Abstract: SA-PO613
We Propose a Single Heterozygous Mutation in ATP6V0A4 as a Novel Genetic Cause of dRTA
Session Information
- Noncystic Mendelian Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- Mori, Takayasu, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Chiga, Motoko, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Fujimaru, Takuya, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Mandai, Shintaro, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Watanabe, Shota, Ichinomiya Municipal Hospital, Ichinomiya, Japan
- Nakamura, Yasuhisa, Ichinomiya Municipal Hospital, Ichinomiya, Japan
- Morishita, Takehiro, Ichinomiya Municipal Hospital, Ichinomiya, Japan
- Uemura, Osamu, Aichi Children's Health and Medical Center, Obu, Aichi, Japan
- Imai, Eri, Itabashi Chuo Medical Center, Itabashi-Ku, TOKYO, Japan
- Kaneko, Shuzo, Itabashi Chuo Medical Center, Itabashi-Ku, TOKYO, Japan
- Tsukamoto, Yusuke, Itabashi Chuo Medical Center, Itabashi-Ku, TOKYO, Japan
- Sohara, Eisei, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Rai, Tatemitsu, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Uchida, Shinichi, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
Background
We have recently reported the development of a comprehensive diagnostic panel using next-generation sequencing (NGS) for 166 genes responsible for various inherited kidney diseases such as Gitelman syndrome, nephrogenic diabetes insipidus, Alport syndrome, renal tubular acidosis (RTA), etc., named SPEEDI-KID. Of the 137 families with inherited kidney diseases analyzed so far, three distal RTA (dRTA) families carrying only a single heterozygous variant in the known pathogenic gene, ATP6V0A4, were included. All the cases showed hypokalemic metabolic acidosis with nephrocalcinosis and high urine pH (>6.5). Interestingly, two cases showed late-onset of the disease (40 and 12 y.o., respectively), indicating that the phenotypes of the individuals are relatively milder than the previously reported cases. Genetic diagnosis revealed that each of the three families carried a single heterozygous missense variant in ATP6V0A4 (p.P393L, p.S544L, and p.G822S, respectively), even though autosomal recessive is the known inheritance mode. In all the cases, no other variants in known genes for RTA were detected. Relatively large genomic rearrangement in the alternative allele was excluded by using the NGS data. One family had two affected siblings carrying the same variant. In the other family, possibly affected father and an affected child had the same variant. The variants are extremely rare in general populations (ExAC, 1000G, and ToMMo2K) and in silico prediction scores (SIFT, PolyPhen2, and CADD) are consistent with the concept that these variants are disease-causative. Considering that heterozygous knockout mouse of ATP6V0A4 was reported to present metabolic acidosis under the condition of acid administration, these heterozygous variants could be responsible for the disease.
Conclusion
We propose single heterozygous mutations in ATP6V0A4 can be responsible for dRTA. dRTA with late-onset and mild phenotype caused by heterozygous variants in ATP6V0A4 may be more commonly present.
Funding
- Government Support - Non-U.S.