Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients

J Endocrinol. 2005 Dec;187(3):361-8. doi: 10.1677/joe.1.06103.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / genetics
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Exons / genetics
  • Extracellular Matrix Proteins / genetics*
  • Gene Deletion
  • Humans
  • Hypogonadism / genetics*
  • Kallmann Syndrome / genetics*
  • Male
  • Nerve Tissue Proteins / genetics*
  • Point Mutation / genetics
  • Polymorphism, Genetic / genetics
  • Receptors, LHRH / genetics*
  • Sequence Analysis, DNA / methods
  • Transcription Factors / genetics*


  • ANOS1 protein, human
  • Amino Acids
  • Basic Helix-Loop-Helix Transcription Factors
  • EBF2 protein, human
  • Extracellular Matrix Proteins
  • GNRHR protein, human
  • NSMF protein, human
  • Nerve Tissue Proteins
  • Receptors, LHRH
  • Transcription Factors