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

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 Pedigree United States Vision Disorders
Batten disease Lysosomal Storage Disorders Neuronal Ceroid Lipofuscinosis

Journal

Molecular genetics and metabolism
ISSN: 1096-7206
Titre abrégé: Mol Genet Metab
Pays: United States
ID NLM: 9805456

Informations de publication

Date de publication:
02 2019
Historique:
received: 27 09 2018
revised: 02 12 2018
accepted: 02 12 2018
pubmed: 12 12 2018
medline: 9 8 2019
entrez: 12 12 2018
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ymgme.2018.12.001 PMID: 30528883
pubmed: 30528883
pii: S1096-7192(18)30597-3
doi: 10.1016/j.ymgme.2018.12.001
pii:
doi:

Substances chimiques

CLN6 protein, human 0
Membrane Proteins 0

Types de publication

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

Langues

eng

Pagination

188-195

Informations de copyright

Copyright © 2018. Published by Elsevier Inc.

Auteurs

Joseph J Chin (JJ)

NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.

Babak Behnam (B)

NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.

Mariska Davids (M)

NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.

Prashant Sharma (P)

NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.

Wadih M Zein (WM)

National Eye Institute, National Institute of Health, Bethesda, MD, United States.

Camille Wang (C)

NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.

Xenia Chepa-Lotrea (X)

NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.

William Brian Gallantine (WB)

Department of Neurology, Stanford University, Palo Alto, CA, United States.

Camilo Toro (C)

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.

David R Adams (DR)

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.

Cynthia J Tifft (CJ)

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.

William A Gahl (WA)

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.

May Christine V Malicdan (MCV)

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.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Exome › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Cellules › Cellules du tissu conjonctif › Fibroblastes › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Séquençage nucléotidique à haut débit › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Organisations et économie des soins de santé › Organismes › Gouvernement › Agences gouvernementale américaines › Department of Health and Human Services (USA) › Public Health Service (USA) › National Institutes of Health (USA) › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Erreurs innées du métabolisme › Erreurs innées du métabolisme lipidique › Lipidoses › Céroïdes-lipofuscinoses neuronales › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Pedigree › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › Régions géographiques › Amériques › Amérique du Nord › États-Unis › Novel mutations in CLN6 cause late-infantile...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Troubles sensitifs › Troubles de la vision › Novel mutations in CLN6 cause late-infantile...