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Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification.
Nicoli, Elena-Raluca; Weston, Mary R; Hackbarth, Mary; Becerril, Alissa; Larson, Austin; Zein, Wadih M; Baker, Peter R; Burke, John Douglas; Dorward, Heidi; Davids, Mariska; Huang, Yan; Adams, David R; Zerfas, Patricia M; Chen, Dong; Markello, Thomas C; Toro, Camilo; Wood, Tim; Elliott, Gene; Vu, Mylinh; Zheng, Wei; Garrett, Lisa J; Tifft, Cynthia J; Gahl, William A; Day-Salvatore, Debra L; Mindell, Joseph A; Malicdan, May Christine V.
Afiliación
  • Nicoli ER; Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
  • Weston MR; Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
  • Hackbarth M; Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
  • Becerril A; Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
  • Larson A; Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
  • Zein WM; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD 20892, USA.
  • Baker PR; Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
  • Burke JD; Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Dorward H; Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Davids M; Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
  • Huang Y; Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
  • Adams DR; Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, M
  • Zerfas PM; Diagnostic and Research Services Branch, Office of Research Services, NIH, Bethesda, MD 20892, USA.
  • Chen D; Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Markello TC; Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, M
  • Toro C; Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, M
  • Wood T; Metabolic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA.
  • Elliott G; Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Vu M; National Center for Translational Science, NIH, Rockville, MD 20850, USA.
  • Zheng W; National Center for Translational Science, NIH, Rockville, MD 20850, USA.
  • Garrett LJ; Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Tifft CJ; Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, M
  • Gahl WA; Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda
  • Day-Salvatore DL; Department of Medical Genetics and Genomic Medicine, Saint Peter's University Hospital, New Brunswick, NJ 08901, USA.
  • Mindell JA; Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA. Electronic address: mindellj@ninds.nih.gov.
  • Malicdan MCV; Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda
Am J Hum Genet ; 104(6): 1127-1138, 2019 06 06.
Article en En | MEDLINE | ID: mdl-31155284
ABSTRACT
Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl-/H+ exchanger, CLCN7 (ClC-7), encoded by CLCN7. 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 de novo c.2144A>G variant in CLCN7 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 Xenopus 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 CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 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 CLCN7 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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Variación Genética / Ácidos / Albinismo / Enfermedades por Almacenamiento Lisosomal / Canales de Cloruro / Fibroblastos / Lisosomas Límite: Animals / Female / Humans / Infant / Male Idioma: En Revista: Am J Hum Genet Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Variación Genética / Ácidos / Albinismo / Enfermedades por Almacenamiento Lisosomal / Canales de Cloruro / Fibroblastos / Lisosomas Límite: Animals / Female / Humans / Infant / Male Idioma: En Revista: Am J Hum Genet Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos