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

Joseph J Chin; Babak Behnam; Mariska Davids; Prashant Sharma; Wadih M Zein; Camille Wang; Xenia Chepa-Lotrea; William Brian Gallantine; Camilo Toro; David R Adams; Cynthia J Tifft; William A Gahl; May Christine V Malicdan

doi:10.1016/j.ymgme.2018.12.001

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

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

Affiliations

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.

PMID: 30528883
DOI: 10.1016/j.ymgme.2018.12.001

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.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Adolescent
Adult
Child
Exome / genetics
Female
Fibroblasts / chemistry
High-Throughput Nucleotide Sequencing
Humans
Male
Membrane Proteins / genetics*
Mutation*
National Institutes of Health (U.S.)
Neuronal Ceroid-Lipofuscinoses / diagnosis*
Neuronal Ceroid-Lipofuscinoses / genetics*
Pedigree
United States
Vision Disorders

Substances

CLN6 protein, human
Membrane Proteins