This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart 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 Georgopoulos, N. A. Articles by Vallejo, M. Search for Related Content PubMed PubMed Citation Articles by Georgopoulos, N. A. Articles by Vallejo, M.

Genetic Heterogeneity Evidenced by Low Incidence of KAL-1 Gene Mutations in Sporadic Cases of Gonadotropin-Releasing Hormone Deficiency¹

Reproductive Endocrine Sciences Center and National Center for Infertility Research at Massachusetts General Hospital (N.A.G., F.P.P., W.F.C., M.V.), and the Department of Genetics and Howard Hughes Medical Institute (C.E.S., J.G.S.), Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Mario Vallejo, M.D., Ph.D., Reproductive Endocrine Unit, BHX-516, Massachusetts General Hospital, Boston, MA 02114, Phone: 617-726-5384, Fax: 617-726-5357.

Isolated GnRH deficiency is a heritable condition characterized by a functional deficit in GnRH secretion. Familial cases with different modes of inheritance have been described, and the gene responsible for the X-linked form (KAL-1) has been identified. However, sporadic cases with no documented family history of GnRH deficiency account for the majority of the affected patients. For this reason, we sought to determine the frequency with which KAL-1 gene mutations occur in patients with sporadic GnRH deficiency. Only 1 of 21 patients with sporadic GnRH deficiency was found to bear a defect in the KAL-1 gene (a deletion of 14 bases starting at codon 464). Three types of polymorphic single base substitutions with no apparent correlation with GnRH deficiency were also detected in several patients. In each of 3 different patients with an X-linked mode of inheritance, 3 genetic defects, 2 point mutations and a small intragenic deletion, were detected. These defects consist of a single base mutation introducing a stop codon at position 328, a single base mutation resulting in a phenylalanine to leucine substitution at position 517, and a 9-base deletion at the 3'-exon-intron splice site of exon 8, respectively. All identified genetic defects occur within the fibronectin type III repeats of the predicted protein encoded by the KAL-1 gene. In conclusion, our study indicates that the incidence of genetic defects within the coding region of the KAL-1 gene in patients with sporadic GnRH deficiency is low (5–8%), thus supporting the idea that the X-linked form of inheritance represents the least common form of the disease.

This article has been cited by other articles:

				B. Bhagavath, N. Xu, M. Ozata, R. L. Rosenfield, D. P. Bick, R. J. Sherins, and L. C. Layman KAL1 mutations are not a common cause of idiopathic hypogonadotrophic hypogonadism in humans Mol. Hum. Reprod., March 1, 2007; 13(3): 165 - 170*. [Abstract] [Full Text] [PDF]

				F. Cerrato, J. Shagoury, M. Kralickova, A. Dwyer, J. Falardeau, M. Ozata, G. Van Vliet, P. Bouloux, J. E Hall, F. J Hayes, et al. Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S3 - S10. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition Endocr. Rev., April 1, 2006; 27(2): 101 - 140. [Abstract] [Full Text] [PDF]

				E. B Trarbach, M. T M Baptista, H. M Garmes, and C. Hackel Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients J. Endocrinol., December 1, 2005; 187(3): 361 - 368. [Abstract] [Full Text] [PDF]

				M.-H. Gannage-Yared, C. Dode, I. Ghanem, E. Chouery, N. Jalkh, J.-P. Hardelin, and A. Megarbane Coexistence of Kallmann syndrome and complete androgen insensitivity in the same patient Eur. J. Endocrinol., June 1, 2005; 152(6): 813 - 817. [Abstract] [Full Text] [PDF]

				N. Sato, N. Katsumata, M. Kagami, T. Hasegawa, N. Hori, S. Kawakita, S. Minowada, A. Shimotsuka, Y. Shishiba, M. Yokozawa, et al. 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., March 1, 2004; 89(3): 1079 - 1088. [Abstract] [Full Text] [PDF]

				A. Ulloa-Aguirre, J. A. Janovick, A. Leanos-Miranda, and P. M. Conn Misrouted cell surface GnRH receptors as a disease aetiology for congenital isolated hypogonadotrophic hypogonadism Hum. Reprod. Update, March 1, 2004; 10(2): 177 - 192. [Abstract] [Full Text] [PDF]

				P. M. Conn, A. Leanos-Miranda, and J. A. Janovick Protein Origami: Therapeutic Rescue of Misfolded Gene Products Mol. Interv., September 1, 2002; 2(5): 308 - 316. [Abstract] [Full Text] [PDF]

				J. A. Janovick, G. Maya-Nunez, and P. M. Conn Rescue of Hypogonadotropic Hypogonadism-Causing and Manufactured GnRH Receptor Mutants by a Specific Protein-Folding Template: Misrouted Proteins as a Novel Disease Etiology and Therapeutic Target J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3255 - 3262. [Abstract] [Full Text] [PDF]

				S. N. Kalantaridou and G. P. Chrousos Monogenic Disorders of Puberty J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2481 - 2494. [Full Text] [PDF]

				D. Soderlund, P. Canto, and J. P. Mendez Identification of Three Novel Mutations in the KAL1 Gene in Patients with Kallmann Syndrome J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2589 - 2592. [Abstract] [Full Text] [PDF]

				G. Maya-Nunez, J. A. Janovick, A. Ulloa-Aguirre, D. Soderlund, P. M. Conn, and J. P. Mendez Molecular Basis of Hypogonadotropic Hypogonadism: Restoration of Mutant (E90K) GnRH Receptor Function by a Deletion at a Distant Site J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2144 - 2149. [Abstract] [Full Text] [PDF]

				L C Layman Human gene mutations causing infertility J. Med. Genet., March 1, 2002; 39(3): 153 - 161. [Abstract] [Full Text] [PDF]

				E. I. Rugarli, E. Di Schiavi, M. A. Hilliard, S. Arbucci, C. Ghezzi, A. Facciolli, G. Coppola, A. Ballabio, and P. Bazzicalupo The Kallmann syndrome gene homolog in C. elegans is involved in epidermal morphogenesis and neurite branching Development, January 3, 2002; 129(5): 1283 - 1294. [Abstract] [Full Text] [PDF]

				N. Pitteloud, F. J. Hayes, P. A. Boepple, S. DeCruz, S. B. Seminara, D. T. MacLaughlin, and W. F. Crowley Jr. The Role of Prior Pubertal Development, Biochemical Markers of Testicular Maturation, and Genetics in Elucidating the Phenotypic Heterogeneity of Idiopathic Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 152 - 160. [Abstract] [Full Text] [PDF]

				L. M. B. Oliveira, S. B. Seminara, M. Beranova, F. J. Hayes, S. B. Valkenburgh, E. Schipani, E. M. F. Costa, A. C. Latronico, W. F. Crowley Jr., and M. Vallejo The Importance of Autosomal Genes in Kallmann Syndrome: Genotype-Phenotype Correlations and Neuroendocrine Characteristics J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1532 - 1538. [Abstract] [Full Text]

				Mutational Analysis of DAX1 in Patients with Hypogonadotropic Hypogonadism or Pubertal Delay J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4497 - 4500. [Abstract] [Full Text]

				F. P. Pralong, F. Gomez, E. Castillo, S. Cotecchia, L. Abuin, M. L. Aubert, L. Portmann, and R. C. Gaillard Complete Hypogonadotropic Hypogonadism Associated with a Novel Inactivating Mutation of the Gonadotropin-Releasing Hormone Receptor J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3811 - 3816. [Abstract] [Full Text] [PDF]

				J. W. Persson, K. Humphrey, C. Watson, P. Taylor, D. Leigh, B. McDonald, and I. S. Fraser Investigation of a unique male and female sibship with Kallmann's syndrome and 46,XX gonadal dysgenesis with short stature Hum. Reprod., May 1, 1999; 14(5): 1207 - 1212. [Abstract] [Full Text] [PDF]

				D. P. Merke, T. Tajima, J. Baron, and G. B. Cutler Hypogonadotropic Hypogonadism in a Female Caused by an X-Linked Recessive Mutation in the DAX1 Gene N. Engl. J. Med., April 22, 1999; 340(16): 1248 - 1252. [Full Text] [PDF]

				M. Krams, R. Quinton, J. Ashburner, K. J. Friston, R. S. J. Frackowiak, P.-M. G. Bouloux, and R. E. Passingham Kallmann's syndrome: Mirror movements associated with bilateral corticospinal tract hypertrophy Neurology, March 1, 1999; 52(4): 816 - 816. [Abstract] [Full Text]

				S. B. Seminara, F. J. Hayes, and W. F. Crowley Jr. Gonadotropin-Releasing Hormone Deficiency in the Human (Idiopathic Hypogonadotropic Hypogonadism and Kallmann's Syndrome): Pathophysiological and Genetic Considerations Endocr. Rev., October 1, 1998; 19(5): 521 - 539. [Abstract] [Full Text]

				G. Maya-Nuñez, J. C. Zenteno, A. Ulloa-Aguirre, S. Kofman-Alfaro, and J. P. Mendez A Recurrent Missense Mutation in the KAL Gene in Patients with X-Linked Kallmann's Syndrome J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1650 - 1653. [Abstract] [Full Text]

				L. B. Nachtigall, P. A. Boepple, F. P. Pralong, and W. F. Crowley Adult-Onset Idiopathic Hypogonadotropic Hypogonadism -- A Treatable Form of Male Infertility N. Engl. J. Med., February 6, 1997; 336(6): 410 - 415. [Abstract] [Full Text] [PDF]