Missense mutation of MAL causes a rare leukodystrophy similar to Pelizaeus-Merzbacher disease

Autor: Marilena Elpidorou, James A. Poulter, Katarzyna Szymanska, Wia Baron, Katrin Junger, Karsten Boldt, Marius Ueffing, Lydia Green, John H. Livingston, Eammon G. Sheridan, Colin A. Johnson
Přispěvatelé: Molecular Neuroscience and Ageing Research (MOLAR)
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: European journal of human genetics : EJHG, 860-864. Nature Publishing Group
STARTPAGE=860;ENDPAGE=864;ISSN=1018-4813;TITLE=European journal of human genetics : EJHG
ISSN: 1018-4813
Popis: 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.
Databáze: OpenAIRE
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