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Am J Hum Genet. 2019 Jun 6;104(6):1127-1138. doi: 10.1016/j.ajhg.2019.04.008. Epub 2019 May 30.

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

Collaborators (249)

Acosta MT, Adams DR, Agrawal P, Alejandro ME, Allard P, Alvey J, Andrews A, Ashley EA, Azamian MS, Bacino CA, Bademci G, Baker E, Balasubramanyam A, Baldridge D, Bale J, Barbouth D, Batzli GF, Bayrak-Toydemir P, Beggs AH, Bejerano G, Bellen HJ, Bernstein JA, Berry GT, Bican A, Bick DP, Birch CL, Bivona S, Bohnsack J, Bonnenmann C, Bonner D, Boone BE, Bostwick BL, Botto L, Briere LC, Brokamp E, Brown DM, Brush M, Burke EA, Burrage LC, Butte MJ, Carey J, Carrasquillo O, Chang TCP, Chao HT, Clark GD, Coakley TR, Cobban LA, Cogan JD, Cole FS, Colley HA, Cooper CM, Cope H, Craigen WJ, D'Souza P, Dasari S, Davids M, Dayal JG, Dell'Angelica EC, Dhar SU, Dorrani N, Dorset DC, Douine ED, Draper DD, Duncan L, Eckstein DJ, Emrick LT, Eng CM, Esteves C, Estwick T, Fernandez L, Ferreira C, Fieg EL, Fisher PG, Fogel BL, Forghani I, Fresard L, Gahl WA, Godfrey RA, Goldman AM, Goldstein DB, Gourdine JF, Grajewski A, Groden CA, Gropman AL, Haendel M, Hamid R, Hanchard NA, Hayes N, High F, Holm IA, Hom J, Huang A, Huang Y, Isasi R, Jamal F, Jiang YH, Johnston JM, Jones AL, Karaviti L, Kelley EG, Kiley D, Koeller DM, Kohane IS, Kohler JN, Krakow D, Krasnewich DM, Korrick S, Koziura M, Krier JB, Kyle JE, Lalani SR, Lam B, Lanpher BC, Lanza IR, Lau CC, Lazar J, LeBlanc K, Lee BH, Lee H, Levitt R, Levy SE, Lewis RA, Lincoln SA, Liu P, Liu XZ, Longo N, Loo SK, Loscalzo J, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Majcherska MM, Malicdan MCV, Mamounas LA, Manolio TA, Mao R, Markello TC, Marom R, Marth G, Martin BA, Martin MG, Martínez-Agosto JA, Marwaha S, May T, McCauley J, McConkie-Rosell A, McCormack CE, McCray AT, Metz TO, Might M, Morava-Kozicz E, Moretti PM, Morimoto M, Mulvihill JJ, Murdock DR, Nath A, Nelson SF, Newberry JS, Newman JH, Nicholas SK, Novacic D, Oglesbee D, Orengo JP, Pace L, Pak S, Pallais JC, Palmer CGS, Papp JC, Parker NH, Phillips JA 3rd, Posey JE, Postlethwait JH, Potocki L, Pusey BN, Quinlan A, Raja AN, Renteria G, Reuter CM, Rives L, Robertson AK, Rodan LH, Rosenfeld JA, Rowley RK, Ruzhnikov M, Sacco R, Sampson JB, Samson SL, Saporta M, Schaechter J, Schedl T, Schoch K, Scott DA, Shakachite L, Sharma P, Shashi V, Shields K, Shin J, Signer R, Sillari CH, Silverman EK, Sinsheimer JS, Sisco K, Smith KS, Solnica-Krezel L, Spillmann RC, Stoler JM, Stong N, Sullivan JA, Sutton S, Sweetser DA, Tabor HK, Tamburro CP, Tan QK, Tekin M, Telischi F, Thorson W, Tifft CJ, Toro C, Tran AA, Urv TK, Velinder M, Viskochil D, Vogel TP, Wahl CE, Walley NM, Walsh CA, Walker M, Wambach J, Wan J, Wang LK, Wangler MF, Ward PA, Waters KM, Webb-Robertson BM, Wegner D, Westerfield M, Wheeler MT, Wise AL, Wolfe LA, Woods JD, Worthey EA, Yamamoto S, Yang J, Yoon AJ, Yu G, Zastrow DB, Zhao C, Zuchner S.

Author information

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: mindellj@ninds.nih.gov.
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: malicdanm@mail.nih.gov.

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

PMID:
31155284
PMCID:
PMC6562152
[Available on 2019-12-06]
DOI:
10.1016/j.ajhg.2019.04.008

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