Molecular and clinical research of the growth genes on the sex chromosomes

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<Pseudoautosomal growth gene>We have localized a pseudoautosomal growth gene (P-growth gene) to a roughly 350kb region between DXYS60 and DXYS15 on the basis of genotype-phenotype correlations in 16 patients with partial monosomy of the pseudoautosomal region, and constructed a cosmid contig spanning the critical region. Positional cloning was carried out with c-DNA selection and exon trapping, successfully isolating a novel gene. This gene, termed SHOX,contained a homeobox domain and consisted of five exons. Mutational analysis of the SHOX gene was performed for a total of 91 patients with idiopathic short stature, and identified a nonsense mutation that was co-segregated with short stature in a particular family. Thus, we have cloned a novel homeobox gene, SHOX,that is an excellent candidate for the P-growth gene. This study was carried out as a collaboration work with Dr.Gudrum Rappold's group, Heidelberg University.<Y-specific growth gene>We have assigned a Y-specific growth gene (Y-growth gene) to a roughly 1 Mb region between DYS11 and DYS246 by genotype-phenotype correlations in 13 patients with partial deletion of the Y chromosome long arm, and constructed a yeast artificial chromosome contig which almost spans the critical region. We have also clarified that a novel gene UTY controlling mitosis is present on the critical region, suggesting that DUTY is a candidate for the Y-growth gene. Furthermore, we have proposed that the Y-growth gene controls the sex steroid-independent childhood growth pattern and increases the male final height by 7-10cm independently of the effect of sex steroids. In support of this notion, we have identified eight male patients whose growth pattern is consistent with the Y-growth gene being mutated. This study was carried out as a collaboration work with Dr.Yutaka Nakahori's group, Tokyo University.