Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome

Hardelin, Jean-Pierre; Levilliers, Jacqueline; Blanchard, Stéphane; Carel, Jean-Claude; Leutenegger, Marc; Pinard-Bertelletto, Jean-Pierre; Bouloux, Pierre; Petit, Christine

doi:10.1093/hmg/2.4.373

Cited by 203Hypothalamic control of reproductive hormonesGenetic and Clinical Aspects of Sex Determination and Chromosomal AbnormalitiesSexual Differentiation and Disorders

Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome

Hardelin, Jean-Pierre, Levilliers, Jacqueline, Blanchard, Stéphane, Carel, Jean-Claude, Leutenegger, Marc, Pinard-Bertelletto, Jean-Pierre, Bouloux, Pierre, Petit, Christine·1993·Human Molecular Genetics

DOI 10.1093/hmg/2.4.373

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Abstract

Kallmann syndrome represents the association of hypogonadotropic hypogonadism with anosmia. Three modes of transmission, X chromosome-linked, autosomal recessive and autosomal dominant, have been described. The KAL gene, responsible for the X-linked form of the disease, has been isolated and its intron-exon organization recently determined. We have searched for mutations of the KAL gene in 21 unrelated males affected by familial Kallmann syndrome. In these families, segregation of the disease was suggestive of the X-linked mode of transmission. In 2 families, large Xp22.3 deletions, both including the entire KAL gene, have been detected by Southern blot analysis. Here we report the sequence analysis of the entire coding region of the KAL gene in the 19 remaining patients. The approach consisted of sequencing each of the 14 coding exons and splice site junctions. Each exon was amplified by PCR on the genomic DNA, using oligonucleotides from the flanking intronic sequences as specific primers. Nine point mutations were identified at separate locations in four exons and one splice site, providing strong evidence for heterogeneity in mutations responsible for the X-linked Kallmann syndrome. In addition, the high frequency of unilateral renal aplasia in X-linked Kallmann patients (6 out of 11 males with identified alterations of the KAL gene) should be emphasized.

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KAL1 mutations are present in approximately 5-10% of patients with Kallmann syndrome, with the highest prevalence in families with X-linked inheritance.
“Mutations in KAL1 disrupt the migration of olfactory and GnRH neurons and are reported to be present in approximately 5–10% of patients with Kallmann syndrome (Table 1),7,9–11 with the highest prevalence seen in families with X-linked inheritance patterns.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [10]
Mutations in KAL1 disrupt the migration of olfactory and GnRH neurons.
“Mutations in KAL1 disrupt the migration of olfactory and GnRH neurons”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [10]

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Fechner, A. J., Fong, S., & McGovern, P. G. (2008) · Obstetrical & Gynecological Survey · doi:10.1097/ogx.0b013e3181641278 · Cited by 57 · see citing works
Clinical Manifestations of Impaired GnRH Neuron Development and Function
Kim, H., Bhagavath, B., & Layman, L. C. (2008) · Neurosignals · doi:10.1159/000111561 · Cited by 51 · see citing works
Genetic Analysis in Patients With Kallmann Syndrome: Coexistence of Mutations in Prokineticin Receptor 2 and KAL1
Canto, P., Munguía, P., Söderlund, D., Castro, J. J., & Méndez, J. P. (2008) · Journal of Andrology · doi:10.2164/jandrol.108.005314 · Cited by 51 · see citing works
A Recurrent Missense Mutation in the KAL Gene in Patients with X-Linked Kallmann’s Syndrome1
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The genetic basis of female reproductive disorders: Etiology and clinical testing
Layman, L. C. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.02.016 · Cited by 47 · see citing works
“This has clinical relevance in affected patients as up to 50% of males with KAL1 mutations may have unilateral renal agenesis (Hardelin et al., 1993).”
Background
Familial gonadotropin-releasing hormone resistance and hypogonadotropic hypogonadism in a family with multiple affected individuals
Layman, L. C., McDonough, P. G., Cohen, D., Maddox, M., Tho, S. P. T., & Reindollar, R. H. (2001) · Fertility and Sterility · doi:10.1016/s0015-0282(01)01782-4 · Cited by 46 · see citing works
Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients
Trarbach, E. B., Baptista, M. T. M., Garmes, H. M., & Hackel, C. (2005) · Journal of Endocrinology · doi:10.1677/joe.1.06103 · Cited by 46 · see citing works
“…to the flanking regions of the KAL-1 and GnRH-R exons, sizes of the amplified products and amplification conditions were as reported by Hardelin et al. (1993) and Beranova et al. (2001) respectively, and those for NELF (NM_015537) and EBF2 (NM_022659) are shown in Tables 2 and 3…”
BackgroundMethod
Biochemical dissection of Anosmin‐1 interaction with FGFR1 and components of the extracellular matrix
Murcia‐Belmonte, V., Esteban, P. F., García‐González, D., et al. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07024.x · Cited by 41 · see citing works
Identification of Three Novel Mutations in the KAL1 Gene in Patients with Kallmann Syndrome
Söderlund, D., Canto, P., & Méndez, J. P. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.6.8611 · Cited by 41 · see citing works
An ancient founder mutation in PROKR2 impairs human reproduction
Stefanija, M. A., Jeanpierre, M., Sykiotis, G. P., Young, J., Quinton, R., Abreu, A. P., Plummer, L., Au, M., Balasubramanian, R., Dwyer, A. A., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds264 · Cited by 38 · see citing works
“PROKR2 mutations have been implicated in diverse oligogenic interactions, including mutations in other genes regulating GnRH neuron ontogeny such as PROK2, KAL1 and FGFR1 (11,12,15–17,34).”
BackgroundInfluential
Molecular modelling and experimental studies of mutation and cell-adhesion sites in the fibronectin type III and whey acidic protein domains of human anosmin-1
Robertson, A. N., MacCOLL, G. S., Nash, J. A. B., et al. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3570647 · Cited by 40 · see citing works
Self-citation
Contiguous gene syndrome due to deletion of the first three exons of the Kallmann gene and complete deletion of the steroid sulphatase gene
Maya‐Núñez, G., Cuevas‐Covarrubias, S. A., Zenteno, J. C., et al. (1998) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1998.00406.x · Cited by 40 · see citing works
KAL1 mutations are not a common cause of idiopathic hypogonadotrophic hypogonadism in humans
Bhagavath, B., Xu, N., Özata, M., et al. (2007) · Molecular Human Reproduction · doi:10.1093/molehr/gal108 · Cited by 39 · see citing works
“Initially, gene deletions were identified by Southern blot analysis (Bick et al., 1992), but a variety of point mutations were later characterized ( Hardelin et al., 1993 ).”
BackgroundMethodInfluential
Novel Insights into the Aetiology and Pathogenesis of Hypopituitarism
Dattani, M. (2004) · Hormone Research in Paediatrics · doi:10.1159/000080493 · Cited by 39 · see citing works
Novel insights in FGFR1 regulation: lessons from Kallmann syndrome
Hu, Y., & Bouloux, P.-M. G. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.01.004 · Cited by 38 · see citing works
Self-citation
Greater prevalence of PROKR2 mutations in Kallmann syndrome patients from the Maghreb than in European patients
Sarfati, J., Fouveaut, C., Leroy, C., Jeanpierre, M., Hardelin, J., & Dodé, C. (2013) · European Journal of Endocrinology · doi:10.1530/eje-13-0419 · Cited by 37 · see citing works
Self-citation
Perspective: The Importance of Genetic Defects in Humans in Elucidating the Complexities of the Hypothalamic-Pituitary-Gonadal Axis
Seminara, S. B., & Crowley, W. F. (2001) · Endocrinology · doi:10.1210/endo.142.6.8261 · Cited by 39 · see citing works
“Mutation analysis of patients with Xlinked Kallmann syndrome has revealed a spectrum of coding sequence abnormalities (40, 41).”
Background
Genetics of hypogonadotropic Hypogonadism—Human and mouse genes, inheritance, oligogenicity, and genetic counseling
Louden, E. D., Poch, A., Kim, H., Ben‐Mahmoud, A., Kim, S., & Layman, L. C. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111334 · Cited by 34 · see citing works
Renal dysgenesis and KAL1 gene defects in patients with sporadic Kallmann syndrome
Georgopoulos, N. A., Koika, V., Galli‐Τsinopoulou, A., et al. (2007) · Fertility and Sterility · doi:10.1016/j.fertnstert.2006.12.044 · Cited by 35 · see citing works
The Role of Prokineticins in the Pathogenesis of Hypogonadotropic Hypogonadism
Abreu, A. P., Kaiser, U. B., & Latronico, A. C. (2010) · Neuroendocrinology · doi:10.1159/000308880 · Cited by 34 · see citing works
Mutations in human gonadotropin genes and their physiologic significance in puberty and reproduction
Layman, L. C. (1999) · Fertility and Sterility · doi:10.1016/s0015-0282(98)00431-2 · Cited by 31 · see citing works
Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism – a clinical perspective
Al-Sayed, Y., & Howard, S. R. (2022) · European Journal of Human Genetics · doi:10.1038/s41431-022-01261-0 · Cited by 34 · see citing works
“Thus, genes such as ANOS1 (MIM 300836) [33, 34], CHD7 (MIM 608892) [7, 35], FGFR1 (MIM 136350) [36, 37], PROKR2 (MIM 607123) [38, 39], GNRHR (MIM 138850) [38, 40], TACR3 (MIM 162332) [41, 42] – indeed the majority of these 14 genes – have been repeatedly validated in international cohorts of patients with CHH and KS,…”
Background
Inherited disorders of the gonadotropin hormones
Jameson, J. L. (1996) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(96)03950-0 · Cited by 32 · see citing works
Olfactory System and Demyelination
García‐González, D., Murcia‐Belmonte, V., Clemente, D., & Castro, F. D. (2013) · The Anatomical Record · doi:10.1002/ar.22736 · Cited by 31 · see citing works
“…and intoxication, tumors and skull-cephalic traumas, and the paradigmatic case of genetic anosmia with hypogonadotrophic hypogonadism: Kallmann syndrome (KS; Maestre de San Juan, 1856; Kallmann et al., 1944; Shepherd, 1988; Hardelin et al., 1993; Victor and Ropper, 2001; Dod e and Hardelin, 2009).”
Background
Genetic and Environmental Correlates of Semen Quality
Storgaard, L., Bonde, J. P., Ernst, E., et al. (2006) · Epidemiology · doi:10.1097/01.ede.0000239730.47963.4e · Cited by 31 · see citing works
Renal abnormalities in patients with Kallmann syndrome
Zenteno, Méndez, Maya‐Núñez, et al. (1999) · British Journal of Urology · doi:10.1046/j.1464-410x.1999.00027.x · Cited by 31 · see citing works
Patient described by Chun et al. may not present Antley-Bixler syndrome
Gorlin, R. J. (1999) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19990305)83:1 · Cited by 12 · see citing works
Clinical Genetic Testing for Kallmann Syndrome
Layman, L. C. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1624 · Cited by 29 · see citing works
“The identification of renal agenesis in the RSV-negative group is perhapsunexpectedbecause it hasbeenacommonfinding in males with KAL1 mutations (12).”
Background
X-linked GnRH deficiency: Role of KAL-1 mutations in GnRH deficiency
Hu, Y., & Bouloux, P.-M. G. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.04.001 · Cited by 29 · see citing works
Self-citation
Expanding the genetic spectrum ofANOS1mutations in patients with congenital hypogonadotropic hypogonadism
Gonçalves, C. I., Fonseca, F., Borges, T., et al. (2016) · Human Reproduction · doi:10.1093/humrep/dew354 · Cited by 29 · see citing works
“Primer sequences were previously described (Hardelin et al., 1993), except for the forward primer for exon 1 (5’-TGGGAGGGAGGTCGGCGAGGAGGG-3’) and the reverse primer for exon 10 (5’-GTGAATGGATAAAAGAATGAGTGA-3’), which were designed using Primer 3 Plus (Untergasser et al., 2007).”
Method
The Molecular Basis of Human Hypogonadotropic Hypogonadism
Layman, L. C. (1999) · Molecular Genetics and Metabolism · doi:10.1006/mgme.1999.2912 · Cited by 26 · see citing works
A novel mutation of the KAL1 gene in monozygotic twins with Kallmann syndrome
Matsuo, T., Okamoto, S., Izumi, Y., et al. (2000) · European Journal of Endocrinology · doi:10.1530/eje.0.1430783 · Cited by 29 · see citing works
ERK1/2 signaling is essential for the chemoattraction exerted by human FGF2 and human anosmin‐1 on newborn rat and mouse OPCs via FGFR1
Murcia‐Belmonte, V., Medina-Rodriguez, E. M., Bribián, A., de Castro, F., & Esteban, P. F. (2013) · Glia · doi:10.1002/glia.22609 · Cited by 29 · see citing works
“The E514K and F517L substitutions in FnIII.3 produce a 2-fold and a 6-fold reduced binding affinity to FGFR1 in vitro (Hu et al., 2009), or impede the binding of FnIII.3 (Murcia-Belmonte et al., 2010), canceling the chemotropic effect of anosmin-1 on GN11 cells and NPs (Cariboni et al., 2004; Murcia-Belmonte et al., 2…”
BackgroundInfluential
Anosmin-1 immunoreactivity during embryogenesis in a primitive eutherian mammal
Dellovade, T., Hardelin, J., Soussi‐Yanicostas, N., Pfaff, D. W., Schwanzel‐Fukuda, M., & Petit, C. (2003) · Developmental Brain Research · doi:10.1016/s0165-3806(02)00544-8 · Cited by 28 · see citing works
Self-citation
A Novel Nonsense Mutation of the KAL Gene in Two Brothers withKallmann Syndrome
Jansen, C., Hendriks-Stegeman, B. I., & Jansen, M. (2000) · Hormone Research in Paediatrics · doi:10.1159/000023568 · Cited by 28 · see citing works
“The coding exons of the KAL gene were subsequently amplified by polymerase chain reaction (PCR). The sequences of the KAL primers, the sizes of the amplified products and the PCR conditions were previously described by Hardelin et al. [”
Method
Report of the Fourth International Workshop on Human X Chromosome Mapping 1993 (Part 1 of 4)
Schlessinger, D., Willard, H. F., & Mandel, J. (2008) · Cytogenetics and Cell Genetics · doi:10.1159/000133572 · Cited by 27 · see citing works

The 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
Kallmann's Syndrome and Idiopathic Hypogonadotropic Hypogonadism
Zitzmann, M., & Nieschlag, E. (2004) · Elsevier eBooks · doi:10.1016/b0-12-475570-4/00788-5
Clinical Genetic Testing for Kallmann Syndrome
Layman, L. C. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1624 · Cited by 29 · see citing works
Clinicohormonal Parameters as a Primary Step to Differentiate Normosmic Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome in a Tertiary Care Hospital in Eastern India
Bhadra, R. C., Saha, D., & Baidya, A. (2021) · JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH · doi:10.7860/jcdr/2021/48672.15128
Congenital Hypogonadotropic Hypogonadism of Hypothalamic Origin
Rohayem, J., Tüttelmann, F., Nieschlag, E., & Behre, H. M. (2023) · Springer eBooks · doi:10.1007/978-3-031-31574-9_12 · Cited by 1 · see citing works

Authors: Hardelin, J.-P., Levilliers, J., Blanchard, S., Carel, J.-C., Leutenegger, M., Pinard-Bertelletto, J.-P., Bouloux, P., & Petit, C.
Affiliations: Centre National de la Recherche Scientifique (FR)
Hôpital Saint-Vincent-de-Paul (FR)
Royal Free London NHS Foundation Trust (GB)
Corresponding author: Petit, Christine
ORCID: Hardelin, Jean-Pierre
Carel, Jean-Claude
Petit, Christine
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 1993
Volume: 2
Issue: 4
Pages: 373-377
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/2.4.373
OpenAlex: W2153635587
Cited by: 203
References: 0
Citations by year: 2024: 1 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 2 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 10 · 2014: 4 · 2013: 10 · 2012: 5
FWCI: 7.49
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
HighWire Press Open Archive (submittedVersion)
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords: KAL1, hypogonadotropic hypogonadism, anosmia, mutational heterogeneity, point mutations, splice site mutation, renal aplasia, X-linked inheritance
MeSH terms: Amino Acid Sequence, Base Sequence, DNA, DNA Mutational Analysis, Humans, Genetic Linkage, Male, Molecular Sequence Data, Mutation, Oligodeoxyribonucleotides, X Chromosome, Point Mutation, Sequence Deletion, Kallmann Syndrome

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Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome

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