DPPA5A suppresses the mutagenic TLS and MMEJ pathways by modulating the cryptic splicing of
            <i>Rev1</i>
            and
            <i>Polq</i>
            in mouse embryonic stem cells

Jiang, Fangjie; Wang, Lin; Dong, Yuping; Nie, Wei; Zhou, Hu; Gao, Jing; Zheng, Ping

doi:10.1073/pnas.2305187120

Cited by 4 publications

(3 citation statements)

References 65 publications

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“…We found that genic collapsing analyses of individuals diagnosed with ALS identified known risk genes ( SOD1 , TARDBP , and TBK1 ) and a novel protective gene ( ALKBH3 ). ALKBH3 encodes for AlkB homolog 3, Alpha-Ketoglutarate Dependent Dioxygenase which protects against the cytotoxicity of methylating agents by repair of the specific DNA lesions [ 25 – 27 ]. ALKBH3 potentially acts as a putative hyperactive promotor to suppress transcription associated DNA damage of highly expressed genes [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS

Pottinger,

Motelow,

Povysil

et al. 2024

BMC Genomics

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Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation. Methods Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS. Results A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10–39; OR = 4.73, p = 2 × 10–10; OR = 2.3, p = 7.49 × 10–9, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10–7), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10–16). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10–6). Conclusions In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.

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Section: Discussionmentioning

confidence: 99%

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS

Pottinger,

Motelow,

Povysil

et al. 2024

BMC Genomics

View full text Add to dashboard Cite

show abstract

“…We found that genic burden testing of individuals diagnosed with ALS identified known risk genes (SOD1, TARDBP, and TBK1) and a novel protective gene (ALKBH3). ALKBH3 encodes for AlkB homolog 3, Alpha-Ketoglutarate Dependent Dioxygenase which protects against the cytotoxicity of methylating agents by repair of the specific DNA lesions (26)(27)(28). ALKBH3 potentially acts as a putative hyperactive promotor to suppress transcription associated DNA damage of highly expressed genes (29).…”

Section: Discussionmentioning

confidence: 99%

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifiesANTXR2as a candidate in PLS

Pottinger,

Motelow,

Povysil

et al. 2023

Preprint

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Rare genetic variants have been previously associated with amyotrophic lateral sclerosis (ALS). In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and demonstrated the utility of intolerant domain-based collapsing methods. A first- ever analysis in 166 patients with primary lateral sclerosis (PLS), a motor neuron disease related to ALS, found a candidate association to loss-of-function mutations inANTXR2.

show abstract

“…We found that genic burden testing of individuals diagnosed with ALS identified known risk genes ( SOD1 , TARDBP , and TBK1 ) and a novel protective gene ( ALKBH3 ). ALKBH3 encodes for AlkB homolog 3, Alpha-Ketoglutarate Dependent Dioxygenase which protects against the cytotoxicity of methylating agents by repair of the specific DNA lesions ( 26 – 28 ). ALKBH3 potentially acts as a putative hyperactive promotor to suppress transcription associated DNA damage of highly expressed genes ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS

Pottinger,

Motelow,

Povysil

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation. Methods: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS. Results: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR=19.18, p = 3.67 × 10-39; OR=4.73, p = 2 × 10-10; OR=2.3, p = 7.49 × 10-9, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10-7), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR=10.08, p = 3.62 × 10-16). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p=8.38 x 10-6). Conclusions: In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.

show abstract

DPPA5A suppresses the mutagenic TLS and MMEJ pathways by modulating the cryptic splicing of Rev1 and Polq in mouse embryonic stem cells

Cited by 4 publications

References 65 publications

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifiesANTXR2as a candidate in PLS

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS

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