PMC:6610326 / 29462-32111 JSONTXT

{"project":"2_test","denotations":[{"id":"31316328-8446170-38515431","span":{"begin":158,"end":162},"obj":"8446170"},{"id":"31316328-21944779-38515433","span":{"begin":804,"end":808},"obj":"21944779"},{"id":"31316328-22406228-38515434","span":{"begin":827,"end":831},"obj":"22406228"},{"id":"31316328-24445580-38515435","span":{"begin":850,"end":854},"obj":"24445580"},{"id":"31316328-21944779-38515437","span":{"begin":976,"end":980},"obj":"21944779"},{"id":"31316328-22406228-38515438","span":{"begin":1078,"end":1082},"obj":"22406228"},{"id":"31316328-24515836-38515439","span":{"begin":1105,"end":1109},"obj":"24515836"},{"id":"31316328-22840558-38515440","span":{"begin":1191,"end":1195},"obj":"22840558"},{"id":"31316328-23597494-38515441","span":{"begin":1211,"end":1215},"obj":"23597494"},{"id":"31316328-23111906-38515442","span":{"begin":1237,"end":1241},"obj":"23111906"},{"id":"31316328-23434116-38515443","span":{"begin":1331,"end":1335},"obj":"23434116"},{"id":"31316328-23597494-38515444","span":{"begin":1351,"end":1355},"obj":"23597494"},{"id":"31316328-24011653-38515445","span":{"begin":1382,"end":1386},"obj":"24011653"},{"id":"31316328-26022924-38515446","span":{"begin":1400,"end":1404},"obj":"26022924"},{"id":"31316328-18802454-38515447","span":{"begin":1524,"end":1528},"obj":"18802454"},{"id":"31316328-18309045-38515448","span":{"begin":1549,"end":1553},"obj":"18309045"},{"id":"31316328-20645878-38515449","span":{"begin":1571,"end":1575},"obj":"20645878"},{"id":"31316328-19760257-38515450","span":{"begin":1591,"end":1595},"obj":"19760257"},{"id":"31316328-19741216-38515451","span":{"begin":1662,"end":1666},"obj":"19741216"},{"id":"31316328-19965854-38515452","span":{"begin":1682,"end":1686},"obj":"19965854"},{"id":"31316328-19450904-38515453","span":{"begin":1701,"end":1705},"obj":"19450904"},{"id":"31316328-19251627-38515454","span":{"begin":1727,"end":1731},"obj":"19251627"},{"id":"31316328-19674978-38515455","span":{"begin":1749,"end":1753},"obj":"19674978"},{"id":"31316328-19251628-38515456","span":{"begin":1769,"end":1773},"obj":"19251628"},{"id":"31316328-29605155-38515457","span":{"begin":2393,"end":2397},"obj":"29605155"},{"id":"31316328-22645277-38515458","span":{"begin":2589,"end":2593},"obj":"22645277"},{"id":"31316328-28209650-38515459","span":{"begin":2604,"end":2608},"obj":"28209650"},{"id":"31316328-28057713-38515460","span":{"begin":2622,"end":2626},"obj":"28057713"},{"id":"31316328-29605155-38515461","span":{"begin":2643,"end":2647},"obj":"29605155"}],"text":"The first gene found to harbor mutations causing FALS encodes Cu/Zn superoxide dismutase (SOD1), an enzyme that detoxifies superoxide radicals (Rosen et al., 1993). Mutations in SOD1 account for 12–23.5% of FALS cases, representing 1–2.5% of all ALS, and 186 ALS mutations have now been described1. Since then, mutations in approximatively 26 genes have been identified (Supplementary Table 1 and Figure 2) using genome-wide or exome-wide association studies combined with segregation analysis. Hexanucleotide repeat expansions (GGGGCC) within the first intron of the chromosome 9 open reading frame 72 (C9orf72) gene are the most common cause of FALS and FTD (∼30–50% of FALS, ∼10% of SALS 25% of familial FTD and ∼5% of apparently sporadic ALS and FTD) (DeJesus-Hernandez et al., 2011b; Renton et al., 2011; Majounie et al., 2012; Devenney et al., 2014) (Supplementary Table 1 and Figure 2), in both Europe and North America (DeJesus-Hernandez et al., 2011b; Renton et al., 2011). However, this mutation is much rarer in Asian and Middle Eastern populations (Majounie et al., 2012; Woollacott and Mead, 2014). Healthy individuals possess ≤ 11 GGGGCC repeats in C9orf72 (Rutherford et al., 2012; Harms et al., 2013; van der Zee et al., 2013), whereas hundreds to thousands of repeats are present in ALS/FTD patients (Beck et al., 2013; Harms et al., 2013; van Blitterswijk et al., 2013; Suh et al., 2015). After C9orf72, mutations in SOD1 (20% of FALS), TARDPB encoding TDP-43 (5% of FALS, \u003e50% of FTD) (Rutherford et al., 2008; Sreedharan et al., 2008; Borroni et al., 2010; Kirby et al., 2010), Fused in sarcoma encoding FUS (FUS, 5% of FALS) (Belzil et al., 2009; Blair et al., 2009; Chiò et al., 2009; Kwiatkowski et al., 2009; Neumann et al., 2009; Vance et al., 2009), and CCNF encoding cyclin F (0.6–3.3% of FALS-FTD) are more frequent than the remaining 20 genes mutated in the much rarer forms of FALS (Supplementary Table 1). The physiological functions and properties of the proteins encoded by these genes can be grouped according to their involvement in protein quality control, cytoskeletal dynamics, RNA homeostasis and the DNA damage response. However, it is possible that genetic inheritance could sometimes be missed, due to incomplete penetrance or an oligogenic mode of inheritance, whereby more than one mutated gene is necessary to fully present disease (Nguyen et al., 2018). Consistent with this notion, the frequency of ALS patients carrying two or more mutations in ALS-associated genes is in excess of what would be expected by chance (van Blitterswijk et al., 2012; Veldink, 2017; Zou et al., 2017; Nguyen et al., 2018)."}

{"project":"0_colil","denotations":[{"id":"31316328-8446170-630888","span":{"begin":158,"end":162},"obj":"8446170"},{"id":"31316328-21944779-630890","span":{"begin":804,"end":808},"obj":"21944779"},{"id":"31316328-22406228-630891","span":{"begin":827,"end":831},"obj":"22406228"},{"id":"31316328-24445580-630892","span":{"begin":850,"end":854},"obj":"24445580"},{"id":"31316328-21944779-630894","span":{"begin":976,"end":980},"obj":"21944779"},{"id":"31316328-22406228-630895","span":{"begin":1078,"end":1082},"obj":"22406228"},{"id":"31316328-24515836-630896","span":{"begin":1105,"end":1109},"obj":"24515836"},{"id":"31316328-22840558-630897","span":{"begin":1191,"end":1195},"obj":"22840558"},{"id":"31316328-23597494-630898","span":{"begin":1211,"end":1215},"obj":"23597494"},{"id":"31316328-23111906-630899","span":{"begin":1237,"end":1241},"obj":"23111906"},{"id":"31316328-23434116-630900","span":{"begin":1331,"end":1335},"obj":"23434116"},{"id":"31316328-23597494-630901","span":{"begin":1351,"end":1355},"obj":"23597494"},{"id":"31316328-24011653-630902","span":{"begin":1382,"end":1386},"obj":"24011653"},{"id":"31316328-26022924-630903","span":{"begin":1400,"end":1404},"obj":"26022924"},{"id":"31316328-18802454-630904","span":{"begin":1524,"end":1528},"obj":"18802454"},{"id":"31316328-18309045-630905","span":{"begin":1549,"end":1553},"obj":"18309045"},{"id":"31316328-20645878-630906","span":{"begin":1571,"end":1575},"obj":"20645878"},{"id":"31316328-19760257-630907","span":{"begin":1591,"end":1595},"obj":"19760257"},{"id":"31316328-19741216-630908","span":{"begin":1662,"end":1666},"obj":"19741216"},{"id":"31316328-19965854-630909","span":{"begin":1682,"end":1686},"obj":"19965854"},{"id":"31316328-19450904-630910","span":{"begin":1701,"end":1705},"obj":"19450904"},{"id":"31316328-19251627-630911","span":{"begin":1727,"end":1731},"obj":"19251627"},{"id":"31316328-19674978-630912","span":{"begin":1749,"end":1753},"obj":"19674978"},{"id":"31316328-19251628-630913","span":{"begin":1769,"end":1773},"obj":"19251628"},{"id":"31316328-29605155-630914","span":{"begin":2393,"end":2397},"obj":"29605155"},{"id":"31316328-22645277-630915","span":{"begin":2589,"end":2593},"obj":"22645277"},{"id":"31316328-28209650-630916","span":{"begin":2604,"end":2608},"obj":"28209650"},{"id":"31316328-28057713-630917","span":{"begin":2622,"end":2626},"obj":"28057713"},{"id":"31316328-29605155-630918","span":{"begin":2643,"end":2647},"obj":"29605155"}],"text":"The first gene found to harbor mutations causing FALS encodes Cu/Zn superoxide dismutase (SOD1), an enzyme that detoxifies superoxide radicals (Rosen et al., 1993). Mutations in SOD1 account for 12–23.5% of FALS cases, representing 1–2.5% of all ALS, and 186 ALS mutations have now been described1. Since then, mutations in approximatively 26 genes have been identified (Supplementary Table 1 and Figure 2) using genome-wide or exome-wide association studies combined with segregation analysis. Hexanucleotide repeat expansions (GGGGCC) within the first intron of the chromosome 9 open reading frame 72 (C9orf72) gene are the most common cause of FALS and FTD (∼30–50% of FALS, ∼10% of SALS 25% of familial FTD and ∼5% of apparently sporadic ALS and FTD) (DeJesus-Hernandez et al., 2011b; Renton et al., 2011; Majounie et al., 2012; Devenney et al., 2014) (Supplementary Table 1 and Figure 2), in both Europe and North America (DeJesus-Hernandez et al., 2011b; Renton et al., 2011). However, this mutation is much rarer in Asian and Middle Eastern populations (Majounie et al., 2012; Woollacott and Mead, 2014). Healthy individuals possess ≤ 11 GGGGCC repeats in C9orf72 (Rutherford et al., 2012; Harms et al., 2013; van der Zee et al., 2013), whereas hundreds to thousands of repeats are present in ALS/FTD patients (Beck et al., 2013; Harms et al., 2013; van Blitterswijk et al., 2013; Suh et al., 2015). After C9orf72, mutations in SOD1 (20% of FALS), TARDPB encoding TDP-43 (5% of FALS, \u003e50% of FTD) (Rutherford et al., 2008; Sreedharan et al., 2008; Borroni et al., 2010; Kirby et al., 2010), Fused in sarcoma encoding FUS (FUS, 5% of FALS) (Belzil et al., 2009; Blair et al., 2009; Chiò et al., 2009; Kwiatkowski et al., 2009; Neumann et al., 2009; Vance et al., 2009), and CCNF encoding cyclin F (0.6–3.3% of FALS-FTD) are more frequent than the remaining 20 genes mutated in the much rarer forms of FALS (Supplementary Table 1). The physiological functions and properties of the proteins encoded by these genes can be grouped according to their involvement in protein quality control, cytoskeletal dynamics, RNA homeostasis and the DNA damage response. However, it is possible that genetic inheritance could sometimes be missed, due to incomplete penetrance or an oligogenic mode of inheritance, whereby more than one mutated gene is necessary to fully present disease (Nguyen et al., 2018). Consistent with this notion, the frequency of ALS patients carrying two or more mutations in ALS-associated genes is in excess of what would be expected by chance (van Blitterswijk et al., 2012; Veldink, 2017; Zou et al., 2017; Nguyen et al., 2018)."}