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

Journal article

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 mutation and clinically upper motor neuron-dominant form of ALS-TDP with severe oligodendrogliopathy. The proband presented to the Oxford Motor Neuron Disease Clinic and enrolled in the brain donation programme of the Oxford Brain Bank, enabling integration of clinical observations with molecular neuropathological data, including whole exome-sequencing, repeat-primed PCR, OPTN mRNA and protein analyses, and comparison with both healthy brain tissue and that from sporadic (s) ALS-TDP patients. Please refer to online supplemental data for comprehensive methods. ### Supplementary data [jnnp-2020-325803supp001.pdf] ### Clinical vignette A middle-aged man presented with slowly progressive spastic dysarthria associated with an exaggerated jaw jerk and no other abnormal neurological findings. Dysarthria progressed to anarthria over 2 years and neuropsychometry reported mild abnormalities in executive function, but no evidence of language or behavioural abnormalities. Over the following 4 years, weakness with marked increase in tone but without wasting or fasciculations extended to all four limbs. Mild executive dysfunction continued but there was no progression to frontotemporal dementia. Tongue wasting and fasciculations, …

Authors: Nolan, M; Barbagallo, P; Turner, MR; Keogh, MJ; Chinnery, PF

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BMJ Publishing Group
• Journal: Journal of Neurology, Neurosurgery and Psychiatry
• Volume: 92
• Issue: 9
• Pages: 1022-1024
• Publication date: 2021-03-16
• DOI: 10.1136/jnnp-2020-325803
• EISSN: 1468-330X
• ISSN: 0022-3050
• Language: English
• Keywords: Optineurin; Gene; Biology; Computer science; Mutation; Genetics; Terminal (telecommunication)