TY - JOUR
T1 - Mutations in DHDPSL are responsible for primary hyperoxaluria type III
AU - Belostotsky, Ruth
AU - Seboun, Eric
AU - Idelson, Gregory H.
AU - Milliner, Dawn S.
AU - Becker-Cohen, Rachel
AU - Rinat, Choni
AU - Monico, Carla G.
AU - Feinstein, Sofia
AU - Ben-Shalom, Efrat
AU - Magen, Daniella
AU - Weissman, Irith
AU - Charon, Celine
AU - Frishberg, Yaacov
N1 - Funding Information:
We thank Tsafi Danieli, Yael Keren, and Giora Morozov for excellent technical assistance. We are indebted to Karl Skorecki and Orly Reiner for critical review of the manuscript and for helpful suggestions. This work was supported in part by funding from the Oxalosis and Hyperoxaluria Foundation and by grants DK073354 and U54DK083908 from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health (D.S.M.).
PY - 2010/9/10
Y1 - 2010/9/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2010.07.023
DO - 10.1016/j.ajhg.2010.07.023
M3 - Article
C2 - 20797690
AN - SCOPUS:77956393040
SN - 0002-9297
VL - 87
SP - 392
EP - 399
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -