Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1994-06-30
1998-06-09
Horlick, Kenneth R.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 71, 435 912, 4353201, 530300, 530350, 5303881, 536 235, 536 2431, 536 2433, C12Q 168, C12P 1934, C07H 2104, C07K 14435
Patent
active
057631662
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The subject of the present invention is a nucleotide sequence of the gene associated with the X chromosome-linked Kallmann syndrome, the applications of this sequence or of fragments of this sequence as nucleotide probes or nucleotide primers for the specific amplification of the gene or of fragments of the gene associated with the X chromosome-linked Kallmann syndrome, as well as all or part of the peptide sequences derived from the nucleotide sequence and their applications.
2. Discussion of the Background
Kallmann syndrome is characterized by the association of a hypogonadotropic hypogonadism with anosmia. This syndrome is also called olfactogenital dysplasia because of the existence of cases where an agenesis of the olfactory bulbs exists.
There are several modes of transmission of the syndrome: a mode of transmission linked to the X chromosome, a recessive autosomal mode and a dominant autosomal mode.
The incidence of Kallmann syndrome has been estimated at one male in 10,000. The excess by a factor of 6 to 7 of the number of representatives of the male sex who are carriers of the syndrome compared with the number of representatives of the female sex suggests that the form linked to the X chromosome is the most frequent. In this form, individuals of the female sex can be affected by hyposmia.
The association of the two symptoms remained for a long time enigmatic. However, recent studies have reported a common route for the development of the olfactory neurons and the neurons which synthesize the gonadotrophin-releasing hormone (GnRH).
The origin of both types of neuron is in an olfactory placode.
The central extensions of the olfactory neurons go across the ethmoid up to the inferior face of the forebrain. A contact between the ingrowing olfactory nerves and the forebrain is necessary for the development of the olfactory bulbs. The GnRH-synthesizing neurons also migrate towards the brain, go across the ethmoid bone with the branches of the nervus terminalis.
Finally, they reach the septal preoptic aera and the hypothalamus. This suggests the implication of the Kallmann gene (KAL) in this common embryonic development.
The discovery by Schwanzel-Fukuda et al., 1989 (23) that the GnRH-synthesizing neurons were present only outside the cerebral tissue in a human foetus having an X-linked Kallmann syndrome reinforces this hypothesis.
Genetic linkage analyses and deletion studies have permitted the location of the X-linked KAL gene in the vicinity of the STS (steroid sulphatase) locus in the Xp 22.3 region (Ballabio et al. (6) and (7)).
Analyses of DNA from two individuals having terminal Xp deletions, one having a Kallmann syndrome and not the other, permitted the authors of the present invention to site at least a part of the gene in an interval spanning less than 350 kb (KAL interval) (Petit et al. (20)). This interval is located between 8.6 and 8.95 Mb from the Xp telomere.
SUMMARY OF THE INVENTION
The present inventors have now isolated and sequenced the complementary DNA corresponding to the gene associated with the X chromosome-linked Kallmann syndrome. Starting with a patient LIL 155 having a terminal deletion on the short arm of the X chromosome (Petit et al. (20)) and with a patient AM having a translocation Xp 22.3, Yq 11 (Tiepolo et al., (26)), it was possible to carry out a precise determination of the size of the KAL interval and to sequence the entire interval.
The coding exons of this interval have been searched out. Among 19 potential exons, two proved to be conserved in various animal species.
One of the two was used to isolate cDNA clones obtained from foetal banks.
From the cDNA sequence, the inventors were able to deduce an extracellular protein of 680 amino acids, containing a whey acidic protein (WAP)-type motif whereas another region of the protein exhibits significant homologies with adhesion molecules.
Because of the homology with adhesion molecules, the inventors called the gene associated with the X chromosome-linked Kallm
REFERENCES:
Legouis et al., Cell 67, 423-435 (1991 Oct. 18).
Franco et al., Nature 353, 529-538 (1991 Oct. 10).
Hardelin et al., PNAS 89, 8190-8194 (1992 Sep.).
Petit et al., PNAS 87, 3680-3684 (1990).
Meitinger et al., Am. J. Hum. Genet. 47, 664-669 (1990).
Legouis et al., Cytogenet. Cell Genet. 58 (1-4) Abstract #2074 (1991).
Challoner et al., Nucleic Acids Res. 14(15), 6299-6311 (1986).
Ballabio, Am. J. Hum. Genet. 49(4)(Suppl.), Abstract #55 (1991).
Franco et al., Am. J. Hum. Genet. 49(4)(Suppl.), Abstract #2294 (1991).
Incerti et al., Am. J. Hum. Genet. 49(4)(Suppl.), Abstract #2307 (1991).
Claverie Jean-Michel
Hardelin Jean-Pierre
Legouis Renaud
Levilliers Jacuqeline
Lutfalla Georges
Horlick Kenneth R.
Institut Pasteur
The United States of America as represented by the Department of
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