Abstract | BACKGROUND: METHODS: SLC4A1 mutations in the patient and family members were analyzed by molecular genetic techniques. Protein structure modeling was initially conducted to evaluate the effects of mutations on the three-dimensional structure of the AE1 protein. The mutant kidney anion exchanger 1 (kAE1) plasmid construct was created to study protein expression, localization, and stability in HEK293T cells. RESULTS: We discovered that the patient who had AR dRTA coexisting with mild hemolytic anemia carried a novel compound heterozygous SLC4A1 mutations containing c.1199_1225del (p.Ala400_Ala408del), resulting in Southeast Asian ovalocytosis (SAO), and c.1331C > A (p.Thr444Asn). Homologous modeling and in silico mutagenesis indicated that these two mutations affected the protein structure in the transmembrane regions of kAE1. We found the wild-type and mutant kAE1 T444N to be localized at the cell surface, whereas the mutants kAE1 SAO and SAO/T444N were intracellularly retained. The half-life of the kAE1 SAO, T444N, and SAO/T444N mutants was shorter than that of the wild-type protein. CONCLUSION: These results suggest impaired trafficking and instability of kAE1 SAO/T444N as the likely underlying molecular mechanism explaining the pathogenesis of the novel SLC4A1 compound heterozygous mutation identified in this patient.
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Authors | Nipaporn Deejai, Nunghathai Sawasdee, Choochai Nettuwakul, Wanchai Wanachiwanawin, Suchai Sritippayawan, Pa-Thai Yenchitsomanus, Nanyawan Rungroj |
Journal | BMC medical genomics
(BMC Med Genomics)
Vol. 15
Issue 1
Pg. 228
(10 31 2022)
ISSN: 1755-8794 [Electronic] England |
PMID | 36320073
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2022. The Author(s). |
Chemical References |
- Anion Exchange Protein 1, Erythrocyte
- dirhodium tetraacetate
- Mutant Proteins
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Topics |
- Humans
- Anion Exchange Protein 1, Erythrocyte
(chemistry, genetics, metabolism)
- Mutant Proteins
(genetics, metabolism)
- HEK293 Cells
- Kidney
(metabolism)
- Mutation
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