A CD33 frameshift variant is associated with neuromyelitis optica spectrum disorders

Area of Science:

• Neuroimmunology
• Genetics
• Autoimmune Disorders

Background:

• Neuromyelitis optica spectrum disorder (NMOSD) is a rare neuroimmunology disorder with a higher prevalence in East Asian populations.
• Genetic factors, including human leukocyte antigen (HLA) and interleukin (IL) gene polymorphisms, are implicated in NMOSD pathogenesis.
• While familial cases are rare, genetic predisposition is suspected in NMOSD development.

Purpose of the Study:

• To investigate the genetic basis of NMOSD in a Taiwanese family and a cohort of sporadic patients.
• To identify potential genetic risk loci associated with aquaporin 4 antibody-positive NMOSD.

Main Methods:

• Whole exome sequencing (WES) was performed on an affected mother and daughter with NMOSD and their unaffected father.
• Sanger sequencing of the CD33 gene was conducted on 19 sporadic aquaporin 4 antibody-positive NMOSD patients.
• Genetic variants were analyzed for association with NMOSD status and compared to population controls.

Main Results:

• A 19 base pair deletion in exon 4 of the CD33 gene, causing a frameshift and premature protein truncation, was identified in the NMOSD-affected family members.
• This CD33 frameshift variant was found in 19.04% of sporadic NMOSD patients, significantly higher than the 2% observed in Taiwanese population controls.
• The identified CD33 variant is a potential risk locus for NMOSD, suggesting a role in immune dysregulation.

Conclusions:

• A specific CD33 gene deletion is identified as a potential genetic risk factor for neuromyelitis optica spectrum disorder (NMOSD).
• The loss of function associated with this CD33 variant may disrupt immune system regulation in NMOSD patients.
• Further research with larger cohorts and functional studies is warranted to confirm these findings and elucidate the precise role of CD33 in NMOSD.