3 · Cited by 322 · see citing works
FGFR1 is required for the development of the auditory sensory epithelium.
Pirvola, U., Ylikoski, J., Trokovic, R., Hébert, J., McConnell, S., & Partanen, J. (2002) · Neuron · doi:10.1016/s0896-6273(02)00824-3 · Cited by 302 · see citing works
A Window of Opportunity: The Diagnosis of Gonadotropin Deficiency in the Male Infant 1
Grumbach, M. M. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-2465 · Cited by 281 · see citing works
Quinton, R., Duke, V. M., Robertson, A., Kirk, J. M. W., Matfin, G., de Zoysa, P. A., Azcona, C., MacColl, G., Jacobs, H. S., Conway, G. S., et al. (2001) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2001.01277.x · Cited by 230 · see citing works
Self-citationSato, N. S., Katsumata, N., Kagami, M., Hasegawa, T., Hori, N., KAWAKITA, S., Minowada, S., Shimotsuka, A., Shishiba, Y., Yokozawa, M., et al. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030476 · Cited by 216 · see citing works
FGF signaling through FGFR1 is required for olfactory bulb morphogenesis
Hébert, J. M., Lin, M., Partanen, J. M., Rossant, J., & McConnell, S. K. (2003) · Development · doi:10.1242/dev.00334 · Cited by 213 · see citing works
Oliveira, L. M. B., Seminara, S. B., Beranova, M., Hayes, F. J., Valkenburgh, S. B., Schipani, E., Costa, E. M. F., Latronico, A. C., Crowley, W. F., & Vallejo, M. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.4.7420 · Cited by 210 · see citing works
Self-citationHeterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome
Hardelin, J.-P., Levilliers, J., Blanchard, S., Carel, J.-C., Leutenegger, M., Pinard-Bertelletto, J.-P., Bouloux, P., & Petit, C. (1993) · Human Molecular Genetics · doi:10.1093/hmg/2.4.373 · Cited by 203 · cited 1× · see citing works
“Both neurologic defects (synkinesia and hearing loss) and non-neurologic defects (renal aplasia, high arched palate, labial or palatine cleft and dental agenesis) occur with variable frequency in KS ( Hardelin et al., 1993; Quinton et al., 2001).”
BackgroundSelf-citationPitteloud, N., Hayes, F. J., Boepple, P. A., DeCruz, S., Seminara, S. B., MacLaughlin, D. T., & Crowley, W. F. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.1.8131 · Cited by 201 · see citing works
Self-citationNeuroendocrine-gonadal axis in men: frequent sampling of LH, FSH, and testosterone
Spratt, D. I., O'Dea, L. S., Schoenfeld, D., Butler, J., Rao, P. N., & Crowley, W. F. (1988) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1988.254.5.e658 · Cited by 194 · see citing works
Self-citationSeminara, S. B. (1998) · Endocrine Reviews · doi:10.1210/er.19.5.521 · Cited by 171 · see citing works
Self-citationHormone substitution in male hypogonadism
Zitzmann, M., & Nieschlag, E. (2000) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(99)00227-0 · Cited by 166 · see citing works
Pitteloud, N., Acierno, J. S., Meysing, A. U., Dwyer, A. A., Hayes, F. J., & Crowley, W. F. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1361 · Cited by 160 · see citing works
Self-citationGonzález-Martı́nez, D., Kim, S., Hu, Y., Guimond, S. E., Schofield, J. D., Winyard, P. J. D., Vannelli, G. B., Turnbull, J. E., & Bouloux, P.-M. G. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.3400-04.2004 · Cited by 153 · see citing works
Self-citationKallmann syndrome: 14 novel mutations in<i>KAL1</i>and<i>FGFR1</i>(<i>KAL2</i>): MUTATIONS IN BRIEF
Albuisson, J., Pêcheux, C., Carel, J.-C., Lacombe, D., Leheup, B., Lapuzina, P., Bouchard, P., Legius, E., Matthijs, G., Wasniewska, M., et al. (2005) · Human Mutation · doi:10.1002/humu.9298 · Cited by 146 · see citing works
Fgfr mRNA isoforms in craniofacial bone development
Rice, D. P. C., Rice, R. B., & Thesleff, I. (2003) · Bone · doi:10.1016/s8756-3282(03)00163-7 · Cited by 106 · see citing works
Tsai, P., Moenter, S. M., Postigo, H. R., Majdoubi, M. E., Pak, T. R., Gill, J. C., Paruthiyil, S., Werner, S., & Weiner, R. I. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0330 · Cited by 103 · see citing works
Kallmann's syndrome: is it always for life?
Quinton, Cheow, Tymms, Bouloux, Wu, & Jacobs, J. (1999) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1999.00708.x · Cited by 85 · see citing works
Gill, J. C., Moenter, S. M., & Tsai, P.-S. (2004) · Endocrinology · doi:10.1210/en.2004-0214 · Cited by 81 · see citing works
Developmental aspect of the gonadotropin-releasing hormone system
Tobet, S. A., Bless, E. P., & Schwarting, G. A. (2001) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(01)00616-5 · Cited by 72 · see citing works
Hayes, F. J., McNicholl, D. J., Schoenfeld, D., Marsh, E. E., & Hall, J. E. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.3.5579 · Cited by 70 · see citing works
Self-citationBick, D. P., Schorderet, D. F., Price, P. A., et al. (1992) · Prenatal Diagnosis · doi:10.1002/pd.1970120104 · Cited by 34 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Retinoid signaling determines germ cell fate in mice
Bowles, J., Knight, D., Smith, C., Wilhelm, D., Richman, J., Mamiya, S., Yashiro, K., Chawengsaksophak, K., Wilson, M. J., Rossant, J., et al. (2006) · Science · doi:10.1126/science.1125691 · Cited by 1,011 · see citing works
Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice
Falardeau, J., Chung, W. C. J., Beenken, A., Raivio, T., Plummer, L., Sidis, Y., Jacobson-Dickman, E. E., Eliseenkova, A. V., Ma, J., Dwyer, A., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34538 · Cited by 397 · see citing works
Self-citationDigenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism
Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29884 · Cited by 379 · see citing works
Self-citationThe genetic and molecular basis of idiopathic hypogonadotropic hypogonadism
Bianco, S. D. C., & Kaiser, U. B. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.177 · Cited by 336 · see citing works
The recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions
Semple, R. K., & Topaloglu, A. K. (2010) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03687.x · Cited by 117 · see citing works
Kim, S. ‐., Hu, Y., Cadman, S., & Bouloux, P. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2007.01627.x · Cited by 87 · see citing works
Self-citationGnRH-Deficient Phenotypes in Humans and Mice with Heterozygous Variants in<i>KISS1</i>/<i>Kiss1</i>
Chan, Y.-M., Broder-Fingert, S., Paraschos, S., Lapatto, R., Au, M., Hughes, V., Bianco, S. D. C., Min, L., Plummer, L., Cerrato, F., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0518 · Cited by 68 · see citing works
Self-citationHerbison, A. E. (2007) · Hormone Research in Paediatrics · doi:10.1159/000110583 · Cited by 44 · see citing works
Chan, Y.-M., Lippincott, M. F., Butler, J. P., Sidhoum, V. F., Li, C. X., Plummer, L., & Seminara, S. B. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2233 · Cited by 39 · see citing works
Stamou, M. I., Cox, K. H., & Crowley, W. F. (2015) · Endocrine Reviews · doi:10.1210/er.2015-1045.2016.1.test · Cited by 32 · see citing works
Self-citation
- Authors
- Pitteloud, N., Meysing, A., Quinton, R., Acierno, J. S., Dwyer, A. A., Plummer, L., Fliers, E., Boepple, P., Hayes, F., Seminara, S., Hughes, V. A., Ma, J., Bouloux, P., Mohammadi, M., & Crowley, W. F.
- Affiliations
- Massachusetts General Hospital (US)
- Royal Free London NHS Foundation Trust (GB)
- Amsterdam UMC Location University of Amsterdam (NL)
- New York University (US)
- Corresponding author
- Pitteloud, Nelly
- ORCID
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 254-255
- Pages
- 60-69
- ISSN
- 0303-7207 (ISSN-L)
- OpenAlex
- W2121966708
- Cited by
- 198
- References
- 35
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 7 · 2021: 15 · 2020: 14 · 2019: 15 · 2018: 10 · 2017: 5 · 2016: 8 · 2015: 9 · 2014: 9 · 2013: 9 · 2012: 9
- FWCI
- 15.48
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institutes of Health (5r01dk003892-40)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-03892)
- National Institute of Dental and Craniofacial Research (R01DE013686, 2R01 DE13686-06)
- National Center for Research Resources (M01RR001066, M01-RR01066)
- NIH Clinical Center
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD15788, R01HD015788, U54HD029164, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- Kallmann syndrome, FGFR1, FGFR1 mutation, idiopathic hypogonadotropic hypogonadism, reproductive phenotypes, anosmia, anosmin-1, immunoglobulin-like domains, tyrosine kinase domain, micropenis, cryptorchidism, delayed puberty, testosterone replacement therapy
- MeSH terms
- Adolescent, Olfaction Disorders, Child, Cleft Palate, DNA Mutational Analysis, Female, Gene Frequency, Humans, Hypogonadism, Male, Models, Molecular, Mutation, Pedigree, Phenotype, Puberty, Delayed, Reproduction, Genetic Variation, Cohort Studies, Kallmann Syndrome, Receptor, Fibroblast Growth Factor, Type 1
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 ›
Are you an author, or do you see a problem with this page? Request a review
