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Juvenile hemochromatosis gene (hfe2a), expression products and uses thereofRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic AcidJuvenile hemochromatosis gene (hfe2a), expression products and uses thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070166711, Juvenile hemochromatosis gene (hfe2a), expression products and uses thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] 1. This patent application claims priority of U.S. provisional applications Ser. No. 60/462,867, filed 15 Apr. 2003, Ser. No. US/60/488,607, filed 18 Jul. 2003, and Ser. No. 60/498,458, filed 28 Aug. 2003, the disclosures of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION [0002] The present invention relates generally to the field of iron metabolism diseases, especially juvenile hemochromatosis, to a gene associated therewith, and to methods of using this gene, including expression products thereof, for the screening and identification of agents useful in the treatment of diseases of iron metabolism, including methods of such treatment. BACKGROUND OF THE INVENTION [0003] At least 4 iron-overload disorders labeled hemochromatosis have been identified on the basis of clinical, biochemical, and genetic characteristics. Hemochromatosis type 1 is classic hemochromatosis (sometimes designated "HFE") (see OMIM Number: 235200; Online Mendelian Inheritance in Man, OMIM.TM.. Johns Hopkins University, Baltimore, Md., at www.ncbi.nlm.nih.gov/omim/), an autosomal recessive disorder, which is caused by mutation in a gene designated HFE on chromosome 6p21.3. The medical disorder called juvenile hemochromatosis (sometimes called "JH" or "juvenile haemochromatosis"), is also known as hemochromatosis type 2 ("HFE2"). Hemochromatosis type 3 (HFE3; OMIM 604250), an autosomal recessive disorder, is caused by mutation in the gene encoding transferrin receptor-2 (TFR2; OMIM 604720), which maps to 7q22. Hemochromatosis type 4 (HFE4; OMIM 606069), an autosomal dominant disorder, is caused by mutation in the SLC11A3 gene (OMIM 604653), which encodes ferroportin and maps to 2q32. [0004] In some families juvenile hemochromatosis shows linkage to chromosome 1q21, whereas in others it is caused by mutation in the gene encoding hepcidin antimicrobial peptide, which maps to chromosome 19q13. The two forms of juvenile hemochromatosis (HFE2) are tentatively designated HFE2A and HFE2B, respectively. The present invention relates to the genetic basis of HFE2A, the form of JH linked to chromosome 1q21. [0005] Juvenile hemochromatosis (JH) differs from typical hereditary hemochromatosis. While HFE has a prevalent male expression, JH affects both sexes equally. JH involves iron accumulation, which begins early in life and typically causes clinical symptoms before the age of 30 years. JH is a more severe disease than typical hereditary hemochomotosis, with JH showing hypogonadotropic hypogonadism, heart failure, arrhythmias and/or cardiomyopathy as frequent features. If untreated, the disease is lethal because of cardiac and other complications. [0006] Identification of 1q21 as the chromosomal location of HFE2A was first reported in Roetto et al., Am. J. Hum. Genet. 64:1388-1393 (1999) but this locus did not correspond to the chromosomal location of any known gene involved in iron metabolism. [0007] The present invention provides identification of the hereditary basis for HFE2A, thereby facilitating development of more potent agents for treating diseases of iron metabolism. Administration of the HFE2A gene or protein itself may be therapeutic. Alternatively, the underlying genetic mutation identifies a novel therapeutic target for treating diseases of iron metabolism. This therapeutic target can be used to identify and discover more effective therapeutic agents. Diagnostic compounds, kits and methods using HFE2A are also included which may be used to diagnose JH as well as to diagnose and predict onset and severity of adult hemochromatosis and to distinguish between types of iron metabolism disorders. BRIEF SUMMARY OF THE INVENTION [0008] The invention relates to the discovery that juvenile hemochromatosis (hemochromatosis type 2A, or HFE2A), is caused by a mutation in a human gene found at 1q22 having the nucleotide sequence as set out in SEQ ID Nos. 1-9, and/or the corresponding amino acid sequences as set out in SEQ ID Nos. 10-12. The gene and the protein are referred to herein as HFE2A and also as hemojuvelin, these words referring the gene, the gene product and the protein expressed therefrom, unless the context specifies otherwise. The gene has also been named HFE2, by which is meant the form JH caused by the gene at 1q21. This naming protocol is not essential to the invention claimed herein. [0009] In one aspect, the present invention relates to a method for identifying an agent that modulates hemojuvelin, comprising contacting a test compound with hemojuvelin and determining a change in hemojuvelin activity due to the compound, thereby identifying a modulator of the type being sought. The modulator may be a drug-like small molecule, an antibody, an antisense nucleic acid, a ribozyme or any other compound which changes the activity of the gene or protein. [0010] In one aspect, the present invention relates to method for identifying an agent that modulates HFE2A gene expression, comprising contacting a test compound with a polynucleotide comprising a HFE2A gene and under conditions promoting expression of said gene (i.e., conditions wherein the polynucleotide is being expressed) and determining a change in expression due to the presence of the test compound. This identifies the test compound as such a modulator. In a preferred embodiment, this change in expression is detected as a change in transcription of the gene, preferably where the gene is a mammalian gene and most preferably where the gene is expressed by a cell. [0011] In another aspect, the present invention relates to a method for identifying an agent that modulates HFE2A gene expression, comprising contacting a test compound with a reporter gene operably linked to a promoter sequence and determining a change in expression of the reporter gene due to the test compound, thus identifying a modulator of the construct. Preferably, this is modulation of transcription of said reporter gene operably linked to an HFE2A promoter, most preferably a mammalian HFE2A, such as a mouse, rat or human HFE2A promoter. [0012] In a further aspect, the present invention relates to a method for treating and/or preventing a disorder in an animal comprising administering to an animal afflicted therewith, or at risk of developing said disorder, a therapeutically effective amount of an HFE2A modulator. In a preferred embodiment, the HFE2A modulator exhibits modulating activity in a method of the invention, most preferably wherein said agent was first identified as an HFE2A modulator using said method and was not otherwise known to have such activity. [0013] In a yet further aspect, the present invention relates to a method to diagnose individuals afflicted with or at risk of developing HFE2A or a related disorder comprising determining the nucleic acid sequence of the HFE2A gene in said individual wherein a mutation or polymorphism of said gene identifies said individual as an individual afflicted with or at risk of developing HFE2A or a related disorder. [0014] The present invention also contemplates a method for identifying a compound capable of modulating a HFE2A activity, comprising: (a) contacting a cell which expresses HFE2A with a test compound; and (b) assaying the ability of the test compound to modulate the transcription of a HFE2A nucleic acid or the activity of HFE2A polypeptide, thereby identifying a compound capable of modulating a HFE2A activity. In a preferred embodiment of such method, the compound is an anti-HFE2A polypeptide antibody, a ribozyme or is an antisense HFE2A nucleic acid molecule. In one preferred embodiment thereof, the compound is a HFE2A ribozyme. [0015] The present invention also encompasses an isolated polynucleotide or isolated polypeptide of the genes disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS [0016] FIG. 1 is a schematic of LOC148738 Gene structure. The LOC148738 Gene has four exons and five transcripts. The five transcripts code for 3 proteins of 200 M, 313 M and 426 AA. Exon 2 was predicted by Ensembl from cDNA sequence AK098165.1. The acceptor site for Exon 2 is inferred from the genomic sequence. Exons 3a and 3b have the same acceptor site but different donor sites. Untranslated sequence is white, translated sequence is black. The transcripts are listed from longest to shortest. [0017] FIG. 2 is an alignment of the human, mouse and rat promoter sequences for HFE2A. The transcriptional start site of the human sequence begins at position 1514 of this alignment and exon 1 ends at position 1676. Three repetitive sequences are present within the human sequence, a (TAGA)n at position 58 to 129, an alu repetitive element at position 324 to 603 and a (GGAA)n at position 604 to 702. These sequences are not present in the rodent sequences and possibly define the promoter boundary for the gene. Sequence homology between species is lost 5' of position 844 of this alignment, about 670 bp 5' of the transcriptional start. A putative transcriptional initiation site (TATA) is conserved in all three species, at 27 to 24 bp 5' of the transcriptional start in the human. [0018] FIG. 3 shows a Protein Sequence Alignment of Human LOC148738 426 aa Gene Product (Protein3) and human paralogs; Human Repulsive Guidance Molecule (Human RGM) (NCBI: NP.sub.--064596.1) on Chromosome 15 and ENSESTP00000023393 (Ensembl) identified on Chromosome 5.--Comparison of human paralogs FIG. 4 shows a Sequence Alignment of LOC148738 sequences using clustalx. Human (Protein3), Mouse (Ensembl: ENSMUSESTP00000016634), Rat (Translated from NCBI: AK098165.1 Though annotated as human sequence it is 99.9% identical to Rat genomic sequence and only 86.6% identical to human genomic sequence) and Fugu (Ensembl: SINFRUP00000138308). [0019] FIG. 5 shows a Protein Sequence Alignment of Human LOC148738 gene product and Chicken Repulsive Guidance Molecule (RGM). Human (Protein3), Chicken_RGM (Translation of NCBI: AY128507.1). A=Signal Peptide, B=RGD, C=N-Glycosylation site, D=Partial von Willebrand Type D Domain, E=GPI modification, Arrow=Possible cleavage site. [0020] FIG. 6A shows a summary of high degree of similarity between homologs of several species. Continue reading about Juvenile hemochromatosis gene (hfe2a), expression products and uses thereof... Full patent description for Juvenile hemochromatosis gene (hfe2a), expression products and uses thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Juvenile hemochromatosis gene (hfe2a), expression products and uses thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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