X-linked hypophosphatemic rickets (XLHR) is the most common inherited form of rickets. XLHR is an X-linked dominant disorder since heterozygous females are also affected. There is a great deal of variability in the expression of XLHR. This project is based upon the hypothesis that there are a number of different mutations, including deletions, among individuals with XLHR. The overall goal of this project is to further characterize the XLHR locus, and to identify the gene that is abnormal in this disease. The XLHR gene locus has been mapped to X(p22.1-p22.2).
The aim of Phase I of this project is to develop a detailed (1cM resolution) physical map of this region and to begin to identify mutations in affected individuals. Markers spanning the X(p22.1-p22.2) region will be generated from an X chromosome library, and will be ordered using pulsed field gel electrophoresis. Large deletions in affected individuals will be identified, if present, using the map. If no large deletions are identified, tighter linkage of the markers generated to the XLHR locus will be established using traditional RFLP techniques.
The aim of Phase II of this project is to identify the abnormal gene in XLHR. If a deletion is found in one or more affected patients, the search for the gene will begin in that region. If no deletions are detected, a jumping library will be generated consisting of CpG-rich areas, regions of putative gene transcription. Chromosomal walking will proceed from these regions to localize the XLHR gene. In order to verify that a given DNA sequence could be a candidate gene, the sequence will be hybridized against mammalian DNA from several different species, to tissue-specific RNA, and to tissue-specific CDNA libraries. The long- range goal is to characterize the function of the XLHR gene and its protein product.
| Holm, I A; Nelson, A E; Robinson, B G et al. (2001) Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 86:3889-99 |
| Holm, I A; Huang, X; Kunkel, L M (1997) Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets. Am J Hum Genet 60:790-7 |
