Novel deletion mutations of OPTN in amyotrophic lateral sclerosis in Japanese

Iida, Aritoshi; Hosono, Naoya; Sano, Masaaki; Kamei, Tetsumasa; Oshima, Shuichi; Tokuda, Torao; Nakajima, Masahiro; Kubo, Michiaki; Nakamura, Yusuke; Ikegawa, Shiro

doi:10.1016/j.neurobiolaging.2011.12.037

Cited by 35 publications

(25 citation statements)

References 15 publications

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“…The region encompassing the coding exons of the OPTN gene has been previously found to have a high density of Alu repeats that predisposes OPTN to Alu‐mediated coding region deletions (Iida et al. 2012); in the above mentioned study, authors investigated deletions within the OPTN coding region in patients affected with ALS and found different types of deletions occurring due to Alu‐mediated recombination (Iida et al. 2012).…”

Section: Discussionmentioning

confidence: 99%

“…2012); in the above mentioned study, authors investigated deletions within the OPTN coding region in patients affected with ALS and found different types of deletions occurring due to Alu‐mediated recombination (Iida et al. 2012). In this paper, we present evidence that the upstream region of OPTN is also enriched in Alu repeats and prone to nonhomologous recombination events.…”

Section: Discussionmentioning

confidence: 99%

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Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Schilter

Reis

Сорокина

et al. 2015

Molec Gen & Gen Med

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Genetic causes of ocular conditions remain largely unknown. To reveal the molecular basis for a congenital ocular phenotype associated with glaucoma we performed whole‐exome sequencing (WES) and whole‐genome copy number analyses of patient DNA. WES did not identify a causative variant. Copy number variation analysis identified a deletion of 10p13 in the patient and his unaffected father; the deletion breakpoint contained a single 37‐bp sequence that is normally present in two distinct Alu repeats separated by ~181 kb. The deletion removed part of the upstream region of optineurin (OPTN) as well as the upstream sequence and two coding exons of coiled‐coil domain containing 3 (CCDC3); analysis of the patient's second allele showed normal OPTN and CCDC3 sequences. Studies of zebrafish orthologs identified expression in the developing eye for both genes. OPTN is a known factor in dominant adult‐onset glaucoma and Amyotrophic Lateral Sclerosis (ALS). The deletion eliminates 98 kb of the OPTN upstream sequence leaving only ~1 kb of the proximal promoter region. Comparison of transcriptional activation capability of the 3 kb normal and the rearranged del(10)(p13) OPTN promoter sequences demonstrated a statistically significant decrease for the deleted allele; sequence analysis of the entire deleted region identified multiple conserved elements with possible cis‐regulatory activity. Additional screening of CCDC3 indicated that heterozygous loss‐of‐function alleles are unlikely to cause congenital ocular disease. In summary, we report the first regulatory region deletion involving OPTN, caused by Alu‐mediated nonallelic homologous recombination and possibly contributing to the patient's ocular phenotype. In addition, our data indicate that Alu‐mediated rearrangements of the OPTN upstream region may represent a new source of affected alleles in human conditions. Evaluation of the upstream OPTN sequences in additional ocular and ALS patients may help to determine the role of this region, if any, in human disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Schilter

Reis

Сорокина

et al. 2015

Molec Gen & Gen Med

View full text Add to dashboard Cite

show abstract

“…The greatest enrichment was for LoF variants, which occur in 0.334% of cases and 0.114% of controls (combined dominant LoF model, p=0.013). Whereas the initial studies of OPTN in ALS found a role in only a few families with a recessive genetic model, subsequent studies identified dominant mutations (14, 15). Here, dominant acting variants appeared to make a substantial contribution to sporadic disease.…”

Section: Associations With Other Als Genesmentioning

confidence: 99%

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Cirulli¹,

Lasseigne²,

Petrovski³

et al. 2015

Science

852

754

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Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. Here we report the results of a moderate-scale sequencing study aimed at identifying new genes contributing to predisposition for ALS. We performed whole exome sequencing of 2,874 ALS patients and compared them to 6,405 controls. Several known ALS genes were found to be associated, and the non-canonical IκB kinase family TANK-Binding Kinase 1 (TBK1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

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“…97,[103][104][105] OPTN mutants are especially prevalent in the Japanese population, constituting the second most mutated gene product associated with SALS in Japan. 106 In contrast, this mutation is exceptionally rare in British populations where it is deemed unlikely to be pathologic 107 but can serve as a potential cause of rare rapidly progressive SALS in the Dutch.…”

Section: Optineurin (Optn)mentioning

confidence: 98%

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

Sanford¹

2015

MJM

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Novel deletion mutations of OPTN in amyotrophic lateral sclerosis in Japanese

Cited by 35 publications

References 15 publications

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

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