Glycerol kinase deficiency (GKD) maps to Xp21 and includes this enzyme deficiency as part of the contiguous gene syndrome, complex GKD, as well as of the juvenile (symptomatic with episodic vomiting, acidemia, and stupor) and adult (benign) forms of isolated GKD. Patients with complex GKD have interstitial deletions involving the GK as well as the adrenal hypoplasia congenita (AHC) and/or the Duchenne muscular dystrophy (DMD) loci, with patient phenotypes indicating the gene order: ter...AHC-GKD- DMD...cen. The continuing long term objective of this project is to understand the fundamental relationship between genotype and phenotype among individuals with GKD. Progress toward this objective has included developing yeast artificial chromosome (YAC) contigs in the region between C7 (DXS28) and DMD with only three small gaps; mapping of 28 markers in the region surrounding the AHC and GK loci; identification of deletion breakpoints in all patients with complex GKD including those who had no detectable deletion at the time of the original application; delineation of the specific interval that contains all or part of the GK gene; identification of a YAC insert that contains the entire GK critical region; and successful demonstration of a new method to scan genomic DNA for expressed sequences by establishing the presence of the X-linked human ferritin light chain (FTL) sequence on a cosmid in this region. The objective of improved understanding of genotype-phenotype relationships in patients with GKD will be pursued through the following Specific Aims: (1) Complete the contig in the region surrounding the AHC and GK loci using YACs and cosmids; (2) Clone and characterize expressed sequences in this region of Xp21; and (3) Identify mechanisms responsible for mutations in patients with complex GKD, isolated GKD and isolated involvement of other genes in this region such as AHC. These investigations will test the hypotheses that: (1) Availability of cloned genomic material will facilitate identification of expressed sequences in patients with complex GKD; (20 Individual expressed sequences will correlate with specific phenotypic features in patients with contiguous gene syndromes as well as isolated deficiencies; and (30 Improved information on genomic and expressed sequences will permit identification of mutation mechanisms underlying complex and isolated GKD.
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