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Diagnostic overview of blood-based dysferlin protein assay for dysferlinopathies
Arunkanth Ankala1, Babi R Nallamilli, Laura E Rufibach
1Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia, 30322, USA.
Introduction:
Dysferlin deficiency causes dysferlinopathies. Among peripheral blood mononuclear cells (PBMCs), the dysferlin protein is expressed specifically in CD14(+) monocytes.
Methods:
We quantified dysferlin protein levels in PBMC lysates of 77 individuals suspected clinically of having a dysferlinopathy to screen for true positives. Subsequent molecular confirmation was done by Sanger sequencing and comparative genomic hybridization arrays to establish diagnosis.
Results:
Of the 44 individuals who had significantly reduced dysferlin levels (≤10%), 41 underwent molecular testing. We identified at least 1 mutation in 85% (35 of 41), and 2 mutations, establishing a dysferlinopathy diagnosis, in 61% (25 of 41) of these individuals. Among those with dysferlin protein levels of >10% (33 of 77), only 1 individual (of 14 who underwent molecular testing) had a detectable mutation.
Conclusions:
Our results suggest that dysferlin protein levels of ≤10% in PBMCs, are highly indicative of primary dysferlinopathies. However, this assay may not distinguish carriers from those with secondary dysferlin reduction.
Insights
Low dysferlin protein levels in peripheral blood mononuclear cells (PBMCs) strongly suggest dysferlinopathies. This blood test aids in diagnosing muscular dystrophy, but may not differentiate carriers from secondary reductions.
Area of Science:
- Neuromuscular disorders
- Protein biochemistry
- Genetic diagnostics
Background:
- Dysferlinopathies are caused by dysferlin protein deficiency.
- Dysferlin is specifically expressed in CD14(+) monocytes within PBMCs.
Purpose of the Study:
- To evaluate dysferlin protein levels in PBMCs as a diagnostic marker for dysferlinopathies.
- To correlate protein levels with molecular genetic findings.
Main Methods:
- Quantified dysferlin protein levels in 77 individuals with suspected dysferlinopathy.
- Used Sanger sequencing and CGH arrays for molecular confirmation.
Main Results:
- 44 individuals had significantly reduced dysferlin (≤10%).
- 85% of these (35/41) had at least one mutation; 61% (25/41) had two mutations confirming diagnosis.
- Only 1 of 14 individuals with >10% dysferlin had a detectable mutation.
Conclusions:
- PBMC dysferlin levels ≤10% are highly indicative of primary dysferlinopathies.
- The assay may not distinguish carriers from secondary dysferlin reduction.
