Isolated homozygous R217X OPTN mutation causes knock-out of functional C-terminal optineurin domains and associated oligodendrogliopathy-dominant ALS-TDP


Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative diseasecaused in a minority of individuals by mutations in more than one classical ALS-associated Mendelian gene, consistent with ‘oligogenic’ inheritance.1 This observation complicates the dissection of precise genotype–phenotype relationships. In the absence of comprehensive genomic analysis (such as whole-exome sequencing) and molecular neuropathology, inferences of genotype–phenotype associations may be misleading, with potentially negative consequences for patient counselling, concepts of pathogenesis, disease modelling and patient selection for genomic therapeutics. Mutations in the autophagic adapter OPTN have been reported as causative of ALS2 and are associated with diverse neuropathology, while also coexisting with other Mendelian ALS gene variants.3 4

To help clarify the role of OPTN variants in the pathogenesis of ALS, and refine genotype–phenotype associations, we provide a comprehensive genomic, neuropathological and biochemical analysis of an individual with a novel, isolated, homozygous R217X (c.649A>T) OPTN

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