Novel MAG Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype

• Autor(es): Santos, Mariana ; Damásio, Joana ; Kun-Rodrigues, Celia ; Barbot, Clara ; Sequeiros, Jorge ; Brás, José ; Alonso, Isabel ; Guerreiro, Rita
• Data: 2020
• Identificador Persistente: http://hdl.handle.net/10400.16/2659
• Origem: Repositório Científico da Unidade Local de Saúde de Santo António (ULSSA)
• Assunto(s): cerebellar ataxia; exome sequencing; myelin-associated glycoprotein
• Tipo de Documento: Artigo científico
• Idioma: Inglês
• Contribuidor(es): Repositório Científico da Unidade Local de Saúde de Santo António

Descrição

Homozygous variants in MAG, encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in MAG (c.124T>C; p.Cys42Arg) in a Portuguese family with early-onset autosomal recessive cerebellar ataxia with neuropathy and oculomotor apraxia. We used homozygosity mapping and exome sequencing to identify the MAG variant, and cellular studies to confirm its detrimental effect. Our results showed that this variant reduces protein stability and impairs the post-translational processing (N-linked glycosylation) and subcellular localization of MAG, thereby associating a loss of protein function with the phenotype. Therefore, MAG variants should be considered in the diagnosis of hereditary cerebellar ataxia with oculomotor apraxia, in addition to spastic paraplegia.