Mutations in DHDPSL are responsible for primary hyperoxaluria type III

Ruth Belostotsky, Eric Seboun, Gregory H. Idelson, Dawn S. Milliner, Rachel Becker-Cohen, Choni Rinat, Carla G. Monico, Sofia Feinstein, Efrat Ben-Shalom, Daniella Magen, Irith Weissman, Celine Charon, Yaacov Frishberg

Research output: Contribution to journalArticlepeer-review

135 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)392-399
Number of pages8
JournalAmerican journal of human genetics
Volume87
Issue number3
DOIs
StatePublished - Sep 10 2010

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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