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Human growth gene and short stature gene regionHuman growth gene and short stature gene region description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20090111744, Human growth gene and short stature gene region. Brief Patent Description - Full Patent Description - Patent Application Claims
This application is a divisional of U.S. Ser. No. 10/158,160 filed May 31, 2002, which is a continuation of U.S. Ser. No. 09/147,699, filed Jun. 24, 1999, now abandoned, which is a 371 of PCT/EP97/05355, filed on Sep. 29, 1997, which claims the benefit of U.S. provisional application 60/027,633, filed on Oct. 1, 1996. The present invention relates to the isolation, identification and characterization of newly identified human genes responsible for disorders relating to human growth, especially for short stature or Turner syndrome, as well as the diagnosis and therapy of such disorders. The isolated genomic DNA or fragments thereof can be used for pharmaceutical purposes or as diagnostic tools or reagents for identification or characterization of the genetic defect involved in such disorders. Subject of the present invention are further human growth proteins (transcription factors A, B and C) which are expressed after transcription of said DNA into RNA or mRNA and which can be used in the therapeutic treatment of disorders related to mutations in said genes. The invention further relates to appropriate cDNA sequences which can be used for the preparation of recombinant proteins suitable for the treatment of such disorders. Subject of the invention are further plasmid vectors for the expression of the DNA of these genes and appropriate cells containing such DNAs. It is a further subject of the present invention to provide means and methods for the genetic treatment of such disorders in the area of molecular medicine using an expression plasmid prepared by incorporating the DNA of this invention downstream from an expression promotor which effects expression in a mammalian host cell. Growth is one of the fundamental aspects in the development of an organism, regulated by a highly organised and complex system. Height is a multifactorial trait, influenced by both environmental and genetic factors. Developmental malformations concerning body height are common phenomena among humans of all races. With an incidence of 3 in 100, growth retardation resulting in short stature account for the large majority of inborn deficiencies seen in humans. With an incidence of 1:2500 life-born phenotypic females, Turner syndrome is a common chromosomal disorder (Rosenfeld et al., 1996). It has been estimated that 1-2% of all human conceptions are 45,X and that as many as 99% of such fetuses do not come to term (Hall and Gilchrist, 1990; Robins, 1990). Significant clinical variability exists in the phenotype of persons with Turner syndrome (or Ullrich-Turner syndrome) (Ullrich, 1930; Turner, 1938). Short stature, however, is a consistent finding and together with gonadal dysgenesis considered as the lead symptoms of this disorder. Turner syndrome is a true multifactorial disorder. Both the embryonic lethality, the short stature, gonadal dysgenesis and the characteristic somatic features are thought to be due to monosomy of genes common to the X and Y chromosomes. The diploid dosis of those X-Y homologous genes are suggested to be requested for normal human development. Turner genes (or anti-Turner genes) are expected to be expressed in females from both the active and inactive X chromosomes or Y chromosome to ensure correct dosage of gene product. Haploinsufficiency (deficiency due to only one active copy), consequently would be the suggested genetic mechanism underlying the disease. A variety of mechanisms underlying short stature have been elucidated so far. Growth hormone and growth hormone receptor deficiencies as well as skeletal disorders have been described as causes for the short stature phenotype (Martial et al., 1979; Phillips et al., 1981; Leung et al., 1987; Goddard et al., 1995). Recently, mutations in three human fibroblast growth factor receptor-encoding genes (FGFR 1-3) were identified as the cause of various skeletal disorders, including the most common form of dwarfism, achondroplasia (Shiang et al., 1994; Rousseau et al., 1994; Muenke and Schell, 1995). A well-known and frequent (1:2500 females) chromosomal disorder, Turner Syndrome (45,X), is also consistently associated with short stature. Taken together, however, all these different known causes account for only a small fraction of all short patients, leaving the vast majority of short stature cases unexplained to date. The sex chromosomes X and Y are believed to harbor genes influencing height (Ogata and Matsuo, 1993). This could be deduced from genotype-phenotype correlations in patients with sex chromosome abnormalities. Cytogenetic studies have provided evidence that terminal deletions of the short arms of either the X or the Y chromosome consistently lead to short stature in the respective individuals (Zuffardi et al., 1982; Curry et al., 1984). More than 20 chromosomal rearrangements associated with terminal deletions of chromosome Xp and Yp have been reported that localize the gene(s) responsible for short stature to the pseudoautosomal region (PAR1) (Ballabio et al., 1989, Schaefer et al., 1993). This localisation has been narrowed down to the most distal 700 kb of DNA of the PAR1 region, with DXYS 15 as the flanking marker (Ogata et al., 1992; 1995). Mammalian growth regulation is organized as a complex system. It is conceivable that multiple growth promoting genes (proteins) interact with one another in a highly organized way. One of those genes controlling height has tentatively been mapped to the pseudoautosomal region PAR1 (Ballabio et al., 1989), a region known to be freely exchanged between the X and Y chromosomes (for a review see Rappold, 1993). The entire PAR1 region is approximately 2,700 kb. The critical region for short stature has been defined with deletion patients. Short stature is the consequence when an entire 700 kb region is deleted or when a specific gene within this critical region is present in haploid state, is interrupted or mutated (as is the case with idiotypic short stature or Turner sydrome). The frequency of Turner\'s syndrome is 1 in 2500 females worldwide; the frequency of this kind of idiopathic short stature can be estimated to be 1 in 4.000-5.000 persons. Turner females and some short stature individuals usually receive an unspecific treatment with growth hormone (GH) for many years to over a decade although it is well known that they have normal GH levels and GH deficiency is not the problem. The treatment of such patients is very expensive (estimated costs approximately 30.000 USD p.a.). Therefore, the problem existed to provide a method and means for distinguishing short stature patients on the one side who have a genetic defect in the respective gene and on the other side patients who do not have any genetic defect in this gene. Patients with a genetic defect in the respective gene—either a complete gene deletion (as in Turner syndrome) or a point mutation (as in idiopathic short stature)—should be susceptible for an alternative treatment without human GH, which now can be devised. Genotype/phenotype correlations have supported the existence of a growth gene in the proximal part of Yq and in the distal part of Yp. Short stature is also consistently found in individuals with terminal deletions of Xp. Recently, an extensive search for male and female patients with partial monosomies of the pseudoautosomal region has been undertaken. On the basis of genotype-phenotype correlations, a minimal common region of deletion of 700 kb DNA adjacent to the telomere was determined (Ogata et al., 1992; Ogata et al., 1995). The region of interest was shown to lie between genetic markers DXYS20 (3cosPP) and DXYS15 (113D) and all candidate genes for growth control from within the PAR1 region (e.g., the hemopoietic growth factor receptor a; CSF2RA) (Gough et al., 1990) were excluded based on their physical location (Rappold et al., 1992). That is, the genes were within the 700 kb deletion region of the 2.700 kb PAR1 region. Deletions of the pseudoautosomal region (PAR1) of the sex chromosomes were recently discovered in individuals with short stature and subsequently a minimal common deletion region of 700 kb within PAR1 was defined. Southern blot analysis on DNA of patients AK and SS using different pseudoautosomal markers has identified an Xp terminal deletion of about 700 kb distal to DXYS 15 (113D) (Ogata et al, 1992; Ogata et al, 1995). The gene region corresponding to short stature has been identified as a region of approximately 500 kb, preferably approximately 170 kb in the PAR1 region of the X and Y chromosomes. Three genes in this region have been identified as candidates for the short stature gene. These genes were designated SHOX (also referred to as SHOX93 or HOX93), (SHOX=short stature homeobox-containing gene), pET92 and SHOT (SHOX-like homeobox gene on chromosome three). The gene SHOX which has two separate splicing sites resulting in two variations (SHOX a and b) is of particular importance. In preliminary investigations, essential parts of the nucleotide sequence of the short stature gene could be analysed (SEQ ID No. 8). Respective exons or parts thereof could be predicted and identified (e.g. exon I [G310]; exon II [ET93]; exon IV [G108]; pET92). The obtained sequence information could then be used for designing appropriate primers or nucleotide probes which hybridize to parts of the SHOX gene or fragments thereof. By conventional methods, the SHOX gene can then be isolated. By further analysis of the DNA sequence of the genes responsible for short stature, the nucleotide sequence of exons I-V could be refined (v. The above-mentioned novel homeobox-containing gene, SHOX, which is located within the 170 kb interval, is alternatively spliced generating two proteins with diverse function. Mutation analysis and DNA sequencing were used to demonstrate that short stature can be caused by mutations in SHOX. The identification and cloning of the short stature critical region according to the present invention was performed as follows: Extensive physical mapping studies on 15 individuals with partial monosomy in the pseudoautosomal region (PAR1) were performed. By correlating the height of those individuals with their deletion breakpoints a short stature (SS) critical region of approximately 700 kb was defined. This region was subsequently cloned as an overlapping cosmid contig using yeast artificial chromosomes (YACs) from PAR 1 (Ried et al., 1996) and by cosmid walking. To search for candidate genes for SS within this interval, a variety of techniques were applied to an approximately 600 kb region between the distal end of cosmid 56G10 and the proximal end of 51D11. Using cDNA selection, exon trapping, and CpG island cloning, the two novel genes were identified. The position of the short stature critical interval could be refined to a smaller interval of 170 kb of DNA by characterizing three further specific individuals (GA, AT and RY), who were consistently short. To precisely localize the rearrangement breakpoints of those individuals, fluorescence in situ hybridization (FISH) on metaphase chromosomes was carried out using cosmids from the contig. Patient GA, with a terminal deletion and normal height, defined the distal boundary of the critical region (with the breakpoint on cosmid 110E3), and patient AT, with an X chromosome inversion and normal height, the proximal boundary (with the breakpoint on cosmid 34F5). The Y-chromosomal breakpoint of patient RY, with a terminal deletion and short stature, was also found to be contained on cosmid 34F5, suggesting that this region contains sequences predisposing to chromosome rearrangements. The entire region, bounded by the Xp/Yp telomere, has been cloned as a set of overlapping cosmids. Fluorescence in situ hybridization (FISH) with cosmids from this region was used to study six patients with X chromosomal rearrangements, three with normal height and three with short stature. Genotype-phenotype correlations narrowed down the critical short stature interval to 270 kb of DNA or even less as 170 kb, containing the gene or genes with an important role in human growth. A minimal tiling path of six to eight cosmids bridging this interval is now available for interphase and metaphase FISH providing a valuable tool for diagnostic investigations on patients with idiopathic short stature. Continue reading about Human growth gene and short stature gene region... Full patent description for Human growth gene and short stature gene region Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Human growth gene and short stature gene region patent application. 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