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A Recurrent Missense Mutation in the KAL Gene in Patients with X-Linked Kallmann’s Syndrome¹

Research Unit in Developmental Biology, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguo Social (G.M.-N., J.P.M.); the Department of Genetics, Hospital General de México, Secretaria de Salud; Faculty of Medicine, Universidad Nacional Autonoma de Mexico (J.C.Z., S.K.-A.); and the Department of Reproductive Biology, Instituto Nacional de la Nutrición Salvador Zubirán (A.U.-A.), Mexico City, Mexico

Address all correspondence and requests for reprints to: Juan Pablo Méndez, M.D., Coordinación de Investigación Médica, Unidad de Investigación Médica en Biología del Desarrollo, Avenida Cuauhtémoc 330, Apartado Postal 73–032, Colonia Doctores, C.P. 06725, Mexico DF, Mexico. E-mail: jpmb{at}servidor.unam.mx

Kallmann’s syndrome (KS) is defined by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. Segregation analysis in familial cases has demonstrated diverse inheritance patterns, suggesting the existence of several genes regulating GnRH secretion. Genetic defects have been demonstrated in the KAL gene, located on the Xp22.3 region, explaining the X-linked form of the disease. We report molecular findings regarding the KAL gene in 12 unrelated males with X-linked KS.

PCR of the 14 exons of the KAL gene was performed on genomic DNA. PCR products of all exons were purified and sequenced. Genetic defects in the KAL gene were found in 7 patients. One exhibits a deletion from exon 3 to exon 5. Six individuals present a previously unidentified missense mutation in exon 11, consisting of a G to A substitution at codon 514 (GAA to AAA). In the remaining 5 individuals, no mutations were observed. We also found three different polymorphic changes. The first one, in exon 2, had not been reported previously. The other two were located at exons 11 and 12.

The deletion described, comprises only part (exon 5) of the coding region of the first fibronectin type III-like repeat of the KAL protein. The rest of the deletion comprises part of the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif. The same missense mutation was found in 6 of the 12 patients, indicating the possibility that it derived from a common ancestor or suggesting the presence of a hot spot in this region of the gene.

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