Zhou Zhaowei, Ma Lidan, Zhou Juan, Song Zhijian, Zhang Jinmai, Wang Ke, Chen Boyu, Pan Dun, Li Zhiqiang, Li Changgui, Shi Yongyong
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.
Shandong Gout Clinical Medical Center, Qingdao, 266003, People's Republic of China.
BMC Med Genet. 2018 Aug 10;19(1):142. doi: 10.1186/s12881-018-0595-8.
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.
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.
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.
肾性低尿酸血症（RHUC）是一种异质性遗传疾病，其特征为血清尿酸浓度降低和尿酸排泄分数增加。既往报道显示，两个尿酸转运蛋白基因SLC22A12和/或SLC2A9中的许多功能突变是该疾病的致病遗传因素。然而，仍有一些患者的病因未得到解决，这表明存在其他致病基因或新的突变。在此，我们报告一名SLC22A12基因存在新型复合杂合突变的RHUC患者。
一名27岁女性在常规体检中反复出现低尿酸血症，转诊至我院。在获得患者同意后，分别对患者及其健康父母进行全外显子测序（WES）和桑格测序，以发现和验证致病突变。WES的优先排序方案筛选出患者SLC22A12基因中的两个突变，即c.269G＞A/p.R90H和c.1289_1290insGG/p.M430fsX466。桑格测序进一步证实，患者杂合的c.269G＞A/p.R90H突变（此前已有报道）来自其母亲，而首次发现的杂合c.1289_1290insGG/p.M430fsX466突变来自其父亲。p.R90H在不同物种中高度保守，可能会降低该结构域的稳定性，在硅分析中被认为几乎具有破坏性。p.M430fsX466在C端缺少最后三个跨膜结构域，包括三肽基序（S/T）XΦ（X = 任何氨基酸，Φ = 疏水残基），该基序与支架蛋白PDZK1相互作用，因此可能会通过破坏由URAT1和PDZK1形成的“转运体复合物”导致尿酸转运功能减弱。
我们首次使用WES和桑格测序报告了一名由SLC22A12基因复合杂合突变引起的中国RHUC患者。突变诱导的尿酸转运体复合物结构不稳定或功能异常可能是这种遗传性疾病的主要机制。
