Mutation Hot Spot Region in the HOGA1 Gene Associated with Primary Hyperoxaluria Type 3 in the Chinese Population

Abstract

Background: Primary hyperoxaluria type 3 (PH3) is a rare autosomal recessive disorder that affects glyoxylate metabolism. PH3 is caused by defects in 4-hydroxy-2-oxoglutarate aldolase, which is encoded by the HOGA1 gene. However, only 3 cases of PH3 have been described in Asians until today. This study aimed to determine the clinical and mutation spectra of patients from mainland China with PH3. Methods: We applied targeted next-generation sequencing to four non-consanguineous, unrelated Chinese families with PH3 to identify the genes hosting disease-causing mutations. This approach was confirmed by Sanger sequencing. Results: Five patients (2 boys and 3 girls) from four unrelated Chinese families were admitted because of kidney stones. Five HOGA1 gene sequence mutations were detected, including two novel mutations, c.811C>T (p.R271C) and c.812G>A (p.R271H). These compound heterozygous mutations were detected in a female PH3 patient (patient 4). Other patients included 2 boys who had heterozygous c.834_834+1GG>TT and c.834G>A (p.A278A) mutations (patients 1 and 2), a girl with homozygous c.834G>A (p.A278A) mutation (patient 3), and a girl with heterozygous c.834_834+1GG>TT and c.346C>T (p.Q116X) mutations (patient 5). The mutations in the c.834_834+1 region, including c.834G>A, c.834+1G>T, and c.834_834+1GG>TT, account for 5/8 of alleles in our study and 3/4 of alleles reported among Chinese patients. All patients in this study received hyperhydration and urine alkalinization treatment. Conclusion: Five PH3 cases were reported. Potential mutation hot spot region (c.834_834+1) in the Chinese population and two novel mutations were found.

A report from the European Hyperoxaluria Consortium (OxalEurope) Registry on a large cohort of patients with primary hyperoxaluria type 3

“…However, kidney function is not adequately reported in most instances (64% of patients reported in the literature without data) but presumed normal. Between 2010 and 2019, 151 patients were reported (1-38 patients per paper), 5,6,9,10,19,20,[22][23][24][25][26]28,29,[35][36][37][38][39] and a proportion of these patients are included in this paper. Similar to our data, age of diagnosis/disease onset ranged from 1 month to 48 years of life.…”

“…The splicing mutation c.700þ5G>T is the most frequent European mutation (AF, 45.8%). The inframe mutation c.944_946delAGG (p.Glu135del), the most frequent in patients of Ashkenazi-Jewish descent (AF, 55%), 6 and the c.834_834þ1 HOGA1 region, which is a common pathogenic variant within the Chinese population, 38 were only found in 5.3% and 3.2% of the European patients, respectively. This reflects similar genotype differences between distinct populations, as for PH1.…”

HOGA1 gene pathogenic variants in primary hyperoxaluria type III: Spectrum of pathogenic sequence variants, and phenotypic association

“…This variant was also suggested to affect canonical splice donor nucleotide position as shown by in silico analysis that led to the expression of two transcripts of which the majority of splice product was missing exon 6 (X. Wang et al, 2015;W. Wang et al, 2019).…”

“…A majority of the Chinese patients reported carrying a splice site variant in a homozygous or compound heterozygous state (Supporting Information: Table S1; Fang et al, 2019;He et al, 2019;X. Wang et al, 2015;W. Wang et al, 2019;Y.…”

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies

“…PH3 involves functional loss of the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) enzyme in mitochondria encoded by the HOGA1 gene (Figure ). , Mutations in the HOGA1 gene (also called DHDPSL gene) are responsible for PH3 and have been associated with PH3 patients in different populations. , The exact mechanism by which genetic mutations in the HOGA1 gene contribute to downstream oxalate accumulation is unclear. PH3 likely exists in the first months to years of life with early symptomatic nephrolithiasis .…”