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      SLC4A4 compound heterozygous mutations in exon–intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms coexisting with Turner’s syndrome: a case report

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          Abstract

          Background

          Congenital NBCe1A deficiency with the SLC4A4 mutation causes severe proximal renal tubular acidosis, which often comprises extrarenal symptoms, such as intellectual disability and developmental delay, glaucoma, cataract and band keratopathy. To date, almost all mutations have been found to be homozygous mutations located in exons.

          Case presentation

          We performed direct nucleotide sequencing analysis of exons and exon–intron boundary regions of the SLC4A4 in a patient presenting with severe renal proximal tubule acidosis, glaucoma and intellectual disability and her parents without these signs. The examination revealed compound heterozygous mutations in exon–intron boundary regions, c.1076 + 3A > C and c.1772 − 2A > T, neither of which have been reported previously. While the former mutation was found in the mother, the latter was found in the father. The transcript of the SLC4A4 gene was almost undetectable, and the patient was also diagnosed with Turner’s syndrome.

          Conclusions

          We identified two novel SLC4A4 mutations, c.1076 + 3A > C and c.1772 − 2A > T. When presented in a compound heterozygous state, these mutations caused a phenotype of severe renal proximal tubular acidosis along with glaucoma and mental retardation. This is the first report of congenital proximal renal tubular acidosis carrying compound heterozygous SLC4A4 mutations in exon–intron boundary regions. We suggest that an mRNA surveillance mechanism, nonsense-mediated RNA decay, following aberrant splicing was the reason that the SLC4A4 transcript was almost undetectable in the proband.

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          Most cited references26

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          Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation.

          A fundamental aspect of the biogenesis and function of eukaryotic messenger RNA is the quality control systems that recognize and degrade non-functional mRNAs. Eukaryotic mRNAs where translation termination occurs too soon (nonsense-mediated decay) or fails to occur (non-stop decay) are rapidly degraded. We show that yeast mRNAs with stalls in translation elongation are recognized and targeted for endonucleolytic cleavage, referred to as 'no-go decay'. The cleavage triggered by no-go decay is dependent on translation and involves Dom34p and Hbs1p. Dom34p and Hbs1p are similar to the translation termination factors eRF1 and eRF3 (refs 3, 4), indicating that these proteins might function in recognizing the stalled ribosome and triggering endonucleolytic cleavage. No-go decay provides a mechanism for clearing the cell of stalled translation elongation complexes, which could occur as a result of damaged mRNAs or ribosomes, or as a mechanism of post-transcriptional control.
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            Nonsense-mediated mRNA decay in humans at a glance.

            Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that typifies all eukaryotes examined to date. NMD surveys newly synthesized mRNAs and degrades those that harbor a premature termination codon (PTC), thereby preventing the production of truncated proteins that could result in disease in humans. This is evident from dominantly inherited diseases that are due to PTC-containing mRNAs that escape NMD. Although many cellular NMD targets derive from mistakes made during, for example, pre-mRNA splicing and, possibly, transcription initiation, NMD also targets ∼10% of normal physiological mRNAs so as to promote an appropriate cellular response to changing environmental milieus, including those that induce apoptosis, maturation or differentiation. Over the past ∼35 years, a central goal in the NMD field has been to understand how cells discriminate mRNAs that are targeted by NMD from those that are not. In this Cell Science at a Glance and the accompanying poster, we review progress made towards this goal, focusing on human studies and the role of the key NMD factor up-frameshift protein 1 (UPF1).
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              Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.

              Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm's canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity.
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                Author and article information

                Contributors
                s-horita@umin.ac.jp
                enversimsek06@hotmail.com
                tulaysimsek21@icloud.com
                nyyildirim@yahoo.com
                hishiura@yahoo.co.jp
                motonobunakamura@hotmail.co.jp
                nosatou-tky@umin.ac.jp
                as.zukky@gmail.com
                hiro135413@gmail.com
                a6mb1087@gmail.com
                georgeseki-tky@umin.ac.jp
                tsuji@m.u-tokyo.ac.jp
                mnangaku-tky@umin.ac.jp
                Journal
                BMC Med Genet
                BMC Med. Genet
                BMC Medical Genetics
                BioMed Central (London )
                1471-2350
                18 June 2018
                18 June 2018
                2018
                : 19
                : 103
                Affiliations
                [1 ]ISNI 0000 0004 1764 7572, GRID grid.412708.8, Division of Nephrology and Endocrinology, , The University of Tokyo Hospital, ; 7-3-1, Hongo, Bunkyo, Tokyo, 113 0033 Japan
                [2 ]ISNI 0000 0004 0596 2460, GRID grid.164274.2, Department of Paediatric Endocrinology, , Eskisehir Osmangazi University School of Medicine, ; Esogu Meşelik Yerleşkesi, 26480 Eskisehir, Turkey
                [3 ]ISNI 0000 0004 0596 2460, GRID grid.164274.2, Department of Ophthalmology, , Eskisehir Osmangazi University School of Medicine, ; Esogu Meşelik Yerleşkesi, 26480 Eskisehir, Turkey
                [4 ]ISNI 0000 0004 1764 7572, GRID grid.412708.8, Department of Neurology, , The University of Tokyo Hospital, ; 7-3-1, Hongo, Bunkyo, Tokyo, 113 0033 Japan
                [5 ]Yaizu City Hospital, 1000, Dobara, Yaizu, 425 0055 Japan
                [6 ]ISNI 0000 0004 1764 7572, GRID grid.412708.8, Department of Molecular Neurology, , The University of Tokyo Hospital, ; 7-3-1, Hongo, Bunkyo, Tokyo, 113 0033 Japan
                [7 ]ISNI 0000 0004 0531 3030, GRID grid.411731.1, Institute of Medical Genomics, , International University of Health and Welfare, ; 4-3, Kozunomori, Narita-shi, Chiba-ken, 286 8686 Japan
                Author information
                http://orcid.org/0000-0003-2103-3605
                Article
                612
                10.1186/s12881-018-0612-y
                6006740
                29914390
                e57387c3-3c24-4f84-a96b-99132d32ff39
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 29 November 2017
                : 21 May 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: 16K09640
                Award ID: 17H05085
                Award ID: 17K16071
                Award ID: 16H06750
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;
                Award ID: 16kk0205001h0001
                Award Recipient :
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2018

                Genetics
                slc4a4,nbce1,proximal renal tubular acidosis,compound heterozygous mutations,mrna surveillance,nonsense-mediated decay

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