Two novel AGXT mutations identified in primary hyperoxaluria type-1 and distinct morphological and structural difference in kidney stones

Abstract

Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive oxalate accumulation in plasma and urine, resulting in various phenotypes because of allelic and clinical heterogeneity. This study aimed to detect disease-associated genetic mutations in three PH1 patients in a Chinese family. All AGXT exons and 3 common polymorphisms which might synergistically interact with mutations, including P11L, I340 M and IVSI+74 bp were analyzed by direct sequencing in all family members. It demonstrated that in each of three patients, a previously reported nonsense mutation p.R333* was in cis with a novel missense mutation p.M49L in the minor allele characterized by the polymorphism of 74-bp duplication in intron 1, while the other novel missense mutation p.N72I was in trans with both p.R333* and P.M49L in the major allele. Kidney stones from two sibling patients were also observed though stereomicroscopic examination and scanning electron microscopy. Distinct morphological and inner-structure differences in calculi were noticed, suggesting clinical heterozygosity of PH1 to a certain extent. In brief, two novel missense mutations were identified probably in association with PH1, a finding which should provide an accurate tool for prenatal diagnosis, genetic counseling and screening for potential presymptomatic individuals.

A Putative Mutation Hotspot of the <i>AGXT </i>Gene Associated with Primary Hyperoxaluria Type 1 in the Chinese Population

“…Total 19 genetically diagnosed patients with PH1 were reported in Chinese population (Coulter-Mackie et al 2001Yuen et al 2004;Li et al 2014;Chen et al 2015;Wang et al 2016;Gao et al 2017;Cui et al 2017;Du et al 2018), including one Chinese mixed-Canadian patient (Coulter-Mackie et al 2001). Among the 19 patients, three patients are family members (Wang et al 2016). Thus, there are 17 unrelated patients reported in the previous studies and 4 patients in the present study; namely, there are 41 mutant alleles of the AGXT gene in Chinese population, excluding one allele inherited from a Canadian mother (Coulter-Mackie et al 2001).…”

“…The PH1 variant spectrum in China has not been established, and no mutation hotspot was detected. However, the incidence of kidney stones increased dramatically among adolescents in the general population (Dwyer et al 2012), and PH1 has also been reported in adult patients (Wang et al 2016). These results suggest that PH1 may have been misdiagnosed in Chinese patients with kidney stones especially in adolescents and adults.…”

“…In Tunisia, PH1 accounts for 13.5% of all cases of ESRD in children, and 0.7% of all such cases in North America (Kamoun and Lakhoua 1996). To the best of our knowledge, however, only 19 patients with PH1 have been reported in Chinese population (Coulter-Mackie et al 2001Yuen et al 2004;Li et al 2014;Chen et al 2015;Wang et al 2016;Gao et al 2017;Cui et al 2017;Du et al 2018). These PH1 patients were found in PubMed (https:// www.ncbi.nlm.nih.gov/pubmed/) by searching the keywords: primary hyperoxaluria type 1, China, Chinese, and AGXT.…”

Familial hypomagnesaemia, Hypercalciuria and Nephrocalcinosis associated with a novel mutation of the highly conserved leucine residue 116 of Claudin 16 in a Chinese patient with a delayed diagnosis: a case report

“…The pathogenesis of chronic kidney disease (CKD) in FHHNC remains unclear. In the period of 3 years of follow-up, the patient exhibited a faster decline in renal function compared with the early phase of before 33 years of age, this may be related to the renal interstitial nephritis and accelerated renal parenchyma damage due to UPI, and the inflammation caused by the infection may further promote calcium deposition in the kidney [ 28 ]. Therefore, the nephrocalcinosis and infection played a significant negative impact on the chronic kidney disease (CKD).…”

Genetic and biochemical features of the monogenic hereditary urolithiasis

“…1). Мажорными мутациями гена AGXT считают с.33dupC, G170R, I244T с частотой 32%, 15% и 6%, соответственно [10,11]. Показано, что G170R и некоторые другие частые мутации в ряде случаев находятся в cis-конфигурации и действуют синергично с мутацией P11L.…”