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

Area of Science:

• Neurogenetics
• Molecular Neurology

Background:

• Myelin-associated glycoprotein (MAG) is crucial for myelination.
• Homozygous variants in MAG are linked to hereditary spastic paraplegia (HSP).

Purpose of the Study:

• To identify the genetic cause of early-onset autosomal recessive cerebellar ataxia with neuropathy and oculomotor apraxia in a Portuguese family.
• To investigate the functional consequences of a novel MAG variant.

Main Methods:

• Homozygosity mapping and exome sequencing were employed to identify the genetic variant.
• Cellular studies were conducted to assess the impact of the identified MAG variant on protein function.

Main Results:

• A novel homozygous missense variant (c.124T>C; p.Cys42Arg) in the MAG gene was identified.
• The MAG variant was shown to decrease protein stability, impair N-linked glycosylation, and disrupt subcellular localization.
• These functional impairments link the MAG variant to the observed phenotype.

Conclusions:

• The identified MAG variant causes a loss of protein function, leading to cerebellar ataxia, neuropathy, and oculomotor apraxia.
• MAG variants should be considered in the differential diagnosis of hereditary cerebellar ataxia with oculomotor apraxia, beyond hereditary spastic paraplegia.