Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS.
Neurobiol Dis
; 48(3): 391-8, 2012 Dec.
Article
en En
| MEDLINE
| ID: mdl-22766032
ABSTRACT
UNLABELLED Genetic variants in UBQLN1 gene have been linked to neurodegeneration and mutations in UBQLN2 have recently been identified as a rare cause of amyotrophic lateral sclerosis (ALS). OBJECTIVE:
To test if genetic variants in UBQLN1 are involved in ALS.METHODS:
102 and 94 unrelated patients with familial and sporadic forms of ALS were screened for UBQLN1 gene mutations. Single nucleotide variants were further screened in a larger set of sporadic ALS (SALS) patients and unrelated control subjects using high-throughput Taqman genotyping; variants were further assessed for novelty using the 1000Genomes and NHLBI databases. In vitro studies tested the effect of UBQLN1 variants on the ubiquitin-proteasome system (UPS).RESULTS:
Only two UBQLN1 coding variants were detected in the familial and sporadic ALS DNA set; one, the missense mutation p.E54D, was identified in a single patient with atypical motor neuron disease consistent with Brown-Vialetto-Van Laere syndrome (BVVLS), for whom c20orf54 mutations had been excluded. Functional studies revealed that UBQLN1E54D protein forms cytosolic aggregates that contain mislocalized TDP-43 and impairs degradation of ubiquitinated proteins through the proteasome.CONCLUSIONS:
Genetic variants in UBQLN1 are not commonly associated with ALS. A novel UBQLN1 mutation (E45D) detected in a patient with BVVLS altered nuclear TDP-43 localization in vitro, suggesting that UPS dysfunction may also underlie the pathogenesis of this condition.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Parálisis Bulbar Progresiva
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Proteínas Portadoras
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Proteínas de Ciclo Celular
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Pérdida Auditiva Sensorineural
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Esclerosis Amiotrófica Lateral
Tipo de estudio:
Risk_factors_studies
Límite:
Female
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Humans
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Male
Idioma:
En
Revista:
Neurobiol Dis
Asunto de la revista:
NEUROLOGIA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos