Dystrophin-gene mutation location influences severity of electroretinogram defects in mouse models of Duchenne...

Duchenne muscular dystrophy (DMD) results from mutations in the DMD gene, which differentially affect dystrophin isoforms (Dp427, Dp260, Dp140, Dp71) expressed in distinct brain and retinal cell types. The selective loss of one or more isoforms contributes to heterogeneous cognitive and neuropsychiatric comorbidities. Here, we investigated whether specific mutations differentially affect retinal function by comparing genotype-dependent electroretinographic (ERG) responses in mouse models lacking different dystrophins.

We analyzed in vivo dark-adapted (DA) and light-adapted (LA) flash electroretinograms (ERG) in four adult DMD mouse models: Mdx and mdx5cv mice lacking Dp427; mdx^2Cv mice lacking Dp427 and Dp260; and dmd-null mouse lacking all dystrophins, compared to their respective WT littermate male mice and to ERGs previously recorded in mdx52 mice (lacking Dp427, Dp260 and Dp140).

Mutations affecting the expression of the Dp140 and Dp71 isoforms produced more severe ERG abnormalities, consistent with findings in patients and aligned with intellectual disability severity. ERG parameter analysis revealed unique roles for Dp427 and Dp260 in rod ribbon-synapse transmission, additional Dp260 function in inner retina, and involvement of Dp140/Dp71 in cone photoreceptor pathways.

These findings highlight the relevance of ERG as a potential biomarker for central dysfunction in DMD, and support its translational application for patient stratification and targeted therapeutic approaches.