Human Growth Gene and Short Stature Gene Region

Abstract

Subject of the present invention is an isolated human nucleic acid molecule encoding polypeptides containing a homeobox domain of sixty amino acids having the amino acid sequence of SEQ ID NO: 1 and having regulating activity on human growth. Three novel genes residing within the about 500 kb short stature critical region on the X and Y chromosome were identified. At least one of these genes is responsible for the short stature phenotype. The cDNA corresponding to this gene may be used in diagnostic tools, and to further characterize the molecular basis for the short stature-phenotype. In addition, the identification of the gene product of the gene provides new means and methods for the development of superior therapies for short stature.

1 . A method for the treatment of short stature in patients identified as having a genetic: defect in the human growth gene SHOX, comprising
 a) identifying a genetic defect in a human subject suspected of having a genetic mutation in the SHOX gene having the nucleotide sequence according to SEQ. ID NO. 14, and   b) administering to said patient a therapeutically active amount of human growth hormone.   
     
     
         2 . The method according to  claim 1 , wherein said genetic defect is identified by obtaining a biological sample molecule to be examined, and amplifying said biological sample molecule in the presence of two nucleotide probes completely or in part complementary to any of the DNA sequences of SEQ. ID. NO: 2 to SEQ ID NO. 7. 
     
     
         3 . The method according to  claim 1 , wherein the genetic mutation is caused by a hot spot of mutation in the nucleic acid sequence encoding a protein truncation at amino acid position 195 in the SHOX gene. 
     
     
         4 . The method according to  claim 1 , wherein said patient is not suffering from Turner's Syndrome. 
     
     
         5 . A method for the treatment of short stature in patients identified as having a genetic defect in the human growth gene SHOX, said SHOX gene having the nucleotide sequence according to SEQ. ID NO. 14, comprising
 a) identifying a genetic defect in a human subject suspected of having a genetic mutation in the SHOX gene, comprising
 i) obtaining a biological sample containing a polynucleotide from a human subject, 
 ii) amplifying the polynucleotide of i) in the presence of a primer, wherein said primer is an exon flanking primer or a primer to an exon nucleotide sequence of the SHOX gene according to SEQ ID NO: 14 and wherein the oligonucleotide primer has a length of 18-26 nucleotides and the oligonucleotide sequence of said primer is identical to a partial sequence of an exon nucleotide sequence of the SHOX gene according to SEQ ID NO: 14, and 
 iii) sequencing any amplification product of the polynucleotide of 
 i) to determine the presence of a genetic mutation in the SHOX gene of said human subject, and 
   b) administering to said human subject a therapeutically active amount of human growth hormone.   
     
     
         6 . The method according to  claim 5 , wherein the exon nucleotide sequence in step a) ii) is a polynucleotide sequence selected from the group consisting of SHOX ET93 (SEQ ID NO: 2), SHOX G310 (SEQ ID NO: 3), SHOX ET45 (SEQ ID NO: 4), SHOX G108 (SEQ ID NO: 5), SHOX Va (SEQ ID NO: 6) and SHOX Vb (SEQ ID NO: 7).