Mutations in DHDPSL Are Responsible For Primary Hyperoxaluria Type III

• Published in: American journal of human genetics Vol. 87; no. 3; pp. 392 - 399
• Main Authors: Belostotsky, Ruth, Seboun, Eric, Idelson, Gregory H., Milliner, Dawn S., Becker-Cohen, Rachel, Rinat, Choni, Monico, Carla G., Feinstein, Sofia, Ben-Shalom, Efrat, Magen, Daniella, Weissman, Irith, Charon, Celine, Frishberg, Yaacov
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 10.09.2010; Cell Press; Elsevier (Cell Press); Elsevier
• Subjects: Alleles; Amino Acid Sequence; Base Sequence; Biological and medical sciences; Child; Child, Preschool; Chromosomes; DNA Mutational Analysis; Enzymes; Errors of metabolism; Family; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetic disorders; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Human genetics; Humans; Hydroxyproline - metabolism; Hyperoxaluria, Primary - genetics; Infant; Infant, Newborn; Jews - genetics; Kidney diseases; Life Sciences; Male; Medical genetics; Medical sciences; Metabolic diseases; Metabolic Networks and Pathways; Miscellaneous hereditary metabolic disorders; Molecular and cellular biology; Molecular Sequence Data; Mutation; Mutation - genetics; Oxalates - metabolism; Oxo-Acid-Lyases - chemistry; Oxo-Acid-Lyases - genetics; Patients; Pedigree; Protein synthesis; Proteins - chemistry; Proteins - genetics; Human; Oxalate; Metabolic diseases; Genetics; Hyperoxaluria; Mutation; Enzymopathy; Genetic disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2010.07.023

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.