MAG encodes a transmembrane, cell adhesion molecule in the periaxonal layer of mature, non-compact myelin membranes, and maintains myelin-axon spacing by interacting with specific neuronal glycolipids (gangliosides) (PMIDs: 26179919; 27922006).
MAG was first reported in relation to ‘complex’ autosomal recessive hereditary spastic paraplegia (HSP) in 2014 (PMID: 26179919). Hereditary spastic paraplegia refers to a group of inherited disorders that are characterised by progressive weakness and spasticity of the lower limbs. The term ‘complex’ is included as all individuals presented with additional neurological phenotypes such as ataxia, eye phenotypes, cognitive impairments, and vibratory sense deficits. Age of onset was typically in infancy and early childhood. Symptoms were slowly progressive and can sometimes present early as a static clinical course.
Ten variants (missense and nonsense) have been reported in 8 families in 5 publications. We have included 6 probands and 7 variants in this curation (PMIDs: 26179919, 32629324, 27606346). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) had been reached (additional PMID: 24482476, 31402626). There was no functional evidence for any of the nonsense variants; however, functional evidence for two missense variants were included in the curation. The p.Ser133Arg variants showed accumulation of terminally misfolded proteins in the endoplasmic reticulum leading to their degradation (PMID: 26179919), and p.Arg118Ala/Asp variants demonstrated loss of activity of a highly conserved sialic acid binding site (PMID: 9298990). These studies support the assumption that variants in MAG are responsible for the patients’ phenotypes by acting through a loss of protein function activity.
This gene-disease relationship is further supported by a MAG knockout murine model (PMID: 34546337). The gene was disrupted by insertion of PGK-neo cassette into exon 5. Absence of gene expression was confirmed by Western blot analysis of brains from 26-day-old homozygous mutant mice. Mice showed abnormal Schwann cell morphology, abnormal axon morphology, axon degeneration, and demyelination.
In summary, there is a definitive relationship between MAG and autosomal recessive complex HSP. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on 20th November, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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