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BMC Med Genet. 2018 Aug 10;19(1):142. doi: 10.1186/s12881-018-0595-8.

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

Zhou Z1, Ma L2,3,4, Zhou J1, Song Z1, Zhang J1, Wang K1, Chen B1, Pan D1, Li Z1,5, Li C6,7,8,9, Shi Y10,11,12,13.

Author information

1
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, No. 1954 Huashan Road, Shanghai, 200030, People's Republic of China.
2
Shandong Gout Clinical Medical Center, Qingdao, 266003, People's Republic of China.
3
Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, People's Republic of China.
4
The Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China.
5
Biomedical Sciences Institute, the Qingdao Branch of SJTU Bio-X Institutes, Qingdao University, Qingdao, 266003, People's Republic of China.
6
Shandong Gout Clinical Medical Center, Qingdao, 266003, People's Republic of China. lichanggui@medmail.com.cn.
7
Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, People's Republic of China. lichanggui@medmail.com.cn.
8
The Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China. lichanggui@medmail.com.cn.
9
Metabolic Disease Institute, Qingdao University, Qingdao, 266003, People's Republic of China. lichanggui@medmail.com.cn.
10
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, No. 1954 Huashan Road, Shanghai, 200030, People's Republic of China. shiyongyong@gmail.com.
11
Shandong Gout Clinical Medical Center, Qingdao, 266003, People's Republic of China. shiyongyong@gmail.com.
12
Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, People's Republic of China. shiyongyong@gmail.com.
13
Biomedical Sciences Institute, the Qingdao Branch of SJTU Bio-X Institutes, Qingdao University, Qingdao, 266003, People's Republic of China. shiyongyong@gmail.com.

Abstract

BACKGROUND:

Renal 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 PRESENTATION:

A 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.

CONCLUSIONS:

We 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.

KEYWORDS:

Chinese; Hypouricemia; Mutation; SLC22A12; Whole-exome sequencing

PMID:
30097038
PMCID:
PMC6086067
DOI:
10.1186/s12881-018-0595-8
[Indexed for MEDLINE]
Free PMC Article

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