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

Elena-Raluca Nicoli; Mary R Weston; Mary Hackbarth; Alissa Becerril; Austin Larson; Wadih M Zein; Peter R Baker, 2nd; John Douglas Burke; Heidi Dorward; Mariska Davids; Yan Huang; David R Adams; Patricia M Zerfas; Dong Chen; Thomas C Markello; Camilo Toro; Tim Wood; Gene Elliott; Mylinh Vu; Wei Zheng; Lisa J Garrett; Cynthia J Tifft; William A Gahl; Debra L Day-Salvatore; Joseph A Mindell; May Christine V Malicdan

doi:10.1016/j.ajhg.2019.04.008

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

Journal article

Open access

Peer reviewed

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

Elena-Raluca Nicoli, Mary R Weston, Mary Hackbarth, Alissa Becerril, Austin Larson, Wadih M Zein, Peter R Baker, 2nd, John Douglas Burke, Heidi Dorward, Mariska Davids, …

American journal of human genetics, Vol.104(6), pp.1127-1138

2019-06-06

DOI: https://doi.org/10.1016/j.ajhg.2019.04.008

PMCID: PMC6562152

PMID: 31155284

Abstract

Acids - chemistry

Oocytes - metabolism

Humans

Xenopus laevis

Infant

Male

Chloride Channels - genetics

Albinism - etiology

Fibroblasts - pathology

Lysosomal Storage Diseases - pathology

Genetic Variation

Animals

Lysosomes - metabolism

Albinism - metabolism

Albinism - pathology

Lysosomal Storage Diseases - metabolism

Female

Mice

Lysosomal Storage Diseases - etiology

Chloride Channels - physiology

Fibroblasts - metabolism

Hydrogen-Ion Concentration

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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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.79 Molecular & Cell Biology - Physiology; 1.79.1811 Myotonic Dystrophy
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification
Creators: Elena-Raluca Nicoli - 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
Mary R Weston - Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
Mary Hackbarth - 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
Alissa Becerril - Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
Austin Larson - Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
Wadih M Zein - Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD 20892, USA
Peter R Baker, 2nd - Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
John Douglas Burke - Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
Heidi Dorward - Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
Mariska Davids - 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
Yan Huang - 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
David R Adams - 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
Patricia M Zerfas - Diagnostic and Research Services Branch, Office of Research Services, NIH, Bethesda, MD 20892, USA
Dong Chen - Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
Thomas C Markello - 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
Camilo Toro - 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
Tim Wood - Metabolic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA
Gene Elliott - Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
Mylinh Vu - National Center for Translational Science, NIH, Rockville, MD 20850, USA
Wei Zheng - National Center for Translational Science, NIH, Rockville, MD 20850, USA
Lisa J Garrett - Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
Cynthia J Tifft - 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
William A Gahl - 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
Debra L Day-Salvatore - Department of Medical Genetics and Genomic Medicine, Saint Peter's University Hospital, New Brunswick, NJ 08901, USA
Joseph A Mindell - Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA. Electronic address: mindellj@ninds.nih.gov
May Christine V Malicdan - 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: malicdanm@mail.nih.gov
Publication Details: American journal of human genetics, Vol.104(6), pp.1127-1138
Publisher: United States
Language: English
Resource Type: Journal article
PMID: 31155284
PMCID: PMC6562152
Record Identifier: 991031578319602976