Frontiers in Physiology (Jun 2019)
Dysfunctional LAT2 Amino Acid Transporter Is Associated With Cataract in Mouse and Humans
- Emilia Boiadjieva Knöpfel,
- Emilia Boiadjieva Knöpfel,
- Emilia Boiadjieva Knöpfel,
- Clara Vilches,
- Clara Vilches,
- Simone M. R. Camargo,
- Simone M. R. Camargo,
- Ekaitz Errasti-Murugarren,
- Ekaitz Errasti-Murugarren,
- Andrina Stäubli,
- Andrina Stäubli,
- Clara Mayayo,
- Clara Mayayo,
- Francis L. Munier,
- Nataliya Miroshnikova,
- Nadège Poncet,
- Nadège Poncet,
- Alexandra Junza,
- Alexandra Junza,
- Shomi S. Bhattacharya,
- Shomi S. Bhattacharya,
- Esther Prat,
- Esther Prat,
- Esther Prat,
- Vanita Berry,
- Wolfgang Berger,
- Wolfgang Berger,
- Wolfgang Berger,
- Elise Heon,
- Anthony T. Moore,
- Anthony T. Moore,
- Anthony T. Moore,
- Óscar Yanes,
- Óscar Yanes,
- Virginia Nunes,
- Virginia Nunes,
- Virginia Nunes,
- Manuel Palacín,
- Manuel Palacín,
- Manuel Palacín,
- Francois Verrey,
- Francois Verrey,
- Francois Verrey,
- Barbara Kloeckener-Gruissem,
- Barbara Kloeckener-Gruissem
Affiliations
- Emilia Boiadjieva Knöpfel
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Emilia Boiadjieva Knöpfel
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- Emilia Boiadjieva Knöpfel
- Swiss National Centre of Competence in Research Kidney.CH, University of Zurich, Zurich, Switzerland
- Clara Vilches
- Genes, Disease and Therapy Program, Molecular Genetics Laboratory – IDIBELL, Barcelona, Spain
- Clara Vilches
- U730 and U731, Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain
- Simone M. R. Camargo
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Simone M. R. Camargo
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- Ekaitz Errasti-Murugarren
- U730 and U731, Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain
- Ekaitz Errasti-Murugarren
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Andrina Stäubli
- Institute of Medical Molecular Genetics, University of Zurich, Zurich, Switzerland
- Andrina Stäubli
- Department of Biology, ETH Zurich, Zurich, Switzerland
- Clara Mayayo
- Genes, Disease and Therapy Program, Molecular Genetics Laboratory – IDIBELL, Barcelona, Spain
- Clara Mayayo
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Francis L. Munier
- Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland
- Nataliya Miroshnikova
- Institute of Medical Molecular Genetics, University of Zurich, Zurich, Switzerland
- Nadège Poncet
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Nadège Poncet
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- Alexandra Junza
- 0Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain
- Alexandra Junza
- 1CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain
- Shomi S. Bhattacharya
- 2Andalusian Molecular Biology and Regenerative Medicine Centre – CABIMER, Seville, Spain
- Shomi S. Bhattacharya
- 3UCL Institute of Ophthalmology, London, United Kingdom
- Esther Prat
- Genes, Disease and Therapy Program, Molecular Genetics Laboratory – IDIBELL, Barcelona, Spain
- Esther Prat
- U730 and U731, Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain
- Esther Prat
- 4Genetics Section, Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Vanita Berry
- 2Andalusian Molecular Biology and Regenerative Medicine Centre – CABIMER, Seville, Spain
- Wolfgang Berger
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- Wolfgang Berger
- Institute of Medical Molecular Genetics, University of Zurich, Zurich, Switzerland
- Wolfgang Berger
- 5Neuroscience Center Zurich – ZNZ, University of Zurich and ETH Zurich, Zurich, Switzerland
- Elise Heon
- 6Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, ON, Canada
- Anthony T. Moore
- 2Andalusian Molecular Biology and Regenerative Medicine Centre – CABIMER, Seville, Spain
- Anthony T. Moore
- 7Moorfields Eye Hospital, London, United Kingdom
- Anthony T. Moore
- 8Department of Ophthalmology, School of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Óscar Yanes
- 0Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain
- Óscar Yanes
- 1CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain
- Virginia Nunes
- Genes, Disease and Therapy Program, Molecular Genetics Laboratory – IDIBELL, Barcelona, Spain
- Virginia Nunes
- U730 and U731, Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain
- Virginia Nunes
- 4Genetics Section, Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Manuel Palacín
- U730 and U731, Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain
- Manuel Palacín
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Manuel Palacín
- 9Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
- Francois Verrey
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Francois Verrey
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- Francois Verrey
- Swiss National Centre of Competence in Research Kidney.CH, University of Zurich, Zurich, Switzerland
- Barbara Kloeckener-Gruissem
- Institute of Medical Molecular Genetics, University of Zurich, Zurich, Switzerland
- Barbara Kloeckener-Gruissem
- Department of Biology, ETH Zurich, Zurich, Switzerland
- DOI
- https://doi.org/10.3389/fphys.2019.00688
- Journal volume & issue
-
Vol. 10
Abstract
Cataract, the loss of ocular lens transparency, accounts for ∼50% of worldwide blindness and has been associated with water and solute transport dysfunction across lens cellular barriers. We show that neutral amino acid antiporter LAT2 (Slc7a8) and uniporter TAT1 (Slc16a10) are expressed on mouse ciliary epithelium and LAT2 also in lens epithelium. Correspondingly, deletion of LAT2 induced a dramatic decrease in lens essential amino acid levels that was modulated by TAT1 defect. Interestingly, the absence of LAT2 led to increased incidence of cataract in mice, in particular in older females, and a synergistic effect was observed with simultaneous lack of TAT1. Screening SLC7A8 in patients diagnosed with congenital or age-related cataract yielded one homozygous single nucleotide deletion segregating in a family with congenital cataract. Expressed in HeLa cells, this LAT2 mutation did not support amino acid uptake. Heterozygous LAT2 variants were also found in patients with cataract some of which showed a reduced transport function when expressed in HeLa cells. Whether heterozygous LAT2 variants may contribute to the pathology of cataract needs to be further investigated. Overall, our results suggest that defects of amino acid transporter LAT2 are implicated in cataract formation, a situation that may be aggravated by TAT1 defects.
Keywords
- amino acid transporters LAT2 and TAT1
- gene expression
- cataract
- ocular tissues
- mouse model
- patient screen
