X-linked Dilated Cardiomyopathy with Mutation in the 5′ Splice Site Intron 1 of Dystrophin Gene with Utrophin Upregulation

Abstract

AbstractWe report a teenage boy presented with dilated cardiomyopathy (DCM) with no initial skeletal involvement and initial normal creatine kinases. One year after the heart transplantation, he had exercise-induced transient muscle weakness with elevated creatine kinases (CKs). Muscle biopsy showed normal structures and normal dystrophin immunohistochemical labeling, but utrophin, which is an autosomal homologue of dystrophin, was overexpressed at sarcolemma. Sanger sequencing confirmed a heterozygous c.31 + 1G > A, 5′ splice site point mutation at the first intron of dystrophin gene. A review of previous reports of patients with different point mutations in the same region, the first exon–intron boundary that involved the muscle promotor to exon 1, confirmed a high correlation of cardiospecific phenotype sparing the muscles with this specific site of mutations. The confirmation of upregulation of brain and Purkinje isoforms of dystrophin protein in the skeletal muscles but not in the heart in past studies help to explain the skeletal sparing presentation. X-linked DCM (XLDCM) is an important cause of isolated cardiomyopathy. Routine immunohistochemical staining study including dystrophin in cardiac muscle biopsy, and dystrophin and utrophin labelling on skeletal muscle biopsy for patients with subsequent muscle symptoms or raised creatine kinases, help in the early diagnosis of the XLDCM. Future experimental study to determine the aberrant pre-mRNA splicing of this specific splice site mutation involving exon 1 and intron 1 will help to understand better the underlying complex mechanism of the splicing regulation.