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

Abstract

We 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.

Keywords

dilated cardiomyopathy - X-linked dilated cardiomyopathy - dystrophin gene - utrophin upregulation - splice site mutation

Publikationsverlauf

Eingereicht: 06. Januar 2017

Angenommen: 22. Mai 2017

Publikationsdatum:
24. August 2017 (online)

• References

• 1 Weintraub RG, Semsarian C, Macdonald P. Dilated cardiomyopathy. Lancet 2017;
• 2 Shimizu M, Ino H, Yasuda T. et al. Gene mutations in adult Japanese patients with dilated cardiomyopathy. Circ J 2005; 69 (02) 150-153
• 3 Arbustini E, Diegoli M, Morbini P. et al. Prevalence and characteristics of dystrophin defects in adult male patients with dilated cardiomyopathy. J Am Coll Cardiol 2000; 35 (07) 1760-1768
• 4 Nakamura A. X-linked dilated cardiomyopathy: a cardiospecific phenotype of dystrophinopathy. Pharmaceuticals (Basel) 2015; 8 (02) 303-320
• 5 Haas J, Frese KS, Peil B. et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J 2015; 36 (18) 1123-1135
• 6 Pronicka E, Piekutowska-Abramczuk D, Ciara E. et al. New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. J Transl Med 2016; 14 (01) 174 . Doi: 10.1186/s12967-016-0930-9
• 7 Milasin J, Muntoni F, Severini GM. et al. A point mutation in the 5′ splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy. Hum Mol Genet 1996; 5 (01) 73-79
• 8 Kimura S, Ikezawa M, Ozasa S. et al. Novel mutation in splicing donor of dystrophin gene first exon in a patient with dilated cardiomyopathy but no clinical signs of skeletal myopathy. J Child Neurol 2007; 22 (07) 901-906
• 9 Muntoni F, Melis MA, Ganau A, Dubowitz V. Transcription of the dystrophin gene in normal tissues and in skeletal muscle of a family with X-linked dilated cardiomyopathy. Am J Hum Genet 1995; 56 (01) 151-157
• 10 Bastianutto C, Bestard JA, Lahnakoski K. et al. Dystrophin muscle enhancer 1 is implicated in the activation of non-muscle isoforms in the skeletal muscle of patients with X-linked dilated cardiomyopathy. Hum Mol Genet 2001; 10 (23) 2627-2635
• 11 Holder E, Maeda M, Bies RD. Expression and regulation of the dystrophin Purkinje promoter in human skeletal muscle, heart, and brain. Hum Genet 1996; 97: 232-239
• 12 Yoshida K, Ikeda S, Nakamura A. et al. Molecular analysis of the Duchenne muscular dystrophy gene in patients with Becker muscular dystrophy presenting with dilated cardiomyopathy. Muscle Nerve 1993; 16 (11) 1161-1166
• 13 Muntoni F, Cau M, Ganau A. et al. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med 1993; 329 (13) 921-925
• 14 Feng J, Yan JY, Buzin CH, Sommer SS, Towbin JA. Comprehensive mutation scanning of the dystrophin gene in patients with nonsyndromic X-linked dilated cardiomyopathy. J Am Coll Cardiol 2002; 40 (06) 1120-1124
• 15 Dubowitz V, Sewry CA, Oldfors A. Immunohistochemistry and immunoblotting. Muscle Biopsy: A Practical Approach, 4th ed. Chap 6. Sanders Elsevier; 2013: 192-203
• 16 Finsterer J, Bittner RE, Grimm M. Cardiac involvement in Becker's muscular dystrophy, necessitating heart transplantation, 6 years before apparent skeletal muscle involvement. Neuromuscul Disord 1999; 9 (08) 598-600