This Article Abstract Full Text (PDF) A correction has been published Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Trarbach, E. B. Articles by Latronico, A. C. Search for Related Content PubMed PubMed Citation Articles by Trarbach, E. B. Articles by Latronico, A. C. Related Collections Neuroendocrinology and Pituitary Male Endocrinology

Novel Fibroblast Growth Factor Receptor 1 Mutations in Patients with Congenital Hypogonadotropic Hypogonadism with and without Anosmia

Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular LIM-42 (E.B.T., E.M.F.C., B.B.d.M., A.C.L.), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo; Departamento de Medicina Interna, Divisão de Endocrinologia (B.V., M.d.C.), Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo; and Departamento de Clínica Médica (M.T.M.B., H.M.G.), Disciplina de Endocrinologia e Metabologia da Faculdade de Ciências Médicas da Universidade de Campinas, 05403-900, São Paulo, Brazil

Address all correspondence and requests for reprints to: Ericka B. Trarbach, Ph.D., Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Disciplina de Endocrinologia e Metabologia, Av Dr Enéas de Carvalho Aguiar, 155, 2 degree andar Bloco 6, 05403-900, São Paulo, Brazil. E-mail: trarbach{at}hotmail.com; anacl{at}usp.br.

Abstract

Context: Kallmann syndrome is a clinically and genetically heterogeneous disorder. To date, loss-of-function mutations in the genes encoding anosmin-1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1) have been described in the X-linked and autosomal dominant forms of this syndrome, respectively.

Objective: The objective was to investigate genetic defects in the KAL1 and FGFR1 genes in patients with congenital isolated hypogonadotropic hypogonadism (IHH).

Patients: Eighty patients (71 males and nine females) with IHH were studied, of which 30 were familial. Forty-six of them had olfactory abnormalities.

Methods: The coding regions of both KAL1 and FGFR1 genes were amplified and automatically sequenced. The KAL1 mutations were investigated only in patients with olfactory abnormalities, whereas FGFR1 was studied in the entire group.

Results: Two novel KAL1 mutations, an intragenic deletion of exons 3–6 and a splicing mutation IVS7 + 1G>A, were identified in two of 46 patients with Kallmann syndrome. Eight novel heterozygous FGFR1 mutations (G48S, L245P, R250W, A343V, P366L, K618fsX654, P722S, and V795I) were identified in nine of 80 patients with IHH. Eight of them had olfactory abnormalities. Interestingly, the G48S mutation was identified in a normosmic IHH patient. Two unrelated females, who carried FGFR1 mutations, had anosmia and normal reproductive function.

Conclusion: We identified novel mutations in KAL1 and FGFR1 genes in IHH patients. FGFR1 mutations were identified in 17% of the patients with olfactory abnormalities and in one of 34 normosmic IHH patients. In addition, isolated anosmia was identified in two unrelated females as a partial phenotypic manifestation of FGFR1 defects.

CONGENITAL ISOLATED hypogonadotropic hypogonadism (IHH) is characterized by complete or partial failure of pubertal development due to the impaired secretion of LH and FSH, in the absence of any hypothalamic-pituitary organic cause (1). When IHH is associated with impaired olfactory function (anosmia/hyposmia), it is defined as Kallmann syndrome. This condition is genetically heterogeneous, with reports indicating autosomal dominant, recessive, and X-linked transmission (1). To date, two distinct genes have been implicated in the molecular basis of Kallmann syndrome, the genes encoding anosmin-1 (KAL1) and the fibroblast growth factor receptor 1 (FGFR1) (2).

The KAL1 gene (ENSG0011201) is located at Xp22.3 and comprises 14 exons (3, 4). Anosmin-1 is an extracellular matrix glycoprotein that shows significant homologies with molecules known to play specific roles in neuronal development (5, 6). Experiments in vitro revealed a role for anosmin-1 in the control of different cell function, including cell adhesion and neurite/axonal elongation and fasciculation, and in the migratory activity of GnRH-producing neurons (5, 6, 7). Several KAL1 gene abnormalities (missense, nonsense and splice site mutations, intragenic deletion, and complete gene deletion) have been identified in approximately 8–11% of the sporadic form and in 14–50% of the familial form of Kallmann syndrome (8, 9). Other nonreproductive features are associated with KAL1 gene abnormalities, such as unilateral renal aplasia, mirror movements, sensorineural deafness, high-arched palate, and eye-movement abnormalities (9, 10, 11, 12).

The FGFR1 gene (ENSG0077782), also called KAL2, is located at chromosome 8p12 and comprises 18 exons (13). Dode et al. (14), studying two patients with contiguous gene syndrome due to interstitial deletions at chromosome 8p11.2–12, first reported the association of loss-of-function mutations in FGFR1 with the dominant form of Kallmann syndrome. Since then, several FGFR1 heterozygous mutations were identified in approximately 10% of individuals with Kallmann syndrome (11, 14, 15). In addition to hypogonadotropic hypogonadism, different nonreproductive features including cleft palate, mirror movements, and dental agenesis have also been identified in these patients, with variable phenotypic expression (14, 15). Moreover, a rare case of Kallmann syndrome with reversible hypogonadism was recently associated with a FGFR1 mutation (16). It is noteworthy that most patients with FGFR1 defects described so far were anosmic or hyposmic (11, 14, 15, 16). It has been suggested that anosmin-1 is involved in fibroblast growth factor signaling through FGFR1 (14, 17, 18, 19).

In the present study, we investigated KAL1 and FGFR1 gene mutations in a cohort of Brazilian patients with Kallmann syndrome. Molecular analysis of FGFR1 was also carried out in patients with IHH and normal olfaction to determine the frequency of FGFR1 defects in these patients.

Patients and Methods

Eighty unrelated Brazilian patients (71 males and nine females, aged 17–50 yr) with IHH were selected from three university institutions of Sao Paulo, Brazil. Permanent IHH was documented based on the following criteria: age older than 17 yr, clinical signs and symptoms of hypogonadism, prepubertal testosterone or estradiol levels, low or inappropriately normal gonadotropin levels, normal baseline and stimulated levels of the other anterior pituitary hormones, and normal hypothalamic-pituitary imaging. All patients were questioned regarding their sense of smell. In addition, two objective olfactory tests, Smell Identification Test or Alcohol Sniff Test, were performed in 55 patients with IHH (20). Based on the olfactory questionnaire and objective olfactory test results, 46 individuals were found to have olfactory abnormalities, whereas 34 had a normal sense of smell. GnRH receptor mutations were previously excluded in all normosmic IHH patients (21, 22).

Thirty patients (21 with Kallmann and nine normosmic IHH) had a positive familial history of IHH. Among the 21 patients with familial Kallmann syndrome, autosomal dominant inheritance was predicted in six of them, based on the presence of affected male and female relatives, as well as the direct transmission of the phenotype across generations. Four families had a pattern of transmission suggestive of autosomal recessive inheritance, where both sexes were affected at the same generation. A clear recessive X-linked transmission, characterized by the presence of affected males only and maternal transmission, was observed in one family with Kallmann syndrome. Three of the nine families with normosmic IHH showed an autosomal recessive mode of inheritance. Given the limited sample size and/or only one generation being affected, it was not possible to determine the mode of inheritance in 16 familial IHH. The remaining 50 IHH patients were considered to be sporadic cases.

One hundred adult individuals of both sexes (50 males and 50 females) with normal sexual development at the appropriate chronological age and no history of abnormal sense of smell were used as the control group. The study was approved by the ethical committee of each institution. Informed and written consent was obtained from all patients.

DNA analysis of KAL1 and FGFR1 genes

Genomic DNA was extracted from peripheral blood leukocytes using standard procedures. The KAL1 gene was studied in all Kallmann syndrome patients. DNA was amplified by PCR using previously described primers (12). The PCR amplifications were performed in 20 µl reaction mixes containing 200–500 ng of genomic DNA, 0.2 mM deoxynucleotide triphosphates, 1.5 mM MgCl₂, 0.6 pmol of each of the primers, 1 x PCR buffer, and 1 U Taq polymerase (Amersham Biosciences, Piscataway, NJ). After a first denaturation step (10 min, 95 C), 30 PCR amplification cycles of 30 sec at 95 C, 30 sec at 57 C (except for exon 1, 62 C), and 1 min at 72 C were carried out, followed by a final extension of 10 min at 72 C. The PCR products were electrophoresed on 1.0% agarose gel, stained with ethidium bromide, and photographed. If no amplification product of KAL1 exons was detected, PCR was repeated with the inclusion of primers for the SRY gene, as internal positive control (21).

Exons 2–18 of the FGFR1 gene were amplified in KAL1 mutation-negative cases and normosmic IHH patients. FGFR1 oligonucleotides are shown in Table 1. The FGFR1 amplification conditions were similar to those used in KAL1 gene amplification.

In silico analysis by RepeatMasker software (http://www.repeatmasker.org, accessed in February, 2006) was performed for the identification of repetitive sequences in the KAL1 gene.

Results

Standard and multiplex PCR amplifications revealed an intragenic deletion involving exons 3–6 of the KAL1 gene in a sporadic case of Kallmann syndrome (Fig. 1). In silico analysis of introns 2 and 6 of the KAL1 gene, adjacent regions to this deletion, disclosed several elements of SINE and LINE family repeats (such as Alu, L1, and MIR) and the simple repeat CAAATT in both introns.

View larger version (34K): [in this window] [in a new window]   FIG. 1. PCR amplification of exons 2 (230 bp), 3 (174 bp), 6 (218 bp), and 7 (269 bp) of KAL1 gene in a male patient with Kallmann syndrome. Lanes 1–3 correspond to a normal 46,XY male, affected patient, and negative control, respectively. Exons 2 and 7 were amplified in the patient (lane 2) and control male (lane 1), whereas exons 3 and 6 were amplified only in the male control (lane 1). A product of the SRY gene (317bp) was used as control of amplification.

View larger version (23K): [in this window] [in a new window]   FIG. 2. A, Automatic sequencing showing a KAL1 mutation IVS7 + 1G>T in a familial case of Kallmann syndrome (left) and a normal sequencing (right). Asterisks indicate the mutated base. B, The pedigree is consistent with X-linked transmission. Arrow indicates the proband. Solid symbols indicate IHH and olfactory abnormalities.

View larger version (22K): [in this window] [in a new window]   FIG. 3. Automatic sequencing showing heterozygous mutations in FGFR1 of patients with Kallmann syndrome (cases 2, 3, 4, 5, 6, 7, 8, and 9) and normosmic hypogonadotropic hypogonadism (case 1). The corresponding amino acid is described below the codon sequence. Mutated codons and amino acids are indicated in red. Normal sequence of FGFR1 is shown above.

View larger version (28K): [in this window] [in a new window]   FIG. 4. Pedigrees of six families with Kallmann syndrome due to FGFR1 mutations. Pedigrees 3 and 4 are consistent with an autosomal dominant pattern of inheritance with incomplete penetrance in the first family. In the other families, the mode of inheritance could not be determined by visual inspection. The proband is identified by the arrow. Squares denote male subjects, circles female subjects, triangles spontaneous abortion, lines through symbols deceased individual, and diamonds sex unknown. The numbers inside symbols indicate multiple individuals and "n" indicates unknown number of multiple individuals. All subjects signed with asterisks were evaluated by objective olfactory test. Cardinal clinical features of Kallmann syndrome are described in the key.

Discussion

Hypothalamic GnRH plays a key role in gonadotropin secretion induction from the anterior pituitary. The altered GnRH function may be caused by failure in the embryonic migration of GnRH neurons, defective synthesis, secretion, or action of GnRH. The identification of KAL1, FGFR1, GnRH receptor, and GPR54 mutations in patients with IHH provided new insights in the developmental organization and regulation of hypothalamic GnRH neurons (2).

Here, we describe novel KAL1 and FGFR1 mutations in 11 of 80 IHH patients studied. An intragenic deletion encompassing exons 3–6 and one splicing mutation +1G>T in intron 7 were identified in KAL1 in two patients with sporadic and familial Kallmann syndrome, respectively. We have previously studied KAL1 mutations in Brazilian patients with IHH and olfactory abnormalities (22, 23, 24). Considering the data from previous and current studies, the prevalence of KAL1 mutations in Brazilian male patients with Kallmann syndrome was approximately 22% (27% familial and 16% sporadic cases).

To date, several point mutations, small deletions, and a few single-exon deletions have been identified in Kallmann syndrome patients (9, 12). Large deletions involving more than one exon of KAL1 have been reported for exons 13–14 (25), 3–5 (26), 5–10 (24, 27), and 3–13 (28). Although the breakpoints were not determined in most cases, the flanking intronic regions of these deletions containing repeated elements might promote nonallelic recombination (24). We were able to identify several elements of SINE and LINE family repeats (such as Alu, L1 and MIR) within intronic sequences that are adjacent to the KAL1 exons 3–6 deletion using in silico analysis. Direct copies of the simple repeat CAAATT, previously identified in the deletion breakpoints involving exons 13–14 of KAL1, were also identified (25). These elements have been suggested as putative recombination-promoting factors throughout the genome, which have been associated with several exon and/or gene deletions in humans (29, 30).

Eight novel FGFR1 heterozygous defects (one frameshift and seven missense mutations) were identified in nine of 80 patients (11.2%) with sporadic or familial IHH. Among the Kallmann syndrome patients, the overall incidence of FGFR1 mutations was 17% (28% familial and 8% sporadic). In the familial cases, mutations were identified in two autosomal dominant pedigrees and in four families with undetermined inheritance form. The frequency of FGFR1 mutations observed in this Brazilian series with Kallmann syndrome was significantly higher in the familial than in sporadic cases and slightly higher than the ones found in other populations (11, 14, 15).

The mature FGFR1 protein, one of the four transmembrane receptors for fibroblast growth factor (FGF) ligands, consists of three extracellular Ig-like loops (IgI, IgII, and IgIII), an acid box between the first two Ig loops, a transmembrane domain, and an intracellular split TK domain (31). The FGFR1 mutations described here were widely distributed along the distinct domains of the receptor (Fig. 5). They involved amino acid sequences that are highly conserved across species as well as within the FGFR family, suggesting a critical role of these residues in the receptor signaling pathway. None of these FGFR1 mutations were found in 200 alleles from the control individuals, supporting the functional significance of these mutations.

View larger version (5K): [in this window] [in a new window]   FIG. 5. Structure of FGFR1 containing the functional domains and the distribution of the novel FGFR1 mutations. All mutations were identified in heterozygous state. Gray circle, Missense mutations; , frameshift mutations; SP, signal peptid; AB, acidic box; HBS, heparin binding site; TM, transmembrane domain.

Among the nine FGFR1 mutations identified in Brazilian patients with IHH, a missense mutation at codon 366, characterized by the substitution of proline by leucine within the linker IgII-IgIII domain of the receptor, was identified in one familial patient (case 6) with Kallmann syndrome (Table 2). This mutation was also identified in his two paternal aunts with Kallmann syndrome as well as in his asymptomatic father. Incomplete penetrance of hypogonadism and/or anosmia and an inter- and intrafamilial variety of phenotypic anomalies are frequently described in Kallmann syndrome (35, 36). Recently, one family harboring a nonsense FGFR1 mutation in the TK domain, whose proband presented spontaneous recovery of hypogonadism after androgen replacement therapy, was reported (16). It is possible that other, as yet unidentified factors, such as epigenetic phenomena and/or modifier genes, may compensate the loss-of-function of FGFR1 and/or KAL1 and thus prevent full expression of the phenotype.

We also demonstrated the V795I missense mutation in the carboxyl-terminal tail of the FGFR1 in an anosmic woman who exhibited normal pubertal development with normal basal and GnRH-stimulated gonadotropin as well as estradiol levels. She is the sister of a male patient (case 9, family 6) with Kallmann syndrome. In addition, isolated anosmia and an FGFR1 defect were also identified in another female from family 4. In this family, the frameshift mutation in the catalytic TK domain was found in the mother, who had isolated anosmia, and in her two children—a male propositus (patient 7) and his sister, both affected by Kallmann syndrome. These findings supported the evidence of isolated anosmia as a partial phenotype of FGFR1 mutations in females (14).

Several nonreproductive phenotypes have been described in patients with Kallmann syndrome (9, 11, 15, 24). Some of these anomalies were largely attributed to the mutated KAL1 gene, such as bimanual synkinesis. Here, we described the occurrence of bimanual synkinesis in one familial Kallmann syndrome patient (patient 8, Table 2) harboring the P722S mutation in the catalytic TK2 domain of FGFR1. This mutation was also found in his maternal first cousin, who had Kallmann syndrome, but not bimanual synkinesis. Bimanual synkinesis occurs in approximately 75% of patients carrying KAL1 mutations, but it has rarely been reported in subjects with FGFR1 mutations (18). To date, patient 8 represents the second reported case of FGFR1 mutation with bimanual synkinesis. Interestingly, a different mutation (P722H) disturbing the same 722 codon, although combined with a second mutation (N724K) in the same allele, was described in a patient with Kallmann syndrome and dental agenesis, but not bimanual synkinesia. Structural and biochemical studies showed that this double mutation reduced the TK activity of FGFR1 (34).

The FGFR1 signaling is achieved by receptor conformational changes upon ligand binding, leading to dimerization and subsequent activation by autophosphorylation of TK intracellular domains (37). Heparin or heparin sulfate proteoglycan binding is essential for the dimerization and activation of the FGF-FGFR complex (38). However, the mechanisms and effects of loss-of-function FGFR1 mutations are poorly understood. Inactivating FGFR1 mutations in the IgI might actually augment the autoinhibited state of FGFR1. This region exhibits lower affinity for FGF ligand and heparin but is capable of directly interacting with IgII and IgIII regions, occluding the FGF binding interface and keeping FGFR1 in a "closed" low-activity state (32). FGFR1 variants, located in IgII-IgIII linker and IgIII domain, can interfere with the receptor interaction with the ligands because these regions are predicted to play an important structural role in correct folding of the Ig loops and, consequently, with the ligand binding (39). Additionally, mutations in the transmembrane and juxtamembrane domains of the FGFR1 can affect the rotational positioning of receptor subunits, disrupting a process necessary for biological activity (40).

Recent studies showed that anosmin-1 acts as an FGFR1-specific modulator and coligand that physically interacts with the FGFR1-FGF-heparin sulfate proteoglycan complex and amplifies the resulting downstream signaling responses (17). It is plausible that factors related to anosmin-1 may represent an additional level of complexity in the network of molecules involved in regulation of FGFR signal transduction during development (17). In addition, several studies on the expression patterns of FGF ligands and receptors during central nervous system development indicate the critical role of FGF in the initial generation of neural tissue (19). This activity is also present in the rostral forebrain, directly affecting the olfactory bulb development, which could directly affect the GnRH neuronal migratory activity (41).

Footnotes

This work was supported in part by Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant FAPESP 2005/04726-0).

Disclosure Statement: The authors have nothing to disclose.

First Published Online August 1, 2006

Abbreviations: FGF, Fibroblast growth factor; FGFR1, FGF receptor 1; IHH, isolated hypogonadotropic hypogonadism; MRI, magnetic resonance imaging; TK, tyrosine kinase.

Received December 21, 2005.

Accepted July 24, 2006.

References

1. Seminara SB, Hayes FJ, Crowley Jr WF 1998 Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome): pathophysiological and genetic considerations. Endocr Rev 19:521–539[Abstract/Free Full Text]
2. Karges B, de Roux N 2005 Molecular genetics of isolated hypogonadotropic hypogonadism and Kallmann syndrome. Endocr Dev 8:67–80[Medline]
3. Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, Carrozzo R, Maestrini E, Pieretti M, Taillon-Miller P, Brown CJ, Willard HF, Lawrence C, Persico MG, Camerino G, Ballabio A 1991 A gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 353:529–536[CrossRef][Medline]
4. Legouis R, Hardelin JP, Levilliers J, Claverie JM, Compain S, Wunderle V, Millasseau P, Le Paslier D, Cohen D, Caterina D, Bougueleret L, Dlemarre-Van Der Wall H, Lutfalla G, Weissenbach J, Petit C 1991 The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 67:423–435[CrossRef][Medline]
5. Soussi-Yanicostas N, Faivre-Sarrailh C, Hardelin JP, Levilliers J, Rougon G, Petit C 1998 Anosmin-1 underlying the X chromosome-linked Kallmann syndrome is an adhesion molecule that can modulate neurite growth in a cell-type specific manner. J Cell Sci 111:2953–2965[Abstract]
6. Soussi-Yanicostas N, de Castro F, Julliard AK, Perfettini I, Chedotal A, Petit C 2002 Anosmin-1, defective in the X-linked form of Kallmann syndrome, promotes axonal branch formation from olfactory bulb output neurons. Cell 109:217–228[CrossRef][Medline]
7. Cariboni A, Pimpinelli F, Colamarino S, Zaninetti R, Piccolella M, Rumio C, Piva F, Rugarli EI, Maggi R 2004 The product of X-linked Kallmann’s syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons. Hum Mol Genet 13:2781–2791[Abstract/Free Full Text]
8. Oliveira LM, Seminara SB, Beranova M, Hayes FJ, Valkenburgh SB, Schipani E, Costa EM, Latronico AC, Crowley Jr WF, Vallejo M 2001 The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab 86:1532–1538[Abstract/Free Full Text]
9. Quinton R, Duke VM, de Zoysa PA, Platts AD, Valentine A, Kendall B, Pickman S, Kirk JM, Besser GM, Jacobs HS, Bouloux PM 1996 The neuroradiology of Kallmann’s syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab 81:3010–3017[Abstract/Free Full Text]
10. Soderlund D, Canto P, Mendez JP 2002 Identification of three novel mutations in the KAL1 gene in patients with Kallmann syndrome. J Clin Endocrinol Metab 87:2589–2592[Abstract/Free Full Text]
11. Albuisson J, Pecheux C, Carel JC, Lacombe D, Leheup B, Lapuzina P, Bouchard P, Legius E, Matthijs G, Wasniewska M, Delpech M, Young J, Hardelin JP, Dode C 2005 Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum Mutat 25:98–99[Medline]
12. Hardelin JP, Levilliers J, Blanchard S, Carel JC, Leutenegger M, Pinard-Bertelletto JP, Bouloux P, Petit C 1993 Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. Hum Mol Genet 2:373–377[Abstract/Free Full Text]
13. Ruta M, Burgess W, Givol D, Epstein J, Neiger N, Kaplow J, Crumley G, Dionne C, Jaye M, Schlessinger J 1989 Receptor for acidic fibroblast growth factor is related to the tyrosine kinase encoded by the fms-like gene (FLG). Proc Natl Acad Sci USA 86:8722–8726[Abstract/Free Full Text]
14. Dode C, Levilliers J, Dupont JM, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin JP 2003 Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33:463–465[CrossRef][Medline]
15. Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N, Kawakita S, Minowada S, Shimotsuka A, Shishiba Y, Yokozawa M, Yasuda T, Nagasaki K, Hasegawa D, Hasegawa Y, Tachibana K, Naiki Y, Horikawa R, Tanaka T, Ogata T 2004 Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. J Clin Endocrinol Metab 89:1079–1088[Abstract/Free Full Text]
16. Pitteloud N, Acierno Jr JS, Meysing AU, Dwyer AA, Hayes FJ, Crowley Jr WF 2005 Reversible Kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab 90:1317–1322[Abstract/Free Full Text]
17. Gonzalez-Martinez D, Kim SH, Hu Y, Guimond S, Schofield J, Winyard P, Vannelli GB, Turnbull J, Bouloux P 2004 Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism. J Neurosci 24:10384–10392[Abstract/Free Full Text]
18. Dode C, Hardelin JP 2004 Kallmann syndrome: fibroblast growth factor signaling insufficiency? J Mol Med 82:725–734[CrossRef][Medline]
19. Gonzalez-Martinez D, Hu Y, Bouloux PM 2004 Ontogeny of GnRH and olfactory neuronal systems in man: novel insights from the investigation of inherited forms of Kallmann’s syndrome. Front Neuroendocrinol 25:108–130[CrossRef][Medline]
20. Davidson TM, Murphy C 1997 Rapid clinical evaluation of anosmia. The alcohol sniff test. Arch Otolaryngol Head Neck Surg 123:591–594[Abstract/Free Full Text]
21. Costa EM, Bedecarrats GY, Mendonca BB, Arnhold IJ, Kaiser UB, Latronico AC 2001 Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction. J Clin Endocrinol Metab 86:2680–2686[Abstract/Free Full Text]
22. Trarbach EB, Baptista MTM, Garmes HM, Hackel C 2005 Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients. J Endocrinol 187:361–368[Abstract/Free Full Text]
23. Trarbach EB, Baptista MTM, Maciel-Guerra AT, Hackel C 2001 Cytogenetic analysis and detection of KAL-1 gene deletion with fluorescence in situ hybridization in patients with Kallmann syndrome. Arq Bras Endocrinol Metab 45:552–557
24. Trarbach EB, Monlleo IL, Porciuncula CGG, Fontes MIB, Baptista MTM, Hackel C 2004 Similar interstitial deletions of the KAL-1 gene in two Brazilian families with X-linked Kallmann syndrome. Genet Mol Biol 27:337–341
25. Bick D, Franco B, Sherins RJ, Heye B, Pike L, Crawford J, Maddalena A, Incerti B, Pragliola A, Meitinger T, Ballabio A 1992 Intragenic deletion of the KALIG-1 gene in Kallmann’s syndrome. N Engl J Med 25:1752–1755
26. Maya-Nunez G, Zenteno JC, Ulloa-Aguirre A, Kofman-Alfaro S, Mendez JP 1998 A recurrent missense mutation in the KAL gene in patients with X-linked Kallmann’s syndrome. J Clin Endocrinol Metab 83:1650–1653[Abstract/Free Full Text]
27. Nagata K, Yamamoto T, Chikumi H, Ikeda T, Yamamoto H, Hashimoto K, Yoneda K, Nanba E, Ninomiya H, Ishitobi K 2000 A novel interstitial deletion of KAL1 in a Japanese family with Kallmann syndrome. J Hum Genet 45:237–240[CrossRef][Medline]
28. Massin N, Pecheux C, Eloit C, Bensimon JL, Galey J, Kuttenn F, Hardelin JP, Dode C, Touraine P 2003 X chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene. J Clin Endocrinol Metab 88:2003–2008[Abstract/Free Full Text]
29. Woods-Samuels P, Kazazian HHJ, Antonarakis SE 1991 Nonhomologous recombination in the human genome: deletions in the human factor VIII gene. Genomics 10:94–101[CrossRef][Medline]
30. Han K, Sen SK, Wang J, Callinan PA, Lee J, Cordaux R, Liang P, Batzer MA 2005 Genomic rearrangements by LINE-1 insertion-mediated deletion in the human and chimpanzee lineages. Nucleic Acids Res 33:4040–4052[Abstract/Free Full Text]
31. Groth C, Lardelli M 2002 The structure and function of vertebrate fibroblast growth factor receptor 1. Int J Dev Biol 46:393–400[Medline]
32. Olsen SK, Ibrahimi OA, Raucci A, Zhang F, Eliseenkova AV, Yayon A, Basilico C, Linhardt RJ, Schlessinger J, Mohammadi M 2004 Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity. Proc Natl Acad Sci USA 101:935–940[Abstract/Free Full Text]
33. Kim HG, Herrick SR, Lemyre E, Kishikawa S, Salisz JA, Seminara S, MacDonald ME, Bruns GA, Morton CC, Quade BJ, Gusella JF 2005 Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1. J Med Genet 42:666–672[Free Full Text]
34. Pitteloud N, Acierno JSJ, Meysing A, Eliseenkova AV, Ma J, Ibrahimi OA, Metzger DL, Hayes FJ, Dwyer AA, Hughes VA, Yialamas M, Hall JE, Grant E, Mohammadi M, Crowley Jr WF 2006 Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA 103:6281–6286[Abstract/Free Full Text]
35. Bhagavath B, Podolsky RH, Ozata M, Bolu E, Bick DP, Kulharya A, Sherins RJ, Layman LC 2006 Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil Steril 85:706–713[CrossRef][Medline]
36. Pitteloud N, Meysing A, Quinton R, Acierno Jr JS, Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes FJ, Seminara S, Hughes VA, Ma J, Bouloux P, Mohammadi M, Crowley Jr WF 2006 Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Biol Cell 25:60–69
37. McKeehan WL, Wang F, Kan M 1998 The heparan sulfate-fibroblast growth factor family: diversity of structure and function. Prog Nucleic Acids Res Mol Biol 59:135–176[Medline]
38. Ibrahimi OA, Zhang F, Hrstka SC, Mohammadi M, Linhardt RJ 2004 Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly. Biochemistry 43:4724–4730[CrossRef][Medline]
39. Mohammadi M, Olsen SK, Ibrahimi OA 2005 Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137[CrossRef][Medline]
40. Bell CA, Tynan JA, Hart KC, Meyer AN, Robertson SC, Donoghue DJ 2000 Rotational coupling of the transmembrane and kinase domains of the Neu receptor tyrosine kinase. Mol Biol Cell 11:3589–3599[Abstract/Free Full Text]
41. Hebert JM, Lin M, Partanen J, Rossant J, McConnell SK 2003 FGF signaling through FGFR1 is required for olfactory bulb morphogenesis. Development 130:1101–1111[Abstract/Free Full Text]

This article has been cited by other articles:

				T. Raivio, Y. Sidis, L. Plummer, H. Chen, J. Ma, A. Mukherjee, E. Jacobson-Dickman, R. Quinton, G. Van Vliet, H. Lavoie, et al. Impaired Fibroblast Growth Factor Receptor 1 Signaling as a Cause of Normosmic Idiopathic Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4380 - 4390. [Abstract] [Full Text] [PDF]

				M. Koenigkam-Santos, A.C. Santos, T. Borduqui, B.R. Versiani, J.E.C. Hallak, J.A.S. Crippa, and M. Castro Whole-Brain Voxel-Based Morphometry in Kallmann Syndrome Associated with Mirror Movements AJNR Am. J. Neuroradiol., October 1, 2008; 29(9): 1799 - 1804. [Abstract] [Full Text] [PDF]

				A. P. Abreu, E. B. Trarbach, M. de Castro, E. M. Frade Costa, B. Versiani, M. T. Matias Baptista, H. M. Garmes, B. B. Mendonca, and A. C. Latronico Loss-of-Function Mutations in the Genes Encoding Prokineticin-2 or Prokineticin Receptor-2 Cause Autosomal Recessive Kallmann Syndrome J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 4113 - 4118. [Abstract] [Full Text] [PDF]

				L. M. Cotton, M. K. O'Bryan, and B. T. Hinton Cellular Signaling by Fibroblast Growth Factors (FGFs) and Their Receptors (FGFRs) in Male Reproduction Endocr. Rev., April 1, 2008; 29(2): 193 - 216. [Abstract] [Full Text] [PDF]

				B. M. Riley, M. A. Mansilla, J. Ma, S. Daack-Hirsch, B. S. Maher, L. M. Raffensperger, E. T. Russo, A. R. Vieira, C. Dode, M. Mohammadi, et al. Impaired FGF signaling contributes to cleft lip and palate PNAS, March 13, 2007; 104(11): 4512 - 4517. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) A correction has been published Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Trarbach, E. B. Articles by Latronico, A. C. Search for Related Content PubMed PubMed Citation Articles by Trarbach, E. B. Articles by Latronico, A. C. Related Collections Neuroendocrinology and Pituitary Male Endocrinology