DMPK mRNA Expression in Human Brain Tissue Throughout the Lifespan

Abstract

ObjectiveMyotonic dystrophy is a multisystem disorder caused by a trinucleotide repeat expansion on the myotonic dystrophy protein kinase (DMPK) gene. To determine whether wildtype DMPK expression patterns vary as a function of age, we analyzed DMPK expression in the brain from 99 donors ranging from 5 postconceptional weeks to 80 years old.MethodsWe used the BrainSpan messenger RNA sequencing and the Yale Microarray data sets, which included brain tissue samples from 42 and 57 donors, respectively. Collectively, donors ranged in age from 5 postconceptional weeks to 80 years old. DMPK expression was normalized for each donor across regions available in both data sets. Restricted cubic spline linear regression models were used to analyze the effects of log-transformed age and sex on normalized DMPK expression data.ResultsAge was a statistically significant predictor of normalized DMPK expression pattern in the human brain in the BrainSpan (p < 0.005) and Yale data sets (p < 0.005). Sex was not a significant predictor. Across both data sets, normalized wildtype DMPK expression steadily increases during fetal development, peaks around birth, and then declines to reach a nadir around age 10.ConclusionsPeak expression of DMPK coincides with a time of dynamic brain development. Abnormal brain DMPK expression due to myotonic dystrophy may have implications for early brain development.

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1

“…Phospholemman and phospholamban, which are respectively involved in ion transport and calcium uptake in cardiomyocytes, have also been identified as substrates of DMPK in vitro, although the physiological relevance remains to be determined [ 148 , 149 ]. DMPK is mainly expressed in skeletal and smooth muscles, in the intercalated discs of cardiac muscles as well as in the choroid plexus and the synaptic regions of the developing brain [ 150 , 151 , 152 ]. Homozygous Dmpk knock-out mice manifest late-onset mild myopathy consisting of small variable changes in the size of the head and neck muscle fibers as well as microstructural changes in myofibrillar organization [ 153 , 154 ].…”