Neurologic syndrome associated with homozygous mutation at MAG sialic acid binding site

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Myelin-associated glycoprotein (MAG) is crucial for axon-glial interactions and myelination.
• Mutations in MAG can lead to neurological disorders resembling Pelizaeus-Merzbacher disease.
• Previous studies identified a p.Ser133Arg MAG mutation in a consanguineous family.

Purpose of the Study:

• To investigate the genetic cause of progressive neurological disease in two brothers.
• To identify novel mutations in the MAG gene associated with demyelinating leukodystrophy.
• To elucidate the pathogenic mechanism of a newly identified MAG mutation.

Main Methods:

• Whole exome sequencing was performed on affected individuals.
• Segregation analysis of the identified mutation within the family.
• Analysis of the affected MAG protein domain and its function.

Main Results:

• Two brothers from a nonconsanguineous family presented with progressive cognitive impairment, neuropathy, ataxia, nystagmus, and gait disorder.
• Exome sequencing identified a homozygous missense mutation, p.Arg118His, in the MAG gene.
• The Arg118 residue is located in immunoglobulin domain 1 and is critical for sialic acid binding.

Conclusions:

• The p.Arg118His mutation in MAG is causative of a novel progressive neurological disorder.
• This mutation disrupts sialic acid binding, providing a mechanistic link to disease pathogenesis.
• The findings expand the spectrum of MAG-associated neurological diseases and underscore MAG's importance in nerve function.