Loss of Dp140 dystrophin isoform and intellectual impairment in Duchenne dystrophy

Background: Mental retardation is a clinical feature of Duchenne dystrophy (DD) and affects about one-third of patients. No clear association has been found between DNA mutations, protein expression, and IQ scores, although d istal deletions in the dystrophin gene have been reported in association wi th intellectual impairment. A role for the brain distal dystrophin isoform Dp140 was suggested. Objective: To explore the possible association between cognitive impairment and DNA macrodeletions in the distal part of the gene , including Dp140 gene region. Methods: Sixty-six patients with DD received general intelligence assessment by Wechsler Intelligence Scales measuring full, verbal, and performance IQ. PCR analysis was performed to detect dele tions in the dystrophin gene, and the Dp140 regulatory region was analyzed in a subgroup of 12 patients. Statistical analysis was performed by nonpara metric Wilcoxon rank signed and rank sum tests. Results: Comparison of neur opsychological and genetic data revealed an association between distal macr odeletions and cognitive impairment (p < 0.001). Comparing deletions involv ing the Dp140 gene region with deletions presumably not altering Dp140 expr ession resulted in even greater significance. Conclusions: These data sugge st that in DD, distal dystrophin deletions are associated with intellectual impairment. This study highlights a possible role for the brain distal iso form Dp140 in normal cognitive development.