Genetic and epigenetic determinants of low dysferlin expression in monocytes.
Dysferlinopathies are autosomal recessive inherited muscular dystrophies caused by mutations in the gene DYSF. Dysferlin is primarily expressed in skeletal muscle, cardiac muscle, and peripheral blood monocytes. Expression in skeletal muscle and monocytes strongly correlates in healthy and disease states. We evaluated the efficiency of the monocyte assay to detect carriers and to determine the carrier frequency of dysferlinopathies in the general population. We enrolled 149 healthy volunteers and collected peripheral blood samples for protein analysis. While 18 of these individuals with protein levels in the range of 40%-64% were predicted to be carriers by the monocyte assay, subsequent DYSF sequencing analysis in 14 of 18 detected missense variants in only four. Analysis of DNA methylation patterns at the DYSF locus showed no changes in methylation levels at CpG islands and shores between samples. Our results suggest that: (1) dysferlin expression can also be regulated by factors outside of the dysferlin gene, but not related to DNA methylation; (2) carrier frequency and therefore the number of affected individuals could be higher than previously estimated; and (3) although reliable for evaluating dysferlinopathies, the monocyte assay cannot be used to determine the carrier status; for this, a molecular analysis of DYSF must be performed.
Laboratori de Malalties Neuromusculars, Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Eduard
E
Gallardo
Arunkanth
A
Ankala
Yaiza
Y
Núñez-Álvarez
Madhuri
M
Hegde
Jordi
J
Diaz-Manera
Noemí De
ND
Luna
Ana
A
Pastoret
Mònica
M
Suelves
Isabel
I
Illa
D000328:Adult; D000368:Aged; D001782:Blood Donors; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D000073939:Dysferlin; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011237:Predictive Value of Tests
C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins
DYSF; dysferlin; methylation; monocyte