title: Mutations in DHDPSL are responsible for primary hyperoxaluria type III.
abstract: Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respectively). To determine the etiology of an as yet uncharacterized type of PH, we selected a cohort of 15 non-PH I/PH II patients from eight unrelated families with calcium oxalate nephrolithiasis for high-density SNP microarray analysis. We determined that mutations in an uncharacterized gene, DHDPSL, on chromosome 10 cause a third type of PH (PH III). To overcome the difficulties in data analysis attributed to a state of compound heterozygosity, we developed a strategy of "heterozygosity mapping"-a search for long heterozygous patterns unique to all patients in a given family and overlapping between families, followed by reconstruction of haplotypes. This approach enabled us to determine an allelic fragment shared by all patients of Ashkenazi Jewish descent and bearing a 3 bp deletion in DHDPSL. Overall, six mutations were detected: four missense mutations, one in-frame deletion, and one splice-site mutation. Our assumption is that DHDPSL is the gene encoding 4-hydroxy-2-oxoglutarate aldolase, catalyzing the final step in the metabolic pathway of hydroxyproline.
authors.affiliation: Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Belostotsky
authors.forename: Eric
authors.initials: E
authors.lastname: Seboun
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Idelson
authors.forename: Dawn S
authors.initials: DS
authors.lastname: Milliner
authors.forename: Rachel
authors.initials: R
authors.lastname: Becker-Cohen
authors.forename: Choni
authors.initials: C
authors.lastname: Rinat
authors.forename: Carla G
authors.initials: CG
authors.lastname: Monico
authors.forename: Sofia
authors.initials: S
authors.lastname: Feinstein
authors.forename: Efrat
authors.initials: E
authors.lastname: Ben-Shalom
authors.forename: Daniella
authors.initials: D
authors.lastname: Magen
authors.forename: Irith
authors.initials: I
authors.lastname: Weissman
authors.forename: Celine
authors.initials: C
authors.lastname: Charon
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Frishberg
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D006960:Hyperoxaluria, Primary / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007585:Jews / Q000235:genetics; D008297:Male; D053858:Metabolic Networks and Pathways; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010070:Oxalates / Q000378:metabolism; D007652:Oxo-Acid-Lyases / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D011506:Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D010070:Oxalates; D011506:Proteins; D007652:Oxo-Acid-Lyases; C021415:4-hydroxy-2-oxoglutarate aldolase; D006909:Hydroxyproline
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