Early cardiac failure in a child with Becker muscular dystrophy is due to an abnormally low amount of dystrophin transcript lacking exon 13

Abstract

Two Japanese brothers with Becker muscular dystrophy were shown by polymerase chain reaction (PCR) and cDNA sequence analysis to produce a dystrophin gene transcript lacking a single exon; that is, number 13. Despite having the same deletion mutation, the brothers showed clearly different clinical phenotypes: the younger brother developed cardiac failure at the age of nine, while the elder brother was asymptomatic. As alternative splicing was not responsible for this clinical difference, the amount of dystrophin transcript was examined by using reverse transcription semi-nested and parallel PCR. The results showed that the amount of the dystrophin transcript in the younger brother was 20% of that of the elder brother. This finding suggested that lesser amount of dystrophin transcript in the younger brother was responsible for the early onset of cardiac failure. This would represent a novel molecular mechanism for dystrophinopathy. Key wordsBecker muscular dystrophy, cardiac failure, dystrophin transcript.Duchenne and Becker muscular dystrophies (DMDBMD) are allelic diseases caused by mutation of the dystrophin gene, which extends over 3000 kb on Xp21 and has 79 exons. While DMD patients show very severe clinical symptoms and usually die at around 20 years old, BMD has a slower rate of progression: affected boys will remain ambulatory beyond the age of 16 years and a few may lead near-normal lives. Cardiac failure is one of the leading causes of death of DMD/BMD patients.Although cardiac involvement in dystrophinopathy has long been demonstrated, the pathogenesis of cardiac dysfunction

Gene expression profiling of the aging mouse cardiac myocytes

“…For example, the mRNA level for dystrophin was reduced with aging. In humans, the cardiomyopathies associated with Duchenne muscular dystrophy (19), Becker muscular dystrophy (20) and X-linked dilated cardiomyopathy are all caused by defects in the dystrophin gene (21). Since dystrophin-de®cient mice have an increased vulnerability to acute pressure overload in vivo the aging-associated reduced dystrophin mRNA level might contribute to a reduced threshold for the development of contractile dysfunction upon exposure to increased levels of mechanical stress (22).…”

Cardiac involvement in Becker muscular dystrophy

“…In a study of 19 patients with BMD (20), six of whom were younger than 22 years of age, two had exertional dyspnea. In a report (21) of two brothers with a deletion of exon 13, one developed heart failure at nine years of age, while the older brother was asymptomatic. The different phenotypes were attributed to the amount of dystrophin transcript in the younger brother, which was 20% of that of the older brother.…”

End-Stage Cardiac Disease as an Initial Presentation of Systemic Myopathies: Case Series and Literature Review

“…12 Genetic analysis showed that certain mutations seem to be associated with unique cardiac phenotypes at presentation (eg, missense rod domain lamin A/C mutations in autosomal dominant Emery-Dreifuss muscular dystrophy and A to G tRNA mutations in mitochondrial myopathy). 12,13 Despite the high incidence of cardiomyopathy in muscular dystrophies, such as myotonic dystrophy [14][15][16] and dystrophinopathies, 17,18 cases presenting initially with cardiac symptoms appear to be rare. Cardiac involvement generally increases with the progression of muscular dystrophies but some patients remain without cardiac symptoms for many years after the initial presentation of systemic weakness.…”