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.

Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies

“…1,12 In 2010, Belostotsky et al 13 identified different mutations in the HOGA1 gene (4-hydroxy-2-oxoglutarate aldolase, formerly known as DHDPSL; MIM# 613597) in some of their non-PHI/II patients causing PH type III (PHIII, MIM# 613616). HOGA1 encodes a mitochondrial protein of 327 amino acids (35 kDa).…”

4-Hydroxyglutamate Is a Biomarker for Primary Hyperoxaluria Type 3

“…Since the initial report of HOGA1 mutations causing PH3 (Belostotsky et al 2010), several cohorts of patients with persistent hyperoxaluria of unknown aetiology (also referred to as non-type I/type II PH) have been retrospectively studied, and HOGA1 mutations have been identified in~45% of these patients (Beck et al 2013;Monico et al 2011;Williams et al 2012). These findings have significant implications for the way in which patients with hyperoxaluria are investigated and also suggest possible treatments for PH3, now that the gene and enzyme involved have been identified.…”

“…The diagnosis was confirmed by mutation screening of HOGA1. Three families have been previously described (Belostotsky et al 2010). The affected individuals from the fourth family are compound heterozygotes for the following mutations: c.107C>T and c.944_946delAGG.…”

“…Urinary metabolic profiling is therefore recommended in all children with nephrolithiasis, as timely treatment may prevent stone formation (Habbig et al 2011). Primary hyperoxaluria type 3 (PH3, OMIM 613616) is a recently identified childhood oxalate kidney stone disease caused by mutations in the HOGA1 gene, formerly DHDPSL (Belostotsky et al 2010). A recent study gave an in silico estimate of~1:165,000 for the incidence of PH3 in the US population (Hopp et al 2013).…”

Cellular degradation of 4‐hydroxy‐2‐oxoglutarate aldolase leads to absolute deficiency in primary hyperoxaluria type 3

“…The glyoxylate can then be converted to oxalate through lactate dehydrogenase [6]. Interestingly, HOGA1 possesses an associated catalytic activity where oxaloacetate is converted to pyruvate and carbon dioxide [13].…”