2. Academic Validation
  3. Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification

Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification

  • Am J Hum Genet. 2019 Jun 6;104(6):1127-1138. doi: 10.1016/j.ajhg.2019.04.008.
Elena-Raluca Nicoli 1,  Mary R Weston 2,  Mary Hackbarth 1,  Alissa Becerril 2,  Austin Larson 3,  Wadih M Zein 4,  Peter R Baker 2nd 3,  John Douglas Burke 5,  Heidi Dorward 5,  Mariska Davids 1,  Yan Huang 1,  David R Adams 6,  Patricia M Zerfas 7,  Dong Chen 8,  Thomas C Markello 6,  Camilo Toro 6,  Tim Wood 9,  Gene Elliott 10,  Mylinh Vu 11,  Undiagnosed Diseases Network 12,  Wei Zheng 11,  Lisa J Garrett 10,  Cynthia J Tifft 6,  William A Gahl 13,  Debra L Day-Salvatore 14,  Joseph A Mindell 15,  May Christine V Malicdan 16
Affiliations

Affiliations

  • 1 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.
  • 2 Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
  • 3 Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
  • 4 Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD 20892, USA.
  • 5 Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • 6 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, MD 20892, USA.
  • 7 Diagnostic and Research Services Branch, Office of Research Services, NIH, Bethesda, MD 20892, USA.
  • 8 Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • 9 Metabolic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA.
  • 10 Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • 11 National Center for Translational Science, NIH, Rockville, MD 20850, USA.
  • 12 Undiagnosed Diseases Network, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
  • 13 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, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • 14 Department of Medical Genetics and Genomic Medicine, Saint Peter's University Hospital, New Brunswick, NJ 08901, USA.
  • 15 Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
  • 16 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, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
PMID: 31155284 DOI: 10.1016/j.ajhg.2019.04.008
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.

Keywords

ClC-7 antiporter; chloroquine; cutaneous albinism; lysosomal hyperacidity; lysosomal membrane counterion; lysosomal pH; lysosomal storage disease; oculocutaneous albinism.

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