OPTN 691_692insAG is a founder mutation causing recessive ALS and increased risk in heterozygotes

Abstract

Objective: To detect genetic variants underlying familial and sporadic amyotrophic lateral sclerosis (ALS). Methods:We analyzed 2 founder Jewish populations of Moroccan and Ashkenazi origins and ethnic matched controls. Exome sequencing of 2 sisters with ALS from Morocco was followed by genotyping the identified causative null mutation in 379 unrelated patients with ALS and 1,000 controls. The shared risk haplotype was characterized using whole-genome single nucleotide polymorphism array.Results: We identified 5 unrelated patients with ALS homozygous for the null 691_692insAG mutation in the optineurin gene (OPTN), accounting for 5.8% of ALS of Moroccan origin and 0.3% of Ashkenazi. We also identified a high frequency of heterozygous carriers among patients with ALS, 8.7% and 2.9%, respectively, compared to 0.75% and 1.0% in controls. The risk of carriers for ALS was significantly increased, with odds ratio of 13.46 and 2.97 in Moroccan and Ashkenazi Jews, respectively. We determined that 691_692insAG is a founder mutation in the tested populations with a minimal risk haplotype of 58.5 Kb, encompassing the entire OPTN gene.Conclusions: Our data show that OPTN 691_692insAG mutation is a founder mutation in Moroccan and Ashkenazi Jews. This mutation causes autosomal recessive ALS and significantly increases the risk to develop the disease in heterozygous carriers, suggesting both a recessive mode of inheritance and a dominant with incomplete penetrance. These data emphasize the important role of OPTN in ALS pathogenesis, and demonstrate the complex genetics of ALS, as the same mutation leads to different phenotypes and appears in 2 patterns of inheritance. Amyotrophic lateral sclerosis (ALS) is a complex and heterogeneous neurodegenerative disease, characterized by loss of upper and lower motor neurons, affecting individuals worldwide, with a global incidence of 2-3 people per 100,000 per year.1 The disease leads to respiratory failure and death within 1-5 years after symptom onset. Up to 50% of patients may also have symptoms of cognitive impairment, and about 13% develop symptoms of frontotemporal dementia (FTD). 2,3In the last decade, there has been an exponential increase in the discovery of genes and mutations associated with familial ALS (fALS) and sporadic ALS (sALS), some with biological function evidence for causality. Mutations in C9ORF72, SOD1, TDP-43, and FUS account for the majority of fALS, and although the etiology of most sALS is unknown, about 10% are caused by mutations in genes associated with ALS.

The NGS technology for the identification of genes associated with the ALS. A systematic review

“…After reading the full text, we excluded 20 out of 34 studies clearly not meeting our inclusion criteria (Table ). Finally, 14 papers 35‐48 met the inclusion criteria and were included in our evaluation (Figure 1). Of the selected papers, only 2 studies 39,48 aimed to evaluate the primary research question of determining whether NGS is more accurate than Sanger sequencing to identify pathological mutations of ALS‐associated genes.…”

“…At baseline, age of onset ranged from 18 to 87 years, and site of onset was bulbar for 245 (10.5%) patients, spinal for 675 (29%) patients, with these data being unspecified for the remaining 60.5% of patients. Seven studies 36,40,41,43‐45,47 analysed also healthy samples as control. Characteristics of included studies are summarized in Table 1.…”

“…In 13 studies, 35‐47 NGS allowed to identify already known mutations in 21 genes, and new or rare variants in 27 genes (Figure 3). Identified variants were nonsense or missense mutations leading to a frameshift mutation resulting in a truncated protein and a loss of protein function.…”

OPTN p.Met468Arg and ATXN2 intermediate length polyQ extension in families with C9orf72 mediated amyotrophic lateral sclerosis and frontotemporal dementia

“…In both families, we identified a novel OPTN missense variant (c.1403T>G, p.Met468Arg, rs747481280) in four individuals (family 1, II‐3; family 2, III‐3, III‐5, and III‐7), who are all are diagnosed with ALS‐FTD and are C9orf72 expansion carriers; and one who is also an ATXN2 intermediate length expansion carrier (family 1, II‐3) (Table , Figure , Supplementary Figure S1). Mutations in OPTN have been previously reported to be associated with ALS and FTD (Bury et al, ; Cirulli et al, ; Goldstein et al, ; Li et al, ; Maruyama et al, ; Pottier et al, ); and these variants are summarized in the ALS Online genetics Database (ALSoD), http://alsod.iop.kcl.ac.uk/misc/dataDownload.aspx#C2. We also observed the variant in IV‐4, who is not a C9orf72 expansion carrier, and is currently free of any disease symptoms.…”

Glaucoma-Associated Mutations in the Optineurin Gene Have Limited Impact on Parkin-Dependent Mitophagy

“…2,[15][16][17] However, their associations are currently controversial. 3,4,10,[15][16][17][18][19][20][21][22][23][24] OPTN is a multifunctional protein involved in diverse cellular processes, including the inflammatory response, maintenance of the Golgi apparatus, vesicle trafficking, and signal transduction. 14,25,26 It has been identified as a primary receptor for selective mitochondrial autophagy, also termed mitophagy.…”