Mutations in DHDPSL are responsible for primary hyperoxaluria type III.
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.
Belostotsky
Ruth
R
Shaare Zedek Medical Center, Jerusalem, Israel.
Seboun
Eric
E
Idelson
Gregory H
GH
Milliner
Dawn S
DS
Becker-Cohen
Rachel
R
Rinat
Choni
C
Monico
Carla G
CG
Feinstein
Sofia
S
Ben-Shalom
Efrat
E
Magen
Daniella
D
Weissman
Irith
I
Charon
Celine
C
Frishberg
Yaacov
Y
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*
D010070:Oxalates; D011506:Proteins; D007652:Oxo-Acid-Lyases; C021415:4-hydroxy-2-oxoglutarate aldolase; D006909:Hydroxyproline
Am J Hum Genet. 2007 Aug;81(2):375-82
17668386
Arch Biochem Biophys. 1985 Jan;236(1):82-97
3966804
Kidney Int. 2009 Jun;75(12):1264-1271
19225556
Metabolism. 1985 Oct;34(10):955-61
3930916
J Biol Chem. 1992 May 25;267(15):10507-14
1587831
PLoS One. 2009;4(4):e5280
19399176
Am J Hum Genet. 2010 Jun 11;86(6):850-9
20560205
FEBS Lett. 1986 May 26;201(1):20-4
3709805
Biochem J. 2005 Sep 1;390(Pt 2):529-40
15869466
Methods Enzymol. 1975;41:115-8
165381
Am J Kidney Dis. 2008 Dec;52(6):1096-103
18951670
Am J Hum Genet. 2007 Jun;80(6):1090-102
17503327
Hum Mutat. 2003 Dec;22(6):497
14635115
J Biol Chem. 1997 Dec 5;272(49):30591-4
9388188
Kidney Int. 2002 Aug;62(2):392-400
12110000