Abstract
Objective: Dysferlin deficiency causes dysferlinopathy. This study aimed to expand the mutational spectrum of dysferlinopathies, to further study one case with diagnostic ambiguity, and to identify the diagnostic value of dysferlin expression in total peripheral blood mononuclear cells (PBMC).Methods: The clinical and molecular profiles of dysferlinopathies in eight Chinese patients were evaluated. We also conducted magnetic resonance imaging (6/8) and determined dysferlin protein expression in muscle (7/8) and PBMC (3/8).Results: Nine of the 13 DYSF mutations identified were novel. One patient was homozygous for the Gln111Ter mutation by genomic DNA sequencing but was found to be heterozygous by sequencing of cDNA from total PBMC. A daughter of this patient did not carry any Gln111Ter mutation. Abnormal muscle MRI with predominant involvement of the medial gastrocnemius and soleus muscle was observed in 5/6 patients. Dysferlin levels were significantly reduced (immunohistochemistry/immunoblot) or absent (immunohistochemistry) in muscle and total PBMC (26–39%) for most patients. Sarcoplasmic accumulation of dysferlin was detected in one patient.Conclusion: Genomic DNA sequencing detects frequent homozygous mutations, while fewer heterozygous mutations in cDNA are detected after posttranscription. Total PBMC may serve as an alternative to confirm diagnosis and to guide further testing in dysferlinopathies. Our results contribute to the mutational spectrum of dysferlinopathies.
Highlights
Dysferlinopathies are autosomal recessive muscular dystrophies caused by mutations in DYSF [1]
Magnetic resonance imaging (MRI) of muscle, immunohistochemistry (IHC) of muscle, immunoblotting of dysferlin expression in total peripheral blood mononuclear cells (PBMC), and/or muscle and genetic analysis were obtained from some patients after informed consent
The control PBMC sample was taken from patient 1’s sister with informed consent since she is a non-carrier of DYSF mutations
Summary
Dysferlinopathies are autosomal recessive muscular dystrophies caused by mutations in DYSF [1]. Three classic phenotypes have been described including Miyoshi myopathy Other intermediate proximodistal phenotypes, pseudometabolic myopathy, and hyperCKemia occur [2, 3]. DYSF, a large gene (>230 kb) located on chromosome 2p13, contains 55 exons [1]. Deep intronic mutations can be a common underlying cause of dysferlinopathy [5]. Because these mutations are not concentrated at any “mutational hot spot” [2, 3], DYSF mutation analysis remains challenging and time-consuming
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