Original Article
Brief Report
Isolated Familial Hypogonadotropic Hypogonadism and a GNRH1 Mutation
N Engl J Med 2009; 360:2742-2748June 25, 2009
- Abstract
We investigated whether mutations in the gene encoding gonadotropin-releasing hormone 1 (GNRH1) might be responsible for idiopathic hypogonadotropic hypogonadism (IHH) in humans. We identified a homozygous GNRH1 frameshift mutation, an insertion of an adenine at nucleotide position 18 (c.18-19insA), in the sequence encoding the N-terminal region of the signal peptide–containing protein precursor of gonadotropin-releasing hormone (prepro-GnRH) in a teenage brother and sister, who had normosmic IHH. Their unaffected parents and a sibling who was tested were heterozygous. This mutation results in an aberrant peptide lacking the conserved GnRH decapeptide sequence, as shown by the absence of immunoreactive GnRH when expressed in vitro. This isolated autosomal recessive GnRH deficiency, reversed by pulsatile GnRH administration, shows the pivotal role of GnRH in human reproduction.
Media in This Article
Figure 1
Family Pedigree and Phenotypic Presentation.Figure 2
Molecular Characterization and Functional Consequences of the c.18-19insA GNRH1 Mutation.Article Activity
- Article
Pulsatile secretion of GnRH by hypothalamic neurons is a crucial element of the reproductive cascade, initiating the release of pituitary gonadotropins, gonadal secretion of sex steroids, pubertal development, and gametogenesis. IHH is a clinical syndrome that results from abnormal gonadotropin secretion1 and is characterized by a complete or partial lack of pubertal development. IHH is caused mainly by defective GnRH production or release by the hypothalamus or by defective GnRH-receptor function in the pituitary.2 When IHH is associated with anosmia or hyposmia, the disorder, which is related to abnormal GnRH neuron ontogenesis, is known as Kallmann's syndrome.3 KAL1, the gene responsible for the X-linked form, was identified in 1991.4 More recently, loss-of-function mutations in the genes encoding fibroblast growth factor receptor 1 (FGFR1), prokineticin 2 (PROK2), and prokineticin receptor 2 (PROKR2) were shown to cause several autosomal forms of the syndrome.5,6
Ten years ago, we and others reported normosmic cases of IHH that were caused by loss-of-function mutations of the GnRH-receptor gene.7-9 However, GnRH-receptor mutations accounted for only a subgroup of familial normosmic IHH cases and a small fraction of sporadic cases, indicating that IHH is a heterogeneous condition caused by various genetic defects.1,2 More recently, loss-of-function mutations in the GPR54 gene (encoding G protein–coupled receptor 54)10,11 and in the TAC3 gene (encoding neurokinin B) and its receptor gene (TAC3R)12 have been reported in patients with IHH, thus expanding the known genetic causes of the disorder and indicating that these genes encode essential factors for normal GnRH release and for the initiation of puberty. However, it appears that mutations in known genes account for only a fraction of cases of IHH and that other genes probably remain to be discovered.
An obvious candidate gene for normosmic IHH has been GNRH1, which is located at 8p21–8p11.2. Indeed, in the hypogonadal (hpg) mouse model, hypogonadotropic hypogonadism is linked to a homozygous deletion within the Gnrh1 gene.13 Gene therapy completely reverses the hypogonadal phenotype and restores GnRH expression in hpg mice.14 However, despite the efforts of several teams, no genetic alteration had been reported in the GNRH1 gene12,15-20 in patients with IHH. We describe a family in which IHH was associated with a homozygous frameshift mutation of the GNRH1 gene that completely deleted the GnRH decapeptide sequence.
Case Reports
In a family originating from a Transylvanian mountain village in Romania, two of four children of nonconsanguineous parents were found to have IHH. The index case was a young man (Subject II-1) who was referred at 18 years of age because pubertal development had not occurred (Figure 1AFigure 1
Family Pedigree and Phenotypic Presentation., photo on left). He had typical signs of complete hypogonadism, with small intrascrotal testes (1 ml), no pubic hair (P1), and a microphallus. His height was 162 cm (5 ft 4 in.), his weight 54 kg (119 lb), and his bone age 13.0 years. He had a normal sense of smell on olfactometry21 and had no renal or craniofacial abnormalities. His karyotype was 46,XY. His affected sister (Subject II-4), who was evaluated at 17 years of age (Figure 1A, photo on right), also had complete hypogonadism and a normal sense of smell on olfactometry. She had no breast development and no pubic hair, and menarche had not occurred. Pelvic sonography showed a small uterus (28 mm) and two small ovaries (right, 1.1 ml; left, 1.0 ml), with no visible follicles. Her karyotype was 46,XX. Hormone assays revealed very low plasma testosterone levels in the affected brother and an almost undetectable plasma estradiol level in the affected sister; both siblings had very low levels of plasma gonadotropin and normal levels of prolactin (Table 1Table 1
Hormonal Data for Family Members of the Index Subjects.).Both affected siblings had a blunted response to GnRH bolus administration (100 μg intravenously) but otherwise had normal function of the anterior pituitary, thyroid, and adrenal glands, along with normal levels of ferritin and serum insulin-like growth factor I and normal findings on magnetic resonance imaging of the pituitary and olfactory bulbs. Basal pulsatile luteinizing hormone secretion was evaluated overnight at 10-minute intervals for 6 hours in Subject II-4. She had nonpulsatile luteinizing hormone secretion, but luteinizing hormone pulses, occurring synchronously with GnRH boluses, were detected on day 13 of pulsatile GnRH administration (Figure 1B). Pulsatile GnRH administration also resulted in increased circulating levels of estradiol and inhibin B and in the recruitment of a single dominant follicle of 14 mm seen on ultrasonography. Both pulsatility studies were performed with the patient's written informed consent, in keeping with the provisions of the Declaration of Helsinki and after approval by the local ethics committee.
The unaffected brother (Subject II-2) had normal pubertal development, as did the unaffected sister (Subject II-3), who also had spontaneous regular menses. In the mother (Subject I-2), the onset of menarche had occurred at the age of 13 years; she reported having had spontaneous regular menses, unassisted conception, and normal pregnancies. The father (Subject I-1) reported having had normal pubertal development. The four unaffected family members all had a normal sense of smell on olfactometry and also normal sex steroid and gonadotropin levels (Table 1).
Methods
Hormone Assays
We measured serum levels of luteinizing hormone, follicle-stimulating hormone, and inhibin B and plasma levels of testosterone and estradiol using immunoradiometric assay, enzyme-linked immunosorbent assay, or radioimmunoassay, as reported previously.21,22 Prolactin levels were determined as described in Table 1.
DNA Analysis
All the case subjects and control subjects provided written informed consent for genetic analysis, which was approved by the local ethics committees at hospitals in Cluj-Napoca, Romania, and Le Kremlin-Bicêtre, France. Genomic DNA was isolated from white cells. We sequenced the coding regions of the GnRH-receptor type 1 (GNRHR1) gene, GPR54, the KiSS-1 metastasis-suppressor (KISS1) gene, and FGFR1 from samples obtained from the case subjects, as described previously with minor modifications.5,7,9,10,23 We also sequenced coding regions of the gonadotropin-releasing hormone 2 (GNRH2) gene to rule out involvement of this gene in the phenotype (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Direct genomic sequencing of coding exons and intron–exon junctions of GNRH1 was performed as described in the Supplementary Appendix. The mutation thus detected was confirmed independently on a second polymerase-chain-reaction (PCR) assay. We also screened 445 control subjects for the mutation, including 100 unrelated white eugonadal subjects, 145 unrelated white subjects with sporadic normosmic IHH, and 200 white eugonadal subjects who were ancestrally matched with the case family (i.e., of Romanian origin from the family's village). In all the family members, 11 variable-number tandem repeats were analyzed to evaluate the size of the homozygous segment around the mutation locus (see the Methods section in the Supplementary Appendix).
In Vitro Analysis of the GNRH1 Mutation
The c.18-19insA GnRH1 mutant expression construct was generated by PCR with the human GnRH1, transcript variant 1 cloned in to the pCMV6-XL5 expression vector (SC300137, OriGene) and the Phusion Site-Directed Mutagenesis Kit (Finnzymes Oy, Finland) in accordance with the manufacturer's directions (see the Supplementary Appendix). Empty-vector, wild-type, and mutant GnRH1 expression constructs were transfected into mouse pituitary-tumor AtT20 cells.24 GnRH was measured in the supernatant by radioimmunoassay, as described previously.25
Results
Homozygous GNRH1 Mutation
In GNRHR1, GPR54, KISS1, FGFR1, and GNRH2, gene exons and intron–exon boundaries in the affected male family member (Subject II-1) were identical to reference sequences. In this subject and his affected sister (Subject II-4), sequencing of the GNRH1 coding sequence revealed a homozygous insertion of an adenine at nucleotide position 18 (c.18-19insA mutation), resulting in a frame shift (Figure 2AFigure 2
Molecular Characterization and Functional Consequences of the c.18-19insA GNRH1 Mutation.). This translated defect would result in an aberrant peptide starting at amino acid 7. This aberrant peptide with a truncated peptide-signal sequence devoid of its hydrophobic core lacks the normal GnRH decapeptide sequence and has a total length of 42 amino acids instead of the 92 amino acids of the normal prepro-GnRH peptide (Figure 2B).Both parents were heterozygous for the mutation, as was the unaffected sister. The unaffected brother had no mutation. The frameshift mutation was not found in 200 chromosomes from eugonadal control subjects or in 290 chromosomes from unrelated control subjects with sporadic normosmic IHH. In the 200 ancestrally matched control subjects, one subject was heterozygous for the c.18-19insA mutation. Variable-number tandem-repeat analysis was used to construct a haplotype surrounding the GNRH1 gene. We then studied haplotype transmission within the family and found a homozygous block of 10.2 to 16 Mb in the two affected siblings. Moreover, the control subject carrying the heterozygous c.18-19insA mutation had a haplotype overlapping this homozygous segment (see the Supplementary Appendix).
Mutation Expression in AtT20 Pituitary Cells
The effect of the c.18-19insA mutation was examined by expressing this mutant in AtT20 pituitary cells and comparing it with the wild-type GnRH1 vector and an empty-vector control. GnRH1 (104±31 pg per milliliter) was detected in conditioned medium by wild-type GnRH1 transfected cells, indicating that AtT20 cells are capable of processing and secreting the GnRH peptide. In contrast, GnRH was undetectable in medium conditioned by the c.18-19insA-mutant transfected cells and in the medium of cells transfected with the empty vector (Figure 2C).
Discussion
In a family of subjects with nonsyndromic and normosmic IHH, we used a candidate-gene approach to identify a mutation in the GNRH1 gene in two of the siblings, a teenage brother and sister with normosmic IHH. Both index subjects had complete hypogonadism and sexual infantilism. The severity of gonadotropin deficiency was confirmed by very low levels of sex steroids and plasma gonadotropins in both siblings. The pituitary response to exogenous pulsatile GnRH was studied in the affected sister, giving us the opportunity to distinguish between hypothalamic and pituitary hypogonadotropism. Endogenous luteinizing hormone pulsatility was restored by GnRH administration, suggesting a hypothalamic origin of the gonadotropin deficiency and normal responsiveness of pituitary gonadotrope cells to the neuropeptide in this genetic form of IHH, in keeping with GnRH deficiency.
Both index subjects were homozygous for the mutation, whereas their unaffected parents and sister were heterozygous and had a normal phenotype. The disorder was thus transmitted as an autosomal recessive trait. This suggests that one copy of the GNRH1 gene is sufficient for normal GnRH secretion and for normal function of the gonadotropic axis, thus ruling out haploinsufficiency. In addition, in the heterozygous state, the mutation does not have a dominant negative effect. Because the family reported having had no consanguinity and since no GNRH1 mutation has been found to date (indicating a very rare germinal event), we hypothesized that this homozygous mutation results from a founding event in a more distant common ancestor. This possibility was tested by means of haplotype analysis, which defined a homozygous segment from which we could estimate the founding event 8 to 50 generations ago26 (see the Supplementary Appendix). Such a founding event is further confirmed by the fact that an unaffected, ancestrally matched control subject carrying the heterozygous c.18-19insA mutation shared part of this haplotype.
The normal prepro-GnRH1 peptide consisting of 92 amino acids contains in its N-terminal region a signal peptide (amino acids 1 through 23)27 characterized by a hydrophobic core that is required for targeting to the endoplasmic reticulum. This signal peptide is separated from the GnRH decapeptide by two serine residues. The signal peptide is cleaved, and the propeptide is delivered to the endoplasmic reticulum, where it is cleaved by a convertase between amino acids 33 and 34 at a GKR sequence, producing the active decapeptide GnRH127,28 (Figure 2B). If the frameshift mutation that we identified is translated, it leads to a putative aberrant peptide of 42 amino acids, completely lacking the GnRH1 peptide sequence, including the highly conserved amino acid residues crucial for binding to and activating pituitary GnRH receptor 1.27,28 The main predictable consequence of the homozygous mutation is defective endogenous GnRH synthesis and defective secretion into hypothalamic–pituitary portal blood by GnRH neurons, thus accounting for the total gonadotropin deficiency observed in the two index subjects. In addition, the aberrant peptide, if translated, is likely to be trapped within the cell.29 This mechanism could prevent its extracellular release and subsequent secretion into the portal blood flow. To confirm the functional consequences of the c.18-19insA GNRH1 mutation, we expressed the mutant or the wild-type expression constructs in AtT20 cells. Although the wild-type GNRH1 expression plasmid produced robust amounts of GnRH, no significant GnRH peptide expression was detected in the c.18-19insA mutant construct, demonstrating the inability of the mutant to generate the normal decapeptide.
Twenty years ago, the GnRH-associated peptide (GAP), which is encoded by GNRH1,27,28 was reported to be a potent inhibitor of prolactin secretion in cultures of rat pituitary cells, and active immunization with peptides corresponding to GAP sequences was shown to increase prolactin secretion in rabbits.30 It is noteworthy that the two subjects described here had normal plasma prolactin levels despite carrying homozygous frameshift mutations that led to the putative translation of an aberrant peptide, also completely lacking the GAP peptide sequence. Our data indicate that in the physiologic state in humans, as reported in sheep,31 GAP or putative processed GAP peptides do not act on the pituitary gland to regulate prolactin secretion.
Although most patients with normosmic IHH appear to be deficient in GnRH, as suggested by their generally normal gonadotropin responses to exogenous GnRH, no defects had previously been identified in the gene encoding GnRH (GNRH1). Likewise, we found no mutations in GNRH1 in 145 patients with sporadic IHH. In keeping with previous reports,12,15-20 GNRH1 mutations are probably very rare, implying that other developmental, environmental, or genetic factors can cause IHH. Finally, our results demonstrate the absence of redundancy between GNRH1 and GNRH2 in the reproductive cascade, despite their reported coexpression in certain human neuronal cell lines.32 In conclusion, the GNRH1 mutation reported here appears to be a unique example of a genetic aberration causing complete inactivation of a human hypothalamic hypophysiotropic neurohormone gene.
Supported in part by a grant from the University Paris Sud 11 (Bonus Qualité Recherche).
Dr. Young reports receiving grant support from Ferring and Merck Serono France. No other potential conflict of interest relevant to this article was reported.
Drs. Bouligand and Ghervan and Drs. Guiochon-Mantel and Young contributed equally to this article.
This article (10.1056/NEJMoa0900136) was published on June 17, 2009, at NEJM.org.
This article is dedicated to Roger Guillemin and to the memory of Ernst Knobil.
We thank S. Amselem, B. Fève, Y. Lebouc, E. Milgrom, C. Dodé, and M. Jeanpierre for their helpful discussions and C. Cogliatti and I. Boucly for their technical assistance.
Source Information
From Université Paris-Sud, Faculté de Médecine Paris-Sud and Assistance Publique–Hôpitaux de Paris, Hôpital de Bicêtre, INSERM UMR-S693, Paris (J.B., S.B.-T., P.C., M.L., A.G.-M., J.Y.); Laboratoire de Génétique Moléculaire, Pharmacogénétique et Hormonologie (J.B., S.B.-T., A.G.-M.), and Service d'Endocrinologie et des Maladies de la Reproduction and Centre de Référence des Maladies Endocriniennes Rares de la Croissance (S.S., P.C., M.L., J.Y.) — all in Le Kremlin-Bicêtre, France; the Endocrinology Department, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania (C.G.); the Medical Research Council Human Reproductive Sciences Unit, the Queen's Medical Research Institute, Edinburgh (J.A.T., R.P.M.); and the Research Group for Receptor Biology, Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa (R.P.M.).
Address reprint requests to Dr. Young at the Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France, or at jacques.young@bct.aphp.fr.
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