ITM2B – ABri amyloidosis

Autosomal dominant mutations in ITM2B underlie Familial British dementia characterized by ABri amyloid deposition in the CNS. A novel heterozygous c.800G>C (p.Ser266_Ter267insSerThrValLysLysAsnIleIleGluGluAsn) variant was identified in a Korean kindred segregating with progressive cognitive impairment, cerebral infarction, MRI white matter hyperintensities, and absence of amyloid-β on PET, consistent with ABri amyloidosis pathology (1 proband, 2 affected relatives (PMID:37038821)).

Cellular assays confirm that BRI2 is N-glycosylated at Asn170, a post-translational modification essential for its trafficking to the plasma membrane but dispensable for furin/ADAM10 processing, aligning with a pathogenic mechanism of altered BRI2 handling and amyloid peptide generation ([PMID:21752865]).

Key take-home: ITM2B genetic testing should be considered in dementia cases with atypical amyloid imaging to inform diagnosis and therapeutic strategies.

References

• Journal of Alzheimer's disease : JAD • 2023 • A Novel c.800G>C Variant of the ITM2B Gene in Familial Korean Dementia. PMID:37038821
• Glycobiology • 2011 • Glycosylation of BRI2 on asparagine 170 is involved in its trafficking to the cell surface but not in its processing by furin or ADAM10. PMID:21752865

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