Novel mutations of the AGXT gene causing primary hyperoxaluria type 1.
BACKGROUND
Primary hyperoxaluria type 1 (PH1), an inherited cause of nephrolithiasis, is due to a functional defect of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). A definitive PH1 diagnosis can be established by analyzing AGT activity in liver tissue or mutation analysis of the AGXT gene.


METHODS
The molecular basis of PH1 in three Chinese patients, two with adult-onset and one with childhood-onset recurrent nephrolithiasis, was established by analyzing the entire AGXT gene.


RESULTS
Three novel mutations (c2T>C, c817insAG and c844C>T) and two previously reported mutations (c33insC and 679-IVS6+2delAAgt) were identified. c2T>C converts the initiation codon from ATG to ACG, which predicts significant reduction, if not complete abolition, of protein translation. c817insAG leads to a frameshift and changes the amino acid sequence after codon 274. c844C>T changes glutamine at codon 282 to a termination codon, resulting in protein truncation.


CONCLUSIONS
This is the first report describing AGXT gene mutations in Chinese patients with PH1. AGXT genotypes cannot fully explain the clinical heterogeneity of PH1, and other factors involved in disease pathogenesis remain to be identified. Our experience emphasizes the importance of excluding PH1 in patients with recurrent nephrolithiasis to avoid delay or inappropriate management.
Yuen
Yuet-Ping
YP
Department of Pathology, Princess Margaret Hospital, Hong Kong, China.
Lai
Chi-Kong
CK
Tong
Gensy Mei-Wah
GM
Wong
Ping-Nam
PN
Wong
Francis Kim-Ming
FK
Mak
Siu-Ka
SK
Lo
Kin-Yee
KY
Wong
Andrew Kui-Man
AK
Tong
Sui-Fan
SF
Chan
Yan-Wo
YW
Lam
Ching-Wan
CW
D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis; D006801:Humans; D006959:Hyperoxaluria / Q000235:genetics*; D007669:Kidney Calculi / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012008:Recurrence; D000637:Transaminases / Q000235:genetics*
D000637:Transaminases; C019635:Alanine-glyoxylate transaminase