De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.
Brain
; 144(2): 411-419, 2021 03 03.
Article
em En
| MEDLINE
| ID: mdl-33313762
ABSTRACT
Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Ataxia
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Encéfalo
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Leucoencefalopatias
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Claudinas
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Hipogonadismo
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Anodontia
Limite:
Adolescent
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Child
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Female
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Humans
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Male
Idioma:
En
Revista:
Brain
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Alemanha