de Brouwer et al. A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy. European Journal of Human Genetics (2014) 22, 480–485.
A very interesting observation, underlining the importance of dystrophin isoforms for the understanding of genotype-phenotype correlations in DMD-associated disorders. The authors describe a family with non-specific X-linked intellectual disability and no clinically observable muscular dystrophy; a 3-base pair deletion, c.9711_9713del (p.Leu3238del), in DMD was identified. Linkage analysis, molecular modelling, conservation analysis, and a mildly elevated CK in the index patient supported causality.
It appears that the mutation affects all isoforms of dystrophin by destabilising its C-terminal domain and thus reducing its binding to beta-dystroglycan; however, it seems to especially affect the function of the Dp71 isoform, expressed in brain but not in muscle. Indeed, Dp71 levels were found to be 6.7 times lower in the affected patient’s lymphoblastoid cells than in controls, though the finding was not statistically significant. The reason for the disproportionate functional effect on Dp71 does not appear to be clear.
The finding highlights the importance of dystrophin isoforms in the central nervous system and the importance of taking the possibly differential effects of mutations on the various isoforms when looking for genotype-phenotype correlations in the DMD-associated disorders, as well as establishing mutations in DMD as a potential cause of X-linked intellectual disability without overt muscular dystrophy.
Posted by Alina Levtova, MD.