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Distal renal tubular acidosis caused by tryptophan-aspartate repeat domain 72 (WDR72) mutations.
Clin Genet 2018; 94(5):409-418CG

Abstract

Hereditary distal renal tubular acidosis (dRTA) is a rare genetic disease that is caused by mutations in SLC4A1, ATP6V1B1, or ATP6V0A4. However, there are many families with hereditary dRTA in whom the disease-causing genes are unknown. Accordingly, we performed whole exome sequencing and genetic studies of the members of a family with autosomal recessive dRTA of an unknown genetic etiology. Here, we report compound heterozygous pathogenic variations in tryptophan-aspartate repeat domain 72 (WDR72) (c.1777A>G [p.R593G] and c.2522T>A [p.L841Q]) in three affected siblings of a family with dRTA. Both variants segregated with dRTA in the family and were not observed in normal control subjects. Homologous modeling and in silico mutagenesis indicated that R593G and L841Q alter the H-bond formations in the nearby residues, affecting the WDR72 protein structure. All these evidences indicate that the identified WDR72 variations were probably to have caused hereditary dRTA in the reported family. In addition, homozygous nonsense mutation (c.2686C>T [p.R896X]) was identified in another family, strongly supporting the causal role of WDR72 in dRTA. Based on our literature review, WDR72 mutations associated with dRTA have not been previously described. This is the first identification of pathogenic variations in WDR72 as a cause of hereditary dRTA.

Authors+Show Affiliations

Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.Department of Endocrinology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India.Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Department of Immunology and Immunology Graduate Program, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani, Thailand.Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.Division of Nephrology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.Division of Nephrology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30028003

Citation

Rungroj, N, et al. "Distal Renal Tubular Acidosis Caused By Tryptophan-aspartate Repeat Domain 72 (WDR72) Mutations." Clinical Genetics, vol. 94, no. 5, 2018, pp. 409-418.
Rungroj N, Nettuwakul C, Sawasdee N, et al. Distal renal tubular acidosis caused by tryptophan-aspartate repeat domain 72 (WDR72) mutations. Clin Genet. 2018;94(5):409-418.
Rungroj, N., Nettuwakul, C., Sawasdee, N., Sangnual, S., Deejai, N., Misgar, R. A., ... Yenchitsomanus, P. T. (2018). Distal renal tubular acidosis caused by tryptophan-aspartate repeat domain 72 (WDR72) mutations. Clinical Genetics, 94(5), pp. 409-418. doi:10.1111/cge.13418.
Rungroj N, et al. Distal Renal Tubular Acidosis Caused By Tryptophan-aspartate Repeat Domain 72 (WDR72) Mutations. Clin Genet. 2018;94(5):409-418. PubMed PMID: 30028003.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Distal renal tubular acidosis caused by tryptophan-aspartate repeat domain 72 (WDR72) mutations. AU - Rungroj,N, AU - Nettuwakul,C, AU - Sawasdee,N, AU - Sangnual,S, AU - Deejai,N, AU - Misgar,R A, AU - Pasena,A, AU - Khositseth,S, AU - Kirdpon,S, AU - Sritippayawan,S, AU - Vasuvattakul,S, AU - Yenchitsomanus,P T, Y1 - 2018/08/09/ PY - 2018/05/04/received PY - 2018/06/21/revised PY - 2018/07/17/accepted PY - 2018/7/22/pubmed PY - 2019/11/15/medline PY - 2018/7/21/entrez KW - WDR72 KW - dRTA KW - distal renal tubular acidosis KW - tryptophan-aspartate repeat domain 72 KW - vesicle trafficking defect KW - whole exome sequencing SP - 409 EP - 418 JF - Clinical genetics JO - Clin. Genet. VL - 94 IS - 5 N2 - Hereditary distal renal tubular acidosis (dRTA) is a rare genetic disease that is caused by mutations in SLC4A1, ATP6V1B1, or ATP6V0A4. However, there are many families with hereditary dRTA in whom the disease-causing genes are unknown. Accordingly, we performed whole exome sequencing and genetic studies of the members of a family with autosomal recessive dRTA of an unknown genetic etiology. Here, we report compound heterozygous pathogenic variations in tryptophan-aspartate repeat domain 72 (WDR72) (c.1777A>G [p.R593G] and c.2522T>A [p.L841Q]) in three affected siblings of a family with dRTA. Both variants segregated with dRTA in the family and were not observed in normal control subjects. Homologous modeling and in silico mutagenesis indicated that R593G and L841Q alter the H-bond formations in the nearby residues, affecting the WDR72 protein structure. All these evidences indicate that the identified WDR72 variations were probably to have caused hereditary dRTA in the reported family. In addition, homozygous nonsense mutation (c.2686C>T [p.R896X]) was identified in another family, strongly supporting the causal role of WDR72 in dRTA. Based on our literature review, WDR72 mutations associated with dRTA have not been previously described. This is the first identification of pathogenic variations in WDR72 as a cause of hereditary dRTA. SN - 1399-0004 UR - https://www.unboundmedicine.com/medline/citation/30028003/Distal_renal_tubular_acidosis_caused_by_tryptophan_aspartate_repeat_domain_72__WDR72__mutations_ L2 - https://doi.org/10.1111/cge.13418 DB - PRIME DP - Unbound Medicine ER -