HOGA1 – Primary Hyperoxaluria Type 3

Primary hyperoxaluria type 3 (PH3; MONDO:0013327) is a rare autosomal recessive disorder caused by biallelic loss-of-function mutations in HOGA1, the gene encoding mitochondrial 4-hydroxy-2-oxoglutarate aldolase in glyoxylate metabolism. Affected individuals present in infancy or early childhood with persistent hyperoxaluria (HP:0003159), recurrent nephrolithiasis (HP:0000787) and nephrocalcinosis (HP:0000121), sometimes accompanied by hypercalciuria (HP:0002150).

The first Asian case described a Chinese child with early-onset nephrolithiasis who was compound heterozygous for two novel splice-site mutations in exon 6, c.834_834+1delinsTT confirmed by minigene assay, and c.834G>A, both absent in 100 controls ([PMID:26340091]). This established autosomal recessive inheritance and demonstrated aberrant exon skipping.

A cohort of 12 unrelated Chinese PH3 patients harbored 14 distinct HOGA1 variants—including nonsense, missense and splice-site changes—with a median age of onset of 18.3 months. All presented with urolithiasis; 10/12 showed hyperoxaluria and 2/12 had hypercalciuria, but none had impaired renal function at last follow-up ([PMID:31123811]).

A Tunisian case series expanded the spectrum by identifying homozygous p.Pro190Leu and p.Gly287Val in three PH3 patients aged 3.9 years (median), two with positive family history for urolithiasis. One p.Pro190Leu homozygote developed impaired renal function, whereas p.Gly287Val carriers maintained normal GFR ([PMID:27561601]).

Functional analyses, including hepatic mRNA studies and pSPL3 minigene exon-trapping, confirmed that splice-site and nonsense variants (e.g., c.208C>T (p.Arg70Ter)) abolish HOGA1 enzyme activity, supporting a loss-of-function mechanism ([PMID:26340091], [PMID:22391140]).

Conversely, a retrospective review of seven PH3 patients reported GFR impairment in 2/7, suggesting variable severity within this subtype ([PMID:25972204]).

Collectively, autosomal recessive segregation, at least 23 probands across four independent studies, a broad variant spectrum with recurrent and private alleles, and concordant functional loss-of-function evidence establish a definitive gene–disease relationship. Key take-home: HOGA1 genetic testing should be integrated into diagnostic protocols for childhood hyperoxaluria and urolithiasis to enable early intervention and patient management.

References

• American journal of nephrology • 2015 • Two Novel HOGA1 Splicing Mutations Identified in a Chinese Patient with Primary Hyperoxaluria Type 3. PMID:26340091
• Pediatric nephrology • 2019 • Nine novel HOGA1 gene mutations identified in primary hyperoxaluria type 3 and distinct clinical and biochemical characteristics in Chinese children. PMID:31123811
• Journal of clinical laboratory analysis • 2017 • HOGA1 Gene Mutations of Primary Hyperoxaluria Type 3 in Tunisian Patients. PMID:27561601
• Nephrology Dialysis Transplantation • 2012 • The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3. PMID:22391140
• Pediatric nephrology • 2015 • Renal function can be impaired in children with primary hyperoxaluria type 3. PMID:25972204

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