Missense mutation of MAL causes a rare leukodystrophy similar to Pelizaeus-Merzbacher disease.
Eur J Hum Genet
; 30(7): 860-864, 2022 07.
Article
em En
| MEDLINE
| ID: mdl-35217805
ABSTRACT
Leukodystrophies are a heterogenous group of genetic disorders, characterised by abnormal development of cerebral white matter. Pelizaeus-Merzbacher disease is caused by mutations in PLP1, encoding major myelin-resident protein required for myelin sheath assembly. We report a missense variant p.(Ala109Asp) in MAL as causative for a rare, hypomyelinating leukodystrophy similar to Pelizaeus-Merzbacher disease. MAL encodes a membrane proteolipid that directly interacts with PLP1, ensuring correct distribution during myelin assembly. In contrast to wild-type MAL, mutant MAL was retained in the endoplasmic reticulum but was released following treatment with 4-phenylbutyrate. Proximity-dependent identification of wild-type MAL interactants implicated post-Golgi vesicle-mediated protein transport and protein localisation to membranes, whereas mutant MAL interactants suggested unfolded protein responses. Our results suggest that mislocalisation of MAL affects PLP1 distribution, consistent with known pathomechanisms for hypomyelinating leukodystrophies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doenças Neurodegenerativas
/
Doença de Pelizaeus-Merzbacher
Tipo de estudo:
Etiology_studies
Limite:
Humans
Idioma:
En
Revista:
Eur J Hum Genet
Ano de publicação:
2022
Tipo de documento:
Article