Human osteoporosis gene

Details Human osteoporosis gene Human osteoporosis gene

2000-09-14

2003-10-07

Chan, Christina (Department: 1644)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C536S023500

Reexamination Certificate

active

06630304

ABSTRACT:

BACKGROUND OF THE INVENTION
Osteoporosis is a debilitating disease characterized by low bone mass and deterioration of bone tissue, as defined by decreased bone mineral density (BMD). A direct result of the experienced microarchitectural deterioration is susceptibility to fractures and skeletal fragility, ultimately causing high mortality, morbidity and medical expenses worldwide. Postmenopausal woman are at greater risk than others because the estrogen deficiency and corresponding decrease in bone mass experienced during menopause increase both the probability of osteoporotic fracture and the number of potential fracture sites. Yet aging women are not the only demographic group at risk. Young woman who are malnourished, ammenorrheic, or insufficiently active are at risk of inhibiting bone mass development at an early age. Furthermore, androgens play a role in the gain of bone mass during puberty, so elderly or hypogonadal men face the risk of osteoporosis if their bones were insufficiently developed.
The need to find a cure for this disease is complicated by the fact that there are many contributing factors that cause osteoporosis. Nutrition (particularly calcium, vitamin D and vitamin K intake), hormone levels, age, sex, race, body weight, activity level, and genetic factors all account for the variance seen in bone mineral density among individuals. Currently, the drugs approved to treat osteoporosis act as inhibitors of bone reabsorption, and include methods such as hormone replacement therapy (HRT), selective estrogen receptor modulators, calcitonin, and biophosphonates. However, these treatments may not individually reduce risk with consistent results and while some therapies improve BMD when coadministered, others show no improvement or even lose there efficacy when used in combination. Clearly, as life expectancy increases and health and economic concerns of osteoporosis grow, a solution for the risks associated with this late-onset disease is in great demand. Early diagnosis of the disease or predisposition to the disease would be desirable.
SUMMARY OF THE INVENTION
As described herein, it has been discovered that polymorphisms in the gene for human bone morphogenetic protein 2 (BMP2) have been correlated through human linkage studies to a number of osteoporosis phenotypes. In particular, it has been discovered that one or more single nucleotide polymorphisms within the nucleotide sequence encoding the BMP2 gene product is correlated to osteoporosis. Accordingly, this invention pertains to an isolated nucleic acid molecule containing the BMP2 gene of SEQ ID NO:1 (Table 1) having at least one altered nucleotide and to gene products encoded thereby (referred to herein as a “variant BMP2 gene” or “variant BMP2 gene product”).
A number of polymorphisms have been observed in the BMP2 gene, as follows:
Promoter Region:
A to G at nucleotide position 420;
A to G at nucleotide position 472;
G to C at nucleotide position 1464;
G to A at nucleotide position 1722;
C to A at nucleotide position 1914;
Coding Region:
T to G at nucleotide position 3747; resulting in an amino acid change from serine to alanine at amino acid position 37;
A to G at nucleotide position 3899; no amino acid change;
G to T at nucleotide position 3918; resulting in an amino acid change from alanine to serine at amino acid position 94;
A to T at nucleotide position 11980; resulting in an amino acid change from arginine to serine at amino acid position 189;
3′ UTR and Downstream Region:
C to T at nucleotide position 12571;
T to C at nucleotide position 13066;
A to G at nucleotide position 13209;
C to A at nucleotide position 13296; and
at least one deletion in nucleotides at positions 13533-13536.
All numbering is relative to SEQ ID NO. 1. Thus, in preferred embodiments, the isolated nucleic acid molecule of the invention can have one or a combination of these single nucleotide polymorphisms. These polymorphisms may be part of a group of other polymorphisms in the BMP2 gene which contributes to the presence, absence or severity of osteoporosis.
The invention also relates to DNA constructs comprising the nucleic acid molecules described herein operatively linked to a regulatory sequence, and to recombinant host cells, such as bacterial cells, fungal cells, plant cells, insect cells and mammalian cells, comprising the nucleic acid molecules described herein operatively linked to a regulatory sequence.
The invention also pertains to methods of diagnosing osteoporosis in an individual. The methods include detecting the presence of a mutation in the BMP2 gene. The invention additionally pertains to pharmaceutical compositions comprising the BMP2 nucleic acids of the invention and to kits for carrying out the methods described herein. The methods of the invention allow the accurate diagnosis of osteoporosis at or before disease onset, thus reducing or minimizing the debilitating effects of osteoporosis.
DETAILED DESCRIPTION OF THE INVENTION
As described herein, Applicants have completed a genome wide scan on patients with various forms of osteoporosis and identified a region on chromosome 20 linked to osteoporosis. Until now there have been no known linkage studies of osteoporosis in humans showing any connection to this region of the chromosome. Based on the linkage studies conducted, Applicants have discovered a direct relationship between BMP2 and osteoporosis. Although the BMP2 gene from normal individuals is known, there have been no studies directly investigating BMP2 and osteoporosis. Moreover, there have been no variant forms reported that have been associated with osteoporosis. The linkage studies are based on four genome wide scans encompassing affected persons having different osteoporosis phenotypes; i.e., hip, spine, combined and combined severe (e.g., patients having vertebral compression fracture, hip fracture, other osteoporosis related low impact fracture). From the data obtained in the linkage study, a region on chromosome 20, specifically the BMP2 gene, was identified. The variant BMP2 gene has previously unreported nucleotide changes that were observed in the patient population, as follows:
Promoter Region:
A to G at nucleotide position 420;
A to G at nucleotide position 472;
G to C at nucleotide position 1464;
G to A at nucleotide position 1722;
C to G at nucleotide position 1914;
Coding Region:
T to G at nucleotide position 3747; resulting in an amino acid change from serine to alanine at amino acid position 37;
A to G at nucleotide position 3899; no amino acid change;
G to T at nucleotide position 3918; resulting in an amino acid change from alanine to serine at amino acid position 94;
A to T at nucleotide position 11980; resulting in an amino acid change from arginine to serine at amino acid position 189;
3′ UTR and Downstream Region:
C to T at nucleotide position 12571;
T to C at nucleotide position 13066;
A to G at nucleotide position 13209;
C to A at nucleotide position 13296; and
at least one deletion in nucleotides at positions 13533-13536.
All nucleotide positions are relative to SEQ ID NO: 1. The polymorphism at nucleotide position 3747 appears statistically more frequent in the osteoporosis test population than in the control population.
NUCLEIC ACIDS OF THE INVENTION
Accordingly, the invention pertains to an isolated nucleic acid molecule comprising the human BMP2 gene having at least one nucleotide alteration and correlated with incidence of osteoporosis. The term, “variant BMP2”, as used herein, refers to an isolated nucleic acid molecule in chromosome 20 having at least one altered nucleotide that is associated with a susceptibility to a number of osteoporosis phenotypes, and also to a portion or fragment of the isolated nucleic acid molecule containing the alteration (e.g., cDNA or the gene) and encoding a variant BMP2 polypeptide (e.g., the polypeptide having SEQ ID NO: 2, as shown in Table 1). In a preferred embodiment, the isolated nucleic acid molecules comprises a polymorphism selected from the group consisting of: A to G at nucleotide position 420; A to G at nu

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