Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-10-05
2004-12-21
Fredman, Jeffrey (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023100
Reexamination Certificate
active
06833244
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to probes, assays and kits for diagnosing infertility in men.
2. Description of the Prior Art
In the medical study and practice of human reproduction, infertility is usually defined as the inability to conceive after 1 year of trying. The term infertility is not the same as sterility, since many couples ultimately may achieve a pregnancy after 1 year of unprotected intercourse. Over 4.5 million American men and women—or roughly 1 out of 5 (15-20%) couples—fail when attempting their first pregnancy. In these couples, about half of the men will have a significant abnormality that makes them unable to father children. Male infertility may be caused by abnormalities in the testes or other areas of the male reproductive tract, as well as immune system defects. Yet the most common cause of male infertility is disordered sperm production. Other medical conditions that could cause infertility include a varicocele, abnormalities of the testes, penis, prostate or secondary sex traits.
Four main factors govern male fertility: hormones, sperm production, the ductal system of sperm delivery, and sexual function. Among these factors, physical variables that affect the structure of the testes are particularly important. There are many types of male infertility with a variety of causes and results.
“Varicocele” describes dilated internal spermatic veins forming the pampiniform plexus. This dilation results from increased intra-abdominal and hydrostatic pressures transmitted to the internal spermatic veins. Varicoceles have been associated with a common type of male infertility in which there is loss of ipsilateral testicular volume, oligozoospermia with increased numbers of sperm with a tapered head shape (“stress pattern”), impaired sperm motility and a reduced ability to undergo an acrosome reaction.
Approximately 40% of males from infertile couples present with varicocele. The mechanism(s) underlying the production of infertility with varicocele, however, are poorly characterized. The most widely accepted explanation for the pathophysiology of varicocele in male infertility is abnormally elevated testicular temperature due to impaired heat transfer by the scrotum and/or changes in testicular blood flow. Although men with varicocele exhibit higher mean scrotal temperatures, there is a large overlap with the range of scrotal temperatures in fertile men. More importantly, only 13% of men with varicocele are infertile, and, although varicocele repair has been documented 30 to reduce testicular temperature, only ⅓ of infertile men with varicocele-associated infertility will experience a return of fecundity following varicocele correction. These findings suggest that varicocele may not be a primary cause of infertility and that it is the interaction of varicocele with other factors that produces the infertile state.
Other etiologies of human male infertility include such conditions as cryptorchidism, retrograde ejaculation, testicular tumor, endocrine disorders, Kallmann's syndrome, fertile eunuch syndrome, congenital adrenal hyperplasia, Prader-Willi syndrome, Lawrence-Moon-Biedl syndrome, hemochromatosis, primary hypogonadism, Klinefelter's syndrome, XX disorder, XYY syndrome, mixed gonadal dysgenesis, Noonan syndrome, Myotonic dystrophy, 5-alpha-reductase deficiency, androgen receptor deficiency, among other known conditions.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide oligonucleotide probes for determining hyposperrnatogenesis associated infertility.
It is therefore an object of the present invention to provide oligonucleotide probes for determining varicocele associated infertility.
It is another object of the present invention to provide assays for determining hypospermatogenesis associated infertility.
It is another object of the present invention to provide assays for determining varicocele associated infertility.
It is yet another object of the present invention to provide kits for determining hypospermatogenesis associated infertility.
It is yet another object of the present invention to provide kits for determining varicocele associated infertility.
According to first broad aspect of the present invention, there is provided a method for diagnosing an individual as having hypospernatogenesis or varicocele associated infertility, which comprises demonstrating in the individual the presence or absence of a variant form of a gene in exons 6, 7, 8 or 9 of the L-VDCC &agr;1c transcript.
According to a second broad aspect of the present invention, there is provided an ligonucleotide hybridization probe for diagnosing an individual as having infertility or a predisposition thereto, which probe comprises a sequence of nucleotides such that under suitably stringent conditions the probe specifically binds to a variant form of a gene in exons 6, 7, 8 or 9 of the L-VDCC &agr;1c transcript; and fails to show significant hybridization to genetic material derived from individuals lacking said variant form of said gene.
According to a third broad aspect of the present invention, there is provided an oligonucleotide primer selected from the group of primers consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4.
According to a fourth broad aspect of the present invention, there is provided an assay kit which comprises an oligonucleotide hybridization probe for diagnosing an individual as having infertility or a predisposition thereto, which probe comprises a sequence of nucleotides such that under suitably stringent conditions the probe specifically binds to a variant form of a gene in exons 6, 7, 8 or 9 of the LVDCC &agr;1c transcript; and fails to show significant hybridization to genetic material derived from individuals lacking said variant form of said gene.
According to a fifth broad aspect of the present invention, there is provided an assay kit that comprises an oligonucleotide primer selected from the group of primers consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4.
Other objects and features of the present invention will be apparent from the following detailed description of the preferred embodiment.
REFERENCES:
Goodwin et al. Molecular Human Reproduction, vol. 6, No. 2, pp. 127-236, Feb. 2000, see especially p. 132.*
Backx, P.H. et al., “Molecular Localization of an Ion-Binding Site Within the Pore of Mammalian Sodium Channels”; Science, Jul. 10, 1992, vol. 257, pp. 248-251.
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Tanabe, T. et al., “Repeat I of the dihydropryridine receptor is critical in determining calcium channel activation kinetics”; Nature, Aug. 29, 1991, vol. 352, pp. 800-803.
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Benoff Susan
Goodwin Leslie
Hurley Ian R.
Pergolizzi Robert G.
Amster Rothstein & Ebenstein LLP
Fredman Jeffrey
North Shore - Long Island Jewish Research Institute
Switzer Juliet C.
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