The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type III

During the last years, the group of patients with the typical clinical signs of primary hyperoxaluria (PH), but negative diagnostic results for the two types of PH known up till then has grown increasingly larger [1, 2]. It was, however, always obvious that the dramatic clinical course of most of these patients with unclassified hyperoxaluria, e.g. recurrent calcium-oxalate (CaOx) kidney stones already during the first years of life, together with the severeness of hyperoxaluria (>0.8 mmol/ 1.73 m/day), could not be based on a secondary origin. This was also proved by low intestinal oxalate absorption and hence, it was long speculated that another yet undefined defect of the glyoxylate metabolism could be a reason for at least a third type of autosomal recessive inherited PH [3]. In 2010, mutations in the HOGA1 gene (4-hydroxy2-oxoglutarate aldolase, formerly known as DHDPSL, OMIM 613616) were then found to cause PH type III in a group of patients with up to then unclassified hyperoxaluria [4]. HOGA1, located on chromosome 10q24, consists of seven exons encoding a mitochondrial protein of 328 amino acids (35 kDa). The enzyme is expressed in the liver and kidney and catalyzes the final step of the mitochondrial hydroxyproline metabolism from 4hydroxy-2-oxoglutarate to glyoxylate and pyruvate. Therefore, it was assumed that accumulation of the oxalate precursor glyoxylate results in subsequent increased oxalate generation and a gain-of-function mechanism was proposed, although demonstration of the predicted HOGA activity of the recombinant protein had failed [4].