De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.
Am J Hum Genet
; 108(1): 186-193, 2021 01 07.
Article
en En
| MEDLINE
| ID: mdl-33417887
ABSTRACT
POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ataxia
/
ARN Polimerasa III
/
Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias
Tipo de estudio:
Prognostic_studies
Límite:
Adolescent
/
Adult
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Am J Hum Genet
Año:
2021
Tipo del documento:
Article
País de afiliación:
Canadá