Renal hypouricemia caused by novel compound heterozygous mutations in the SLC22A12 gene: a case report with literature review

Abstract

BackgroundRenal hypouricemia (RHUC) is a heterogeneous genetic disorder that is characterized by decreased serum uric acid concentration and increased fractional excretion of uric acid. Previous reports have revealed many functional mutations in two urate transporter genes, SLC22A12 and/or SLC2A9, to be the causative genetic factors of this disorder. However, there are still unresolved patients, suggesting the existence of other causal genes or new mutations. Here, we report an RHUC patient with novel compound heterozygous mutations in the SLC22A12 gene.Case presentationA 27-year-old female presenting with recurrent hypouricemia during routine checkups was referred to our hospital. After obtaining the patient’s consent, both the patient and her healthy parents were analyzed using whole-exome sequencing (WES) and Sanger sequencing to discover and validate causal mutations, respectively. The prioritization protocol of WES screened out two mutations of c.269G > A/p.R90H and c.1289_1290insGG/p.M430fsX466, which are both located in the SLC22A12 gene, in the patient. Sanger sequencing further confirmed that the patient’s heterozygous c.269G > A/p.R90H mutation, which has been reported previously, derived from her mother, and the heterozygous c.1289_1290insGG/p.M430fsX466 mutation, which was found for the first time, derived from her father. p.R90H, which is highly conserved among different species, may decrease the stability of this domain and was considered to be almost damaging in silicon analysis. p.M430fsX466 lacks the last three transmembrane domains, including the tripeptide motif (S/T)XΦ (X = any amino acid and Φ = hydrophobic residue), at the C-terminal, which interact with scaffolding protein PDZK1 and thus will possibly lead to weak functioning of urate transport through the disruption of the “transporter complex” that is formed by URAT1 and PDZK1.ConclusionsWe report a Chinese patient with RHUC, which was caused by compound heterozygous mutations of the SLC22A12 gene, using WES and Sanger sequencing for the first time. Mutation-induced structural instability or malfunction of the urate transporter complex may be the main mechanisms for this hereditary disorder.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0595-8) contains supplementary material, which is available to authorized users.

Amplicon targeted resequencing for SLC2A9 and SLC22A12 identified novel mutations in hypouricemia subjects

“…In the second family, the hypouricemia patient had compound heterozygous SLC22A12: p.T217M plus SLC2A9: p.P516T but his affected mother only had one heterozygous SLC22A12: p.T217M (Li et al, ). To summarize, SLC2A9: p.R90H allele accounted for 27.8% (5/9*2) among the hypouricemia patients which was much greater than that in Japan and Korea (Zhou et al, ), while W258X was not detected in any hypouricemia patient in Chinese samples. The SLC22A12 mutants were of major subtype responsibility for hRHUC, which was identical in varied ethnicities (Claverie‐Martin et al, ; Zhou et al, ).…”

“…To summarize, SLC2A9: p.R90H allele accounted for 27.8% (5/9*2) among the hypouricemia patients which was much greater than that in Japan and Korea (Zhou et al, ), while W258X was not detected in any hypouricemia patient in Chinese samples. The SLC22A12 mutants were of major subtype responsibility for hRHUC, which was identical in varied ethnicities (Claverie‐Martin et al, ; Zhou et al, ). The high incidence of hRHUC1 (OMIM #220150) has been reported in the Asian region and is attributed to the high frequency of the p.W258X (2.30%–2.37%) and p.R90H (0.40%) in SLC22A12 among Japanese (Iwai et al, ; Taniguchi et al, ) and general Korean populations (Lee et al, ), which is indicative of a founder mutation in the Asian continent.…”

“…Not surprisingly, the SLC22A12 : p.W258X mutation showed a protective effect against gout incidence in comparison with healthy controls (Taniguchi et al, ). As in Caucasians, Israel–Arab, Iraqi jews (Zhou et al, ), Pakistan (Jeannin et al, ) and India (Chakraborty & Sural, ), scattered hypouricemia cases have also been reported in China which displayed dispersed mutation spectrum. For example, homozygous SLC22A12 : p.R90H was found in two brothers with hypouricemia (Yan, Cheng, Chen, & Lin, ), compound heterozygous SLC22A12: p.P78L plus p.Q382L (Lam et al, ), homozygous SLC2A9: p.W238X (Shen et al, ), homozygous splicing mutation c.1215+1 G>A in SLC2A9 (Mou, Jiang, & Hu, ), and compound heterozygous SLC22A12: p.R90H plus p.M430fsX466 (Zhou et al, ) were found in each hypouricemia patient, respectively.…”

“…Although sanger sequencing is the golden standard for DNA detection but is time-consuming and laborious (Sommen & Van Camp, 2013), next-generation sequencing (NGS) based targeted resequencing has evolved to correctly diagnose genetic diseases in a more cost-effective and time-saving mode (Adams & Eng, 2018;Sommen & Van Camp, 2013). Using the NGS method and incorporating the parent-offspring trios, we successfully confirmed a hRHUC patient cosegregated with novel compound heterozygous mutations in SLC22A12 (Zhou et al, 2018).…”

“…With the popularity of genetic testing methods, more hRHUC patients have been reported. Notably, most published literatures on hypouricemia focused on case report or case serials (Zhou et al, 2018), which lack essential statistics through comparison with normal controls and may result in false reports of causative mutations to hypouricemia, especially in the Han Chinese population. Moreover, most reported hRHUC patients were mainly diagnosed using traditional Sanger sequencing (Kim et al, 2015;Windpessl, Ritelli, Wallner, & Colombi, 2016) or locus-specific polymerase chain reaction (PCR) reaction (Takagi, Omae, Makanga, Kawahara, & Inazu, 2013) for one gene SLC22A12 or SLC2A9.…”