OPTN – Amyotrophic Lateral Sclerosis

OPTN (HGNC:17142) is implicated in autosomal recessive and autosomal dominant forms of amyotrophic lateral sclerosis (ALS; MONDO:0004976). To date, at least 13 unrelated ALS probands have been reported with OPTN loss-of-function variants, including two siblings with homozygous exon 5 deletions (n=2) (PMID:22152722), a Danish family segregating c.493C>T (p.Gln165Ter) (n=2) (PMID:21852022), and a large Italian cohort identifying heterozygous nonsense, frameshift and splice mutations in familial and sporadic cases (n=9) (PMID:21613650).

Segregation analysis has demonstrated cosegregation of OPTN variants in seven affected relatives across three families: two sib pairs with homozygous or compound heterozygous deletions (PMID:22152722; PMID:38689506) and a father–child pair with a heterozygous nonsense allele (PMID:21852022). Case–control and population screenings confirm that OPTN variants are rare in healthy individuals, supporting a pathogenic role in ALS.

The inheritance is primarily autosomal recessive for homozygous LOF alleles, but heterozygous truncating and missense mutations act in a dominant manner with incomplete penetrance. One recurrent variant is c.493C>T (p.Gln165Ter), which has been reported in multiple affected individuals and is absent from population controls. The phenotypic spectrum includes classical limb-onset ALS with rapid progression to respiratory failure and occasional frontotemporal dementia overlap.

Functional studies support a loss-of-function mechanism. OPTN deficiency or mutation impairs selective autophagy and disrupts linear ubiquitin binding through the UBAN domain, leading to deregulated NF-κB activation and increased neuronal apoptosis (PMID:23721573; PMID:23357852). OPTN also interacts with TBK1, and both proteins colocalize in TDP-43-negative inclusions in ALS motor neurons (PMID:25943890).

Although OPTN mutations are rare (<1% of sporadic and 1–3% of familial ALS), their presence in multiple independent cohorts, concordant segregation, and concordant functional data support a Strong gene–disease association. A minority of screening studies in primarily Caucasian sporadic cohorts identified no pathogenic OPTN variants, but these findings do not undermine the overall genetic and experimental concordance.

Key Take-home: OPTN LOF variants confer a strong, clinically actionable risk for ALS; comprehensive OPTN sequencing is recommended in familial or early-onset ALS for diagnosis, genetic counselling, and potential therapeutic stratification.

References

• Journal of medical case reports • 2011 • Severe brain atrophy after long-term survival seen in siblings with familial amyotrophic lateral sclerosis and a mutation in the optineurin gene: a case series PMID:22152722
• Neurobiology of aging • 2012 • Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS PMID:21852022
• Journal of neurology, neurosurgery, and psychiatry • 2011 • Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis PMID:21613650
• Annals of clinical and translational neurology • 2024 • Clinical heterogeneity within the ALS-FTD spectrum in a family with a homozygous optineurin mutation PMID:38689506
• Journal of neurochemistry • 2013 • Optineurin suppression causes neuronal cell death via NF-κB pathway PMID:23721573
• Autophagy • 2013 • M98K-OPTN induces transferrin receptor degradation and RAB12-mediated autophagic death in retinal ganglion cells PMID:23357852
• Acta neuropathologica • 2015 • Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease PMID:25943890

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