Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis.
Neurobiol Aging
; 58: 239.e11-239.e20, 2017 10.
Article
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| MEDLINE
| ID: mdl-28716533
ABSTRACT
Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c.1462G>A, p.Ala488Thr, A488T) adjacent to this hotspot UBQLN2 domain was identified in a sporadic case of ALS. These mutations are conserved in mammals, are absent from ExAC and gnomAD browsers, and are predicted to be deleterious by SIFT in silico analysis. Patient lymphoblasts carrying a UBQLN2 mutation showed absence of ubiquilin-2 accumulation, disrupted binding with HSP70, and impaired autophagic pathway. Our results confirm the role of PXX repeat in ALS pathogenesis, show that UBQLN2-linked disease can manifest like a SP phenotype, evidence a highly reduced disease penetrance in females carrying UBQLN2 mutations, which is important information for genetic counseling, and underline the pivotal role of ubiquilin-2 in proteolysis regulation pathways.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fenotipo
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Ubiquitinas
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Paraplejía Espástica Hereditaria
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Proteínas HSP70 de Choque Térmico
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Proteínas de Ciclo Celular
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Mutación Missense
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Demencia Frontotemporal
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Estudios de Asociación Genética
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Proteolisis
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Esclerosis Amiotrófica Lateral
Límite:
Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Neurobiol Aging
Año:
2017
Tipo del documento:
Article
País de afiliación:
Francia