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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 6 2589-2592
Copyright © 2002 by The Endocrine Society

The Impact of the Human Genome on Endocrinology: Original Articles

Identification of Three Novel Mutations in the KAL1 Gene in Patients with Kallmann Syndrome

D. Söderlund, P. Canto and J. P. Méndez

Research Unit in Developmental Biology, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México, D.F., México 06725

Address all correspondence and requests for reprints to: Juan Pablo Méndez, M.D., Unidad de Investigación Médica en Biología del Desarrollo, Coordinación de Investigación Médica, Coahuila 5, Colonia Roma, C. P. 06703, Apartado Postal A-047 México, D. F., México 06725. E-mail: . jpmb{at}servidor.unam.mx

Abstract

Kallmann’s syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. Genetic defects have been observed throughout the KAL1 gene, located on the Xp22.3 region, in less than 50% of the patients. We report the molecular study of the KAL1 gene in 12 males with KS. PCR of the 14 exons of the KAL1 gene was performed on genomic DNA. PCR products of all exons were purified and sequenced. Three novel genetic defects were found. One patient exhibited a complete deletion of exon 5. The second presented a duplication of nucleotides 158–168; this insertion causes a termination codon (TGA) within the same exon. The third presented a mutation in exon 6, in which codon 262 changes from arginine to a stop codon. In the remaining nine individuals, no mutations were found. Three previously reported polymorphic changes were also documented. The deletion of exon 5 occurs within the region encoding the first fibronectin type III-like repeat of the KAL1 protein, this being the first KS patient who exhibits a complete deletion of a single exon of the KAL1 gene. The duplication of nucleotides in exon 1 is located in the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif, affecting the KAL1 protein either by interrupting the normal transcription or stopping the translation at the stop codon. The last novel mutation, a stop codon in exon 6, is located within the region encoding the first fibronectin type III-like repeat of the KAL1 protein. The absence of mutations in the majority of patients suggests the possibility of the existence of other genes involved or that in certain individuals the presence of various polymorphisms within the KAL1 gene could predispose to disease, as has been demonstrated in other pathological entities.

KALLMANN'S SYNDROME (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. This disorder is caused by a neuronal migration arrest involving both the olfactory and the GnRH-producing neurons (1). Migration of both types of neurons is detained within the meninges above the cribriform plate (2).

A gene (KAL1), which spans 210 kb of genomic DNA in Xp22.3, has 14 coding exons, escapes X inactivation, and has a nonfunctional homologue at Yq11.2. This gene encodes a protein that shares homology with molecules involved in neuronal migration and axonal path finding (3, 4). Several mutations that occur throughout the gene in patients bearing this defect have been identified (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15). However, in a large number of patients studied, no mutations have been found, suggesting that these may occur more likely in autosomal genes (8, 9, 10, 11, 16). A recent report by Oliveira et al. (15) strongly indicates that the majority of both familial and sporadic KS is either autosomal dominant or recessive in their etiology. Nevertheless, in an important percentage of patients with familial KS and proven X-linked kindreds, no mutations have been documented throughout the coding sequence of the KAL1 gene, suggesting that mutations may occur in noncoding regions of this gene or another X-linked gene is the cause of this disorder (1, 8, 11, 17).

Human KS is clinically and genetically heterogeneous; within a single sibship individuals bearing a complete KS, normosmic idiopathic hypogonadotropic hypogonadism and isolated anosmia have been reported (15, 16). Furthermore, in a report by Matsuo et al. (13), the study of male monozygotic twins with the same KAL1 mutation showed the presence of different phenotypes as well as different responses of LH and FSH to GnRH. On the basis of these findings, attempts to correlate genotype and phenotype have been unsuccessful.

In the present study, we report the molecular findings of 12 unrelated male patients with KS.

Subjects and Methods

Twelve unrelated males recently diagnosed with KS were studied. In four patients pedigree inspection revealed an apparent X-linked mode of inheritance. In the remaining probands, lack of accurate information made it impossible to determine the inheritance pattern. X-linked mode of transmission was determined in accordance with the following criteria: the presence of at least two affected males, absence of affected females, absence of male-to-male transmission, and absence of consanguinity. All individuals were of Mexican mestizo ethnic origin and from different geographic locations. Informed consent was obtained from all subjects participating in the study.

Patients ranged in age from 18–29 yr. Anosmia or hyposmia detected by performing the olfactory test described by Rosen et al. (18) had been present since early childhood. During adolescence there was absence of or subnormal pubertal development. The high resolution G-banded karyotype was 46,XY, and computed axial tomography of the hypothalamic-pituitary region did not demonstrate any disorder in any of the patients. The most outstanding clinical characteristics as well as the findings of the iv pyelograms of the patients are shown in Table 1Go.


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  		Table 1. Clinical characteristics and pyelogram findings in 12 patients with KS

 
In all patients hypogonadotropic hypogonadism was documented. Gonadotropin levels were always below the normal adult male range, and serum T concentrations were in the prepubertal range (<4.1 nmol/liter).

Baseline plasma levels of LH, FSH, and T were measured as described previously (10).

Genomic DNA was prepared from peripheral blood leukocytes by standard techniques (19). For each PCR amplification, genomic DNA (0.5–1.0 µg) in the presence of 0.1 mM dNTP, 2U Taq DNA polymerase (Ampli Taq, Perkin-Elmer Corp., Branchburg, NJ), and 250 nM of each specific set of KAL1 primers was used. The sequences of the KAL1 primers and splice site junctions, sizes of the amplified products, and PCR conditions were previously described by Hardelin et al. (20); dimethyl sulfoxide concentrations were slightly modified (10). Thirty cycles of PCR amplifications were performed in a Thermal Cycler (PE Applied Biosystems, Foster City, CA) with denaturation at 94 C for 1 min, annealing at 55–63 C for 1 min and extension at 72 C for 1 min.

PCR products of the 14 exons of the KAL1 gene were purified by QIAEX II (QIAGEN GmbH, Hilden, Germany). These products were then sequenced (300 nmol DNA template/reaction) on an ABI 377 automated DNA sequencer (PE Applied Biosystems) using the DNA sequencing kit BigDye Terminator Cycle Sequencing Ready Reaction (Perkin-Elmer Corp.). PCR conditions for cycle sequencing were identical to those described above. For all exons both strands were sequenced and compared.

Each mutation or sequence variation was confirmed in three independent PCR amplifications and sequencing.

Results

Genetic defects of the KAL1 gene were found in 3 of the 12 patients. A complete deletion of exon 5 was observed in patient 6; the remaining exons of the gene amplified in a normal fashion (Fig. 1Go).



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  		Figure 1. PCR amplification of exons 4–6 of the KAL1 gene in DNA from patient 6 (P) and a normal control (C). Deletion of exon 5 is observed in the patient’s DNA.

 
In patient 5, direct sequencing of the KAL1 gene revealed the presence of a novel mutation in exon 1. Nucleotides 158–168 were found to be duplicated. This 11-bp insertion caused a termination codon (TGA) within the same exon, 19 codons after the insertion (Fig. 2Go).



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  		Figure 2. Nucleotide sequence of part of exon 1 of the KAL1 gene in patient 5. Nucleotides 158–168 are duplicated. The insertion causes a frameshift and a premature termination codon (PTC), 19 codons after the insertion within the same exon.

 
A novel mutation was found in exon 6 of patient 12 where a C->T mutation changing codon 262 from CGA (arginine) to TGA (premature termination signal) was observed (Fig. 3Go). In the remaining nine individuals, no mutations were found.



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  		Figure 3. Point mutation detected in patient 12. Part of the corresponding exon 6 sequence is shown together with the normal sequence. The asterisk shows the C-to-T substitution at codon 262, which changes arginine into a premature termination codon.

 
Likewise, we observed three different polymorphic changes (codons 78, 534, and 611) which have been previously described by our group (11) in normal males in frequencies of 54%, 48%, and 24%, respectively. Seven patients exhibited all three polymorphisms, whereas two individuals had two polymorphisms and two others had one polymorphism.

Discussion

In 1991 Franco et al. (3) and Legouis et al. (4) described that the KAL1 gene was disrupted in patients with KS, whereas Bick et al. (5) described the first intragenic deletion of this gene in 1992. Since then, other authors (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) have found different mutations widely distributed throughout the 14 exons of the gene in patients with KS. However, in many of these reports, no mutations have been detected in approximately 50% of the patients studied (8, 9, 10, 11, 16). Because of the fact that even after analyzing basic genetic criteria, it is not always possible to distinguish correctly among different modes of genetic transmission (15), some associated anomalies in KS patients like mirror movements, unilateral renal agenesis, and synkinesia have been suggested to be specific of the X-linked form of the disease (8, 21, 22). Moreover, synkinesia has been proposed as a clinical marker of the X-linked form of KS (23). Taking this into consideration, in this study we included 12 patients in whom pedigree inspection revealed an apparent X-linked mode of inheritance in four of them, whereas in the remaining eight, synkinesia was documented; however, we found causal mutations of the KAL1 gene in only three of the patients studied.

The first molecular abnormality detected was a complete deletion of exon 5 observed in patient 6. This deletion occurred within the region encoding the first fibronectin type III-like repeat of the KAL1 protein, which is involved in processes of neuronal migration and axonal targeting (24). To our knowledge, this is the first KS patient who exhibited a complete deletion of a single exon of the KAL1 gene.

The second novel mutation was found in patient 5 who presented a duplication of nucleotides in exon 1. This 11-bp insertion caused a premature termination signal 19 codons after the duplication. This mutation is located in the conserved cysteine-rich N-terminal region, which corresponds to the whey acidic protein motif (3). The existing mutation may have affected the KAL1 protein by two means: either the insertion interrupted the normal transcription or the translation was stopped at the stop codon, resulting in the loss of stability of the truncated protein.

The third novel mutation was detected in patient 12, who at codon 262 (exon 6) presented a stop codon. As in the first mutation described above, this one was located within the region encoding the first fibronectin type III-like repeat of the KAL1 protein.

The absence of abnormalities in the KAL1 gene in 75% of the patients studied extend and confirm previous reports that the frequency of mutations in the coding sequence of the KAL1 gene is low. A recent report by Oliveira et al. (15) concluded that autosomal genes are clearly responsible for the majority of KS cases. However, it is still noteworthy that this percentage is still low even when an X-linked inheritance mode is strongly suggested and/or clinical characteristics specific of X-linked KS are present. Furthermore, in a previous report by our group, we could not demonstrate a KAL1 gene mutation in a family with X-linked KS associated with X-linked ichthyosis (17). On this basis, we can conclude that despite the fact that the majority of KS patients have an autosomal disorder, there are some X-linked KS patients in whom we have not determined the underlying cause of the disorder. The hypothesis of the existence of a second X-linked gene responsible for KS or the possibility that the existing defects are located in the regulatory regions of the KAL1 gene promoter, in the untranslated regions of exons 1 and 14 and within introns creating a new splice site cannot be ruled out.

Likewise, the presence of various polymorphic changes in affected individuals (five of the nonmutated patients had three polymorphisms, whereas two of them had two polymorphisms) should be noted. In this study, 9 of the 12 patients and 7 of the 9 individuals without a mutation exhibited two or more polymorphisms. In a previous study by our group, 8 of 12 patients exhibited more than one polymorphism, whereas only 26% of the controls had two polymorphic changes (11). The possibility that in certain individuals the presence of various polymorphisms within the KAL1 gene could predispose to disease should be considered, as has been demonstrated in hereditary elliptocytosis, Creutzfeldt-Jakob disease, diabetes mellitus type 2, IgA nephropathy, and rheumatoid arthritis (25, 26, 27, 28, 29, 30).

Acknowledgments

We thank Leonor Enciso from the Unidad de Instrumentos, Coordinación de Investigación Médica, Instituto Mexicano del Seguro Social, for technical assistance.

Footnotes

This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACyT), México, Grant G29790 M and Coordinación de Investigación Médica, Instituto Mexicano del Seguro Social, México Grant FP0038/788.

D.S. is a postgraduate student from the Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F.

Abbreviations: KS, Kallmann’s syndrome.

Received December 10, 2001.

Accepted March 10, 2002.

References

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