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Mol Genet Metab. 2019 Feb;126(2):188-195. doi: 10.1016/j.ymgme.2018.12.001. Epub 2018 Dec 3.

Novel mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis without visual impairment in two unrelated patients.

Author information

1
NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.
2
National Eye Institute, National Institute of Health, Bethesda, MD, United States.
3
Department of Neurology, Stanford University, Palo Alto, CA, United States.
4
NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.
5
NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States. Electronic address: malicdanm@mail.nih.gov.

Abstract

CLN6 is a transmembrane protein located in the endoplasmic reticulum that is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis (LINCL), and teenage and adult onset NCL without visual impairment. Here we describe two pediatric patients with LINCL from unrelated families who were evaluated at the National Institutes of Health. Both children exhibited typical phenotypes associated with LINCL except that they lacked the expected visual impairment. Whole exome sequencing identified novel biallelic mutations in CLN6, i.e., c.218-220dupGGT (p.Trp73dup) and c.296A > G (p.Lys99Arg) in Proband 1 and homozygous c.723G > T (p.Met241Ile) in Proband 2. Expression analysis in dermal fibroblasts showed a small increase in CLN6 protein levels. Electron micrographs of these fibroblasts demonstrated large numbers of small membrane-bound vesicles, in addition to lipofuscin deposits. LysoTracker™ Red intensity was increased in fibroblasts from both patients. This study supports a role for CLN6 in lysosomal homeostasis, and highlights the importance of considering CLN6 mutations in the diagnosis of Batten Disease even in patients with normal vision.

KEYWORDS:

Batten disease; Lysosomal Storage Disorders; Neuronal Ceroid Lipofuscinosis

PMID:
30528883
DOI:
10.1016/j.ymgme.2018.12.001
[Indexed for MEDLINE]

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