The C57BL/10ScSn‐Dmdmdx/J (BL10‐mdx) mouse has been the most commonly used model for Duchenne muscular dystrophy (DMD) for decades. Their muscle dysfunction and pathology is, however, less severe than in patients with DMD, which complicates preclinical studies. Recent discoveries indicate that disease severity is exacerbated when muscular dystrophy mouse models are generated on a DBA2/J genetic background. Knowledge on the natural history of animal models is pivotal for high‐quality preclinical testing. However, for BL10‐mdx mice on a DBA2/J background (D2‐mdx), limited data are available. We addressed this gap in the natural history knowledge. First, we compared histopathological aspects in skeletal muscles of young D2‐mdx, BL10‐mdx, and wild‐type mice. Pathology was more pronounced in D2‐mdx mice and differed in severity between muscles within individuals. Secondly, we subjected D2‐mdx mice to a functional test regime for 34 weeks and identified that female D2‐mdx mice outperform severely impaired males, making females less useful for functional preclinical studies. Direct comparisons between 10‐ and 34‐wk‐old D2‐mdx mice revealed that disease pathology ameliorates with age. Heart pathology was progressive, with some features already evident at a young age. This natural history study of the D2‐mdx mouse will be instrumental for experimental design of future preclinical studies.—Van Putten, M., Putker, K., Overzier, M., Adamzek, W. A., Pasteuning‐Vuhman, S., Plomp, J. J., Aartsma‐Rus, A. Natural disease history of the D2‐mdx mouse model for Duchenne muscular dystrophy. FASEB J. 33, 8110–8124 (2019). http://www.fasebj.org

ObjectiveTo determine the small vessel disease spectrum associated with cysteine altering NOTCH3 variants in community dwelling individuals, by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants.MethodsThe exome- and genome sequencing datasets of UK Biobank (n=50,000) and cohorts of cognitively healthy elderly (n=751) were queried for cysteine altering NOTCH3 variants. Brain MRI’s of individuals harboring such variants were scored according to STRIVE criteria and clinical information was extracted using ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex matched UK Biobank controls and clinically diagnosed patients from the Dutch CADASIL registry.ResultsWe identified 108 individuals harboring a cysteine altering NOTCH3 variant (2.2/1000), of which 75% has a variant which has been previously reported in CADASIL pedigrees. Almost all variants were located in one of the NOTCH3 protein epidermal growth factor-like repeat domains 7-34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p=0.006), but lower than in CADASIL patients with the same variants (p<0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70. There was no increased risk of stroke.ConclusionsAlthough community dwelling individuals harboring a cysteine altering NOTCH3 variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to non-penetrance.