A number sign (#) is used with this entry because of evidence that amyotrophic lateral sclerosis-12 (ALS12) is caused by homozygous or heterozygous mutation in the optineurin gene (OPTN; 602432) on chromosome 10p13.

Primary open angle glaucoma-1E (POAG; see 137760) is an allelic disorder caused by distinct missense mutations and segregating in an autosomal dominant manner.

For a general phenotypic description and discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).

Of 6 Japanese individuals from consanguineous marriages who had ALS, Maruyama et al. (2010) identified 3 with mutations in the OPTN gene. Two were sibs. One member of the sib pair developed muscle weakness of her left arm at 33 years of age that progressed to dysphagia requiring endotracheal intubation. She was bedridden by age 34 and died at age 57. Her brother also had onset with left arm weakness at 36 years of age and 1 year later developed dysphagia, dysarthria, and tongue fasciculations. He likewise required endotracheal intubation, was bedridden by age 37, and died at the age of 55. The third patient from a consanguineous family developed dysarthria at 52 years of age and had muscle weakness of her left upper and lower extremities starting at 54 years of age. Her deep tendon reflex was exaggerated, but there was no pathologic reflex. She was still breathing independently at 60 years of age. These 3 individuals were homozygous for mutation in OPTN; 4 other heterozygous individuals identified in a separate analysis had onset in their 50s with slow progression. All individuals with mutations of OPTN showed onset from 30 to 60 years of age. Most of them showed a relatively slow progression and long duration before respiratory failure, although the clinical phenotypes were not homogeneous.

The transmission pattern of ALS12 in some of the families reported by Maruyama et al. (2010) was consistent with autosomal recessive inheritance, whereas other families showed autosomal dominant inheritance.

Pottier et al. (2015) reported a deceased patient (Case B) showing digenic inheritance of a neurodegenerative disorder: whole-exome sequencing identified heterozygous mutations in the OPTN (G538EfsX27) and TBK1 (604834; R117X) genes. He presented with rapidly progressive cognitive and language difficulties at age 68 years, becoming almost mute by age 69. Other features included trouble swallowing, jerky movements of the hands, and slow movements, but there was no obvious clinical evidence of motor neuron disease. The patient showed symptoms of frontal dementia and was diagnosed with primary progressive aphasia. He died at age 72. Postmortem examination showed severe focal cortical atrophy of the frontal lobe, atrophy of the amygdala and hippocampus, loss of pigment in the substantia nigra, and midbrain atrophy. There were p62- (601530) and TDP43 (605078)-positive neuronal and glial inclusions. There was no neuronal loss in the motor cortex or brainstem. He had no family history of a similar disorder.

Using homozygosity mapping in 4 Japanese subjects from consanguineous marriages with ALS, Maruyama et al. (2010) identified a candidate region for the disorder on chromosome 10 containing 17 genes.

Among 8 Japanese patients with ALS, Maruyama et al. (2010) identified homozygosity for 2 null mutations in the OPTN gene, one a deletion of exon 5 (602432.0005) in 2 sibs and the other a nonsense mutation (Q398X; 602432.0006) in 2 individuals thought to be unrelated but who shared a haplotype for a 0.9-Mb region containing the OPTN gene. The authors also identified heterozygosity for a missense mutation (E478G; 602432.0007) within the OPTN ubiquitin-binding domain in 4 individuals from 2 families. The pedigree of one of these families suggested that the disorder is an autosomal dominant trait with incomplete penetrance. Although these 2 families were not known to be related, all affected individuals shared their haplotype for 2.3 Mb on chromosome 10 around the OPTN gene. Neither the Q398X nor the E478G mutations were observed in 781 healthy Japanese volunteers or in over 6,800 (including 1,728 Japanese) individuals in glaucoma studies, in which the entire coding region of the gene was investigated. Collectively, the mutation was absent over a total of 5,000 Japanese chromosomes. The deletion mutation was also absent in 200 Japanese, and not reported in the over 6,800 glaucoma individuals.

In cell transfection assays, Maruyama et al. (2010) observed that nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa-B (NFKB; see 164011) and that E478G (602432.0007) mutant OPTN had a cytoplasmic distribution different from that of wildtype OPTN or OPTN carrying a mutation resulting in primary open angle glaucoma (POAG; see 137760). A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP43 (605078)- or SOD1 (147450)-positive inclusions in sporadic and familial cases of ALS were also noticeably immunolabeled by anti-OPTN antibodies.

Ito et al. (2016) found that OPTN actively suppressed receptor-interacting kinase-1 (RIPK1; 613435)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3 (605817), and mixed lineage kinase domain-like protein (MLKL; 615153). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1(G93A) (147450.0008) transgenic mice and pathologic samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration.