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1 Laboratório de Genética Humana, Centro de Biologia Molecular e Engenharia Genética (CBMEG), UNICAMP, Campinas, 13083970, São Paulo, Brazil
2 Disciplina de Endocrinologia, Departamento de Clínica Médica, Hospital das Clinicas, UNICAMP, Campinas, São Paulo, Brazil
3 Departamento de Genética Médica, Faculdade de Ciências Médicas, UNICAMP, Campinas, 13083970, São Paulo, Brazil
(Requests for offprints should be addressed to E B Trarbach, Hospital das Clínicas Faculdade de Medicina da Universidade de São Paulo, Disciplina de Endocrinologia e Metabologia, Av. Dr, Eneas de Carvalho Aguiar, 155 2 °andar Bloco 6, 05403900, São Paulo, Brazil. Email: trarbach{at}hotmail.com)
We report the results of molecular analysis in a series of twelve Kallmann syndrome (KS) and five normosmic hypogonadotropic hypogonadism (nHH) Brazilian patients. Kallman syndrome 1 (KAL-1) gene analysis was performed in all patients and the gonadotrophin releasing hormone receptor (GnRH-R) gene was investigated in nHH patients using PCR analysis with exon-flanking primers followed by automated sequencing techniques. Two-point mutations at the KAL-1 locus were found in two KS patients. One case exhibited a novel C deletion (del1956C) in exon 12 leading to a premature stop codon at position 617. The second case, a C to T transition at exon 5, showed a stop codon at aminoacid 191 (Arg191X). Renal agenesis and bimanual synkinesis, which are frequently found in patients with the KAL-1 mutation, were observed in these cases. Among the KS patients, two previously reported cases had intragenic deletions of exons 5–10, while a third patient had a KAL-1 gene microdeletion detected by fluorescence in situ hybridization. For the nHH patients, no abnormalities were observed at the exonic and flanking sequences of the KAL-1 or GnRH-R genes. Nasal embryonic LHRH factor (NELF) and early B-cell factor 2 (EBF2) exons were evaluated in KAL-1/GnRH-R mutation-negative cases (seven KS and five nHH) by sequence analysis but no mutations were identified in the coding regions in these patients. In conclusion, this report includes the description of a novel point mutation of the KAL-1 gene and suggests that the KAL-1 mutations and deletions might be more prevalent in KS Brazilian patients than previously described in other series. NELF and EBF2 genes have been considered good candidates for HH and a large number of patients need to be studied to assess their contribution to reproductive function.
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