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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Lysosomal Storage and Albinism Due to Effects of a <italic>De Novo CLCN7</italic> Variant on Lysosomal Acidification</title><author><name sortKey="Nicoli, Elena Raluca" sort="Nicoli, Elena Raluca" uniqKey="Nicoli E" first="Elena-Raluca" last="Nicoli">Elena-Raluca Nicoli</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Weston, Mary R" sort="Weston, Mary R" uniqKey="Weston M" first="Mary R." last="Weston">Mary R. Weston</name><affiliation><nlm:aff id="aff3">Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Hackbarth, Mary" sort="Hackbarth, Mary" uniqKey="Hackbarth M" first="Mary" last="Hackbarth">Mary Hackbarth</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Becerril, Alissa" sort="Becerril, Alissa" uniqKey="Becerril A" first="Alissa" last="Becerril">Alissa Becerril</name><affiliation><nlm:aff id="aff3">Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Larson, Austin" sort="Larson, Austin" uniqKey="Larson A" first="Austin" last="Larson">Austin Larson</name><affiliation><nlm:aff id="aff4">Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA</nlm:aff></affiliation></author><author><name sortKey="Zein, Wadih M" sort="Zein, Wadih M" uniqKey="Zein W" first="Wadih M." last="Zein">Wadih M. Zein</name><affiliation><nlm:aff id="aff5">Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Baker, Peter R" sort="Baker, Peter R" uniqKey="Baker P" first="Peter R." last="Baker">Peter R. Baker</name><affiliation><nlm:aff id="aff4">Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA</nlm:aff></affiliation></author><author><name sortKey="Burke, John Douglas" sort="Burke, John Douglas" uniqKey="Burke J" first="John Douglas" last="Burke">John Douglas Burke</name><affiliation><nlm:aff id="aff6">Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Dorward, Heidi" sort="Dorward, Heidi" uniqKey="Dorward H" first="Heidi" last="Dorward">Heidi Dorward</name><affiliation><nlm:aff id="aff6">Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Davids, Mariska" sort="Davids, Mariska" uniqKey="Davids M" first="Mariska" last="Davids">Mariska Davids</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Huang, Yan" sort="Huang, Yan" uniqKey="Huang Y" first="Yan" last="Huang">Yan Huang</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Adams, David R" sort="Adams, David R" uniqKey="Adams D" first="David R." last="Adams">David R. Adams</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Zerfas, Patricia M" sort="Zerfas, Patricia M" uniqKey="Zerfas P" first="Patricia M." last="Zerfas">Patricia M. Zerfas</name><affiliation><nlm:aff id="aff8">Diagnostic and Research Services Branch, Office of Research Services, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Chen, Dong" sort="Chen, Dong" uniqKey="Chen D" first="Dong" last="Chen">Dong Chen</name><affiliation><nlm:aff id="aff9">Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff></affiliation></author><author><name sortKey="Markello, Thomas C" sort="Markello, Thomas C" uniqKey="Markello T" first="Thomas C." last="Markello">Thomas C. Markello</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Toro, Camilo" sort="Toro, Camilo" uniqKey="Toro C" first="Camilo" last="Toro">Camilo Toro</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Wood, Tim" sort="Wood, Tim" uniqKey="Wood T" first="Tim" last="Wood">Tim Wood</name><affiliation><nlm:aff id="aff10">Metabolic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA</nlm:aff></affiliation></author><author><name sortKey="Elliott, Gene" sort="Elliott, Gene" uniqKey="Elliott G" first="Gene" last="Elliott">Gene Elliott</name><affiliation><nlm:aff id="aff11">Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Vu, Mylinh" sort="Vu, Mylinh" uniqKey="Vu M" first="Mylinh" last="Vu">Mylinh Vu</name><affiliation><nlm:aff id="aff12">National Center for Translational Science, NIH, Rockville, MD 20850, USA</nlm:aff></affiliation></author><author><name sortKey="Zheng, Wei" sort="Zheng, Wei" uniqKey="Zheng W" first="Wei" last="Zheng">Wei Zheng</name><affiliation><nlm:aff id="aff12">National Center for Translational Science, NIH, Rockville, MD 20850, USA</nlm:aff></affiliation></author><author><name sortKey="Garrett, Lisa J" sort="Garrett, Lisa J" uniqKey="Garrett L" first="Lisa J." last="Garrett">Lisa J. Garrett</name><affiliation><nlm:aff id="aff11">Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Tifft, Cynthia J" sort="Tifft, Cynthia J" uniqKey="Tifft C" first="Cynthia J." last="Tifft">Cynthia J. Tifft</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Gahl, William A" sort="Gahl, William A" uniqKey="Gahl W" first="William A." last="Gahl">William A. Gahl</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Day Salvatore, Debra L" sort="Day Salvatore, Debra L" uniqKey="Day Salvatore D" first="Debra L." last="Day-Salvatore">Debra L. Day-Salvatore</name><affiliation><nlm:aff id="aff14">Department of Medical Genetics and Genomic Medicine, Saint Peter’s University Hospital, New Brunswick, NJ 08901, USA</nlm:aff></affiliation></author><author><name sortKey="Mindell, Joseph A" sort="Mindell, Joseph A" uniqKey="Mindell J" first="Joseph A." last="Mindell">Joseph A. Mindell</name><affiliation><nlm:aff id="aff3">Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Malicdan, May Christine V" sort="Malicdan, May Christine V" uniqKey="Malicdan M" first="May Christine V." last="Malicdan">May Christine V. Malicdan</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31155284</idno><idno type="pmc">6562152</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562152</idno><idno type="RBID">PMC:6562152</idno><idno type="doi">10.1016/j.ajhg.2019.04.008</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000350</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000350</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Lysosomal Storage and Albinism Due to Effects of a <italic>De Novo CLCN7</italic> Variant on Lysosomal Acidification</title><author><name sortKey="Nicoli, Elena Raluca" sort="Nicoli, Elena Raluca" uniqKey="Nicoli E" first="Elena-Raluca" last="Nicoli">Elena-Raluca Nicoli</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Weston, Mary R" sort="Weston, Mary R" uniqKey="Weston M" first="Mary R." last="Weston">Mary R. Weston</name><affiliation><nlm:aff id="aff3">Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Hackbarth, Mary" sort="Hackbarth, Mary" uniqKey="Hackbarth M" first="Mary" last="Hackbarth">Mary Hackbarth</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Becerril, Alissa" sort="Becerril, Alissa" uniqKey="Becerril A" first="Alissa" last="Becerril">Alissa Becerril</name><affiliation><nlm:aff id="aff3">Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Larson, Austin" sort="Larson, Austin" uniqKey="Larson A" first="Austin" last="Larson">Austin Larson</name><affiliation><nlm:aff id="aff4">Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA</nlm:aff></affiliation></author><author><name sortKey="Zein, Wadih M" sort="Zein, Wadih M" uniqKey="Zein W" first="Wadih M." last="Zein">Wadih M. Zein</name><affiliation><nlm:aff id="aff5">Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Baker, Peter R" sort="Baker, Peter R" uniqKey="Baker P" first="Peter R." last="Baker">Peter R. Baker</name><affiliation><nlm:aff id="aff4">Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA</nlm:aff></affiliation></author><author><name sortKey="Burke, John Douglas" sort="Burke, John Douglas" uniqKey="Burke J" first="John Douglas" last="Burke">John Douglas Burke</name><affiliation><nlm:aff id="aff6">Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Dorward, Heidi" sort="Dorward, Heidi" uniqKey="Dorward H" first="Heidi" last="Dorward">Heidi Dorward</name><affiliation><nlm:aff id="aff6">Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Davids, Mariska" sort="Davids, Mariska" uniqKey="Davids M" first="Mariska" last="Davids">Mariska Davids</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Huang, Yan" sort="Huang, Yan" uniqKey="Huang Y" first="Yan" last="Huang">Yan Huang</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Adams, David R" sort="Adams, David R" uniqKey="Adams D" first="David R." last="Adams">David R. Adams</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Zerfas, Patricia M" sort="Zerfas, Patricia M" uniqKey="Zerfas P" first="Patricia M." last="Zerfas">Patricia M. Zerfas</name><affiliation><nlm:aff id="aff8">Diagnostic and Research Services Branch, Office of Research Services, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Chen, Dong" sort="Chen, Dong" uniqKey="Chen D" first="Dong" last="Chen">Dong Chen</name><affiliation><nlm:aff id="aff9">Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA</nlm:aff></affiliation></author><author><name sortKey="Markello, Thomas C" sort="Markello, Thomas C" uniqKey="Markello T" first="Thomas C." last="Markello">Thomas C. Markello</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Toro, Camilo" sort="Toro, Camilo" uniqKey="Toro C" first="Camilo" last="Toro">Camilo Toro</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Wood, Tim" sort="Wood, Tim" uniqKey="Wood T" first="Tim" last="Wood">Tim Wood</name><affiliation><nlm:aff id="aff10">Metabolic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA</nlm:aff></affiliation></author><author><name sortKey="Elliott, Gene" sort="Elliott, Gene" uniqKey="Elliott G" first="Gene" last="Elliott">Gene Elliott</name><affiliation><nlm:aff id="aff11">Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Vu, Mylinh" sort="Vu, Mylinh" uniqKey="Vu M" first="Mylinh" last="Vu">Mylinh Vu</name><affiliation><nlm:aff id="aff12">National Center for Translational Science, NIH, Rockville, MD 20850, USA</nlm:aff></affiliation></author><author><name sortKey="Zheng, Wei" sort="Zheng, Wei" uniqKey="Zheng W" first="Wei" last="Zheng">Wei Zheng</name><affiliation><nlm:aff id="aff12">National Center for Translational Science, NIH, Rockville, MD 20850, USA</nlm:aff></affiliation></author><author><name sortKey="Garrett, Lisa J" sort="Garrett, Lisa J" uniqKey="Garrett L" first="Lisa J." last="Garrett">Lisa J. Garrett</name><affiliation><nlm:aff id="aff11">Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Tifft, Cynthia J" sort="Tifft, Cynthia J" uniqKey="Tifft C" first="Cynthia J." last="Tifft">Cynthia J. Tifft</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Gahl, William A" sort="Gahl, William A" uniqKey="Gahl W" first="William A." last="Gahl">William A. Gahl</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Day Salvatore, Debra L" sort="Day Salvatore, Debra L" uniqKey="Day Salvatore D" first="Debra L." last="Day-Salvatore">Debra L. Day-Salvatore</name><affiliation><nlm:aff id="aff14">Department of Medical Genetics and Genomic Medicine, Saint Peter’s University Hospital, New Brunswick, NJ 08901, USA</nlm:aff></affiliation></author><author><name sortKey="Mindell, Joseph A" sort="Mindell, Joseph A" uniqKey="Mindell J" first="Joseph A." last="Mindell">Joseph A. Mindell</name><affiliation><nlm:aff id="aff3">Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Malicdan, May Christine V" sort="Malicdan, May Christine V" uniqKey="Malicdan M" first="May Christine V." last="Malicdan">May Christine V. Malicdan</name><affiliation><nlm:aff id="aff1">Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl<sup>−</sup>/H<sup>+</sup> exchanger, CLCN7 (ClC-7), encoded by <italic>CLCN7</italic>. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a <italic>de novo</italic> c.2144A>G variant in <italic>CLCN7</italic> in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in <italic>Xenopus</italic> oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys <italic>CLCN7</italic> in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in <italic>Clcn7</italic> variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function <italic>CLCN7</italic> variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31155284</article-id><article-id pub-id-type="pmc">6562152</article-id><article-id pub-id-type="publisher-id">S0002-9297(19)30154-5</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2019.04.008</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Lysosomal Storage and Albinism Due to Effects of a <italic>De Novo CLCN7</italic> Variant on Lysosomal Acidification</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Nicoli</surname><given-names>Elena-Raluca</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref 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ref-type="fn">16</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Malicdan</surname><given-names>May Christine V.</given-names></name><email>malicdanm@mail.nih.gov</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff7" ref-type="aff">7</xref><xref rid="fn2" ref-type="fn">16</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA</aff><aff id="aff2"><label>2</label>Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</aff><aff id="aff3"><label>3</label>Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA</aff><aff id="aff4"><label>4</label>Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA</aff><aff id="aff5"><label>5</label>Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD 20892, USA</aff><aff id="aff6"><label>6</label>Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</aff><aff id="aff7"><label>7</label>Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</aff><aff id="aff8"><label>8</label>Diagnostic and Research Services Branch, Office of Research Services, NIH, Bethesda, MD 20892, USA</aff><aff id="aff9"><label>9</label>Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA</aff><aff id="aff10"><label>10</label>Metabolic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA</aff><aff id="aff11"><label>11</label>Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA</aff><aff id="aff12"><label>12</label>National Center for Translational Science, NIH, Rockville, MD 20850, USA</aff><aff id="aff13"><label>13</label>Undiagnosed Diseases Network, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA</aff><aff id="aff14"><label>14</label>Department of Medical Genetics and Genomic Medicine, Saint Peter’s University Hospital, New Brunswick, NJ 08901, USA</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>mindellj@ninds.nih.gov</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author <email>malicdanm@mail.nih.gov</email></corresp><fn id="fn1"><label>15</label><p id="ntpara0010">These authors contributed equally to this work</p></fn><fn id="fn2"><label>16</label><p id="ntpara0012">These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="ppub"><day>06</day><month>6</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>30</day><month>5</month><year>2019</year></pub-date><volume>104</volume><issue>6</issue><fpage>1127</fpage><lpage>1138</lpage><history><date date-type="received"><day>9</day><month>1</month><year>2019</year></date><date date-type="accepted"><day>10</day><month>4</month><year>2019</year></date></history><abstract id="abs0010"><p>Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl<sup>−</sup>/H<sup>+</sup> exchanger, CLCN7 (ClC-7), encoded by <italic>CLCN7</italic>. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a <italic>de novo</italic> c.2144A>G variant in <italic>CLCN7</italic> in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in <italic>Xenopus</italic> oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys <italic>CLCN7</italic> in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in <italic>Clcn7</italic> variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function <italic>CLCN7</italic> variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.</p></abstract><kwd-group id="kwrds0010"><title>Keywords</title><kwd>lysosomal pH</kwd><kwd>lysosomal storage disease</kwd><kwd>oculocutaneous albinism</kwd><kwd>chloroquine</kwd><kwd>ClC-7 antiporter</kwd><kwd>lysosomal hyperacidity</kwd><kwd>lysosomal membrane counterion</kwd><kwd>cutaneous albinism</kwd></kwd-group></article-meta><notes><p id="misc0010">Published: May 30, 2019</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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