Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families.
Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families.
复制标题
DOI：
10.1002/mgg3.205
复制
发表时间：
2016-05
影响因子：
2
通讯作者：
Vargas-Poussou R
中科院分区：
文献类型：
--
作者：
Escobar LI;Simian C;Treard C;Hayek D;Salvador C;Guerra N;Matos M;Medeiros M;Enciso S;Camargo MD;Vargas-Poussou R
常染色体隐性遗传性远端肾小管酸中毒（dRTA）是一种罕见的疾病，其特征是高尿酸性代谢性酸中毒伴正常阴离子间隙、低钾血症、高钙尿、低柠檬酸尿、肾钙质沉着症和保守的肾小球滤过率。在某些情况下，神经感觉性耳聋是相关的。dRTA在生命的最初几个月内发展，主要表现为发育不良、呕吐、脱水和厌食。研究了九个不相关的家庭：七个儿童，一个青少年和一个患有dRTA的成年人。四个孩子的听力得到了保护。通过桑格测序分析负责隐性dRTA的基因的编码区。在基因ATP 6V 1B 1和ATP 6V 0A 4中发现了分子缺陷。我们在ATP 6V 1B中发现了三种纯合突变：移码突变（p.Ile386Hisfs*56）、外显子10中的核苷酸替换（p.Pro346Arg）和内含子5中的新剪接突变。三名患者是纯合子的一个新的（p.Arg743Trp）和一个已知的（p.Asp411Tyr）错义突变的ATP 6V 0A 4基因。3例患者为复合杂合子：1例先证者显示2个新突变，移码突变p.Val52Metfs*25和外显子18-21的大缺失; 2例先证者分别显示错义突变p.Asp411Tyr和第二突变p.Arg194Ter和c.1691+2dup。 墨西哥家系中的隐性dRTA与ATP 6V 0A 4和ATP 6V 1B 1基因有关。所有检测到的ATP 6V 1B 1突变均为纯合子，所有患者均在婴儿早期发生感音神经性听力损失（SNHL）。在一名婴儿和三名儿童中发现了ATP 6V 0A 4突变，而在一名青少年和一名成人中发现了ATP 6V 0A 4突变，证实了该性状的表型变异性。在四个墨西哥家庭中检测到的突变p.Asp411Tyr是由于创始人效应。这些突变的筛查可以为该人群的dRTA诊断提供快速而有价值的工具。
Autosomal recessive distal renal tubular acidosis (dRTA) is a rare disease characterized by a hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis, and conserved glomerular filtration rate. In some cases, neurosensorial deafness is associated. dRTA is developed during the first months of life and the main manifestations are failure to thrive, vomiting, dehydration, and anorexia. Nine unrelated families were studied: seven children, a teenager, and an adult with dRTA. Hearing was preserved in four children. Coding regions of the genes responsible for recessive dRTA were analysed by Sanger sequencing. Molecular defects were found in the genes ATP6V1B1 and ATP6V0A4. We identified three homozygous variants in ATP6V1B: a frameshift mutation (p.Ile386Hisfs*56), a nucleotide substitution in exon 10 (p.Pro346Arg), and a new splicing mutation in intron 5. Three patients were homozygous for one novel (p.Arg743Trp) and one known (p.Asp411Tyr) missense mutations in the ATP6V0A4 gene. Three patients were compound heterozygous: one proband displayed two novel mutations, the frameshift mutation p.Val52Metfs*25, and a large deletion of exons 18–21; two probands showed the missense mutation p.Asp411Tyr and as a second mutation, p.Arg194Ter and c.1691+2dup, respectively. ATP6V0A4 and ATP6V1B1 genes were involved in recessive dRTA of Mexican families. All ATP6V1B1 mutations detected were homozygous and all patients developed sensorineural hearing loss (SNHL) early in infancy. ATP6V0A4 mutations were found in one infant and three children without SNHL, and in one teenager and one adult with SNHL confirming the phenotypic variability in this trait. The mutation p.Asp411Tyr detected in four Mexican families was due to a founder effect. Screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA in this population.