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© 1993 Oxford University Press

OTHER

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

Jean-Pierre Hardelin, Jacqueline Levilliers, Stéphane Blanchard, Jean-Claude Carel1, Marc Leutenegger2, Jean-Pierre Pinard-Bertelletto3, Pierre Bouloux4 and Christine Petit*

Unité de Génétique Moléculaire Humaine (CNRS URA 1445) Institut Pasteur 25, rue du Docteur Roux, 75724 Paris Cédex 15 1Ho{ring}pital St Vincent de Paul, Endocrinologie Pédiatrique 82, avenue Denfert Rochereau, 75674 Paris Cédex 14 2Ho{ring}pital Robert Debré, Diabétologie-Métabolisme, rue Alexis Carrel 51092 Reims Cédex 3Hospices Civils de Beaune, Centre Hospitalier Philippe le Bon avenue Guigone de Salins, 21203 Beaune Cédex, France 4Royal Free Hospital, Department of Medicine Pond Street, Hampstead, London NW3 2QG, UK

* To whom correspondence should be addressed

Received December 22, 1992; Accepted January 22, 1993

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 Kallman patients (6 out of 11 males with identified alterations of the KAL gene) should be emphasized.


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