Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analyses
Abstract Introduction Mutations in the angiogenin (ANG) gene are known to be associated with both familial and sporadic amyotrophic lateral sclerosis (ALS). The majority of disease‐causing mutations of ANG result in loss of either ribonucleolytic activity, nuclear translocation activity or both. Met...
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| Format: | Article |
| Language: | English |
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Wiley
2019-06-01
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| Series: | Brain and Behavior |
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| Online Access: | https://doi.org/10.1002/brb3.1293 |
| _version_ | 1811331526805159936 |
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| author | Kornélia Tripolszki Judit Danis Aditya K. Padhi James Gomes Renáta Bozó Zsófia F. Nagy Dóra Nagy Péter Klivényi József I. Engelhardt Márta Széll |
| author_facet | Kornélia Tripolszki Judit Danis Aditya K. Padhi James Gomes Renáta Bozó Zsófia F. Nagy Dóra Nagy Péter Klivényi József I. Engelhardt Márta Széll |
| author_sort | Kornélia Tripolszki |
| collection | DOAJ |
| description | Abstract Introduction Mutations in the angiogenin (ANG) gene are known to be associated with both familial and sporadic amyotrophic lateral sclerosis (ALS). The majority of disease‐causing mutations of ANG result in loss of either ribonucleolytic activity, nuclear translocation activity or both. Methods We sequenced ANG gene from a total of 136 sporadic ALS patients and 112 healthy controls of Hungarian origin. To elucidate the role of the R33W mutation in the disease mechanism, computational, and functional analyses were performed. Results Mutation screening revealed a mutation located in the signal peptide (M‐24I) and two mutations that affect the mature protein (R33W, V103I). The R33W mutation, which has not been previously detected in ALS patients, affects the key amino acid of the nuclear translocation signal of the ANG protein. Molecular dynamics simulations suggested that the R33W mutation results in partial loss of ribonucleolytic activity and reduced nuclear translocation activity. The ribonucleolytic assay and nuclear translocation assay of the R33W ANG protein confirmed the molecular dynamics results. Conclusions In the Hungarian ALS population, the observed frequency of ANG mutations was 2.9%, which is higher than previously reported for sporadic cohorts. The evidence from computational and functional analyses support the deleterious effect of the novel R33W variant detected in this study. |
| first_indexed | 2024-04-13T16:21:56Z |
| format | Article |
| id | doaj.art-63843e9b7a1a41d9aa57cddebaf96b4a |
| institution | Directory Open Access Journal |
| issn | 2162-3279 |
| language | English |
| last_indexed | 2024-04-13T16:21:56Z |
| publishDate | 2019-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Brain and Behavior |
| spelling | doaj.art-63843e9b7a1a41d9aa57cddebaf96b4a2022-12-22T02:39:55ZengWileyBrain and Behavior2162-32792019-06-0196n/an/a10.1002/brb3.1293Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analysesKornélia Tripolszki0Judit Danis1Aditya K. Padhi2James Gomes3Renáta Bozó4Zsófia F. Nagy5Dóra Nagy6Péter Klivényi7József I. Engelhardt8Márta Széll9Department of Medical Genetics University of Szeged Szeged HungaryMTA‐SZTE Dermatological Research Group Szeged HungaryKusuma School of Biological Sciences Indian Institute of Technology Delhi New Delhi IndiaKusuma School of Biological Sciences Indian Institute of Technology Delhi New Delhi IndiaDepartment of Dermatology and Allergology University of Szeged Szeged HungaryDepartment of Medical Genetics University of Szeged Szeged HungaryDepartment of Medical Genetics University of Szeged Szeged HungaryDepartment of Neurology University of Szeged Szeged HungaryDepartment of Neurology University of Szeged Szeged HungaryDepartment of Medical Genetics University of Szeged Szeged HungaryAbstract Introduction Mutations in the angiogenin (ANG) gene are known to be associated with both familial and sporadic amyotrophic lateral sclerosis (ALS). The majority of disease‐causing mutations of ANG result in loss of either ribonucleolytic activity, nuclear translocation activity or both. Methods We sequenced ANG gene from a total of 136 sporadic ALS patients and 112 healthy controls of Hungarian origin. To elucidate the role of the R33W mutation in the disease mechanism, computational, and functional analyses were performed. Results Mutation screening revealed a mutation located in the signal peptide (M‐24I) and two mutations that affect the mature protein (R33W, V103I). The R33W mutation, which has not been previously detected in ALS patients, affects the key amino acid of the nuclear translocation signal of the ANG protein. Molecular dynamics simulations suggested that the R33W mutation results in partial loss of ribonucleolytic activity and reduced nuclear translocation activity. The ribonucleolytic assay and nuclear translocation assay of the R33W ANG protein confirmed the molecular dynamics results. Conclusions In the Hungarian ALS population, the observed frequency of ANG mutations was 2.9%, which is higher than previously reported for sporadic cohorts. The evidence from computational and functional analyses support the deleterious effect of the novel R33W variant detected in this study.https://doi.org/10.1002/brb3.1293amyotrophic lateral sclerosisangiogeninmolecular dynamicsmutation screeningnuclear translocationribonucleolytic activity |
| spellingShingle | Kornélia Tripolszki Judit Danis Aditya K. Padhi James Gomes Renáta Bozó Zsófia F. Nagy Dóra Nagy Péter Klivényi József I. Engelhardt Márta Széll Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analyses Brain and Behavior amyotrophic lateral sclerosis angiogenin molecular dynamics mutation screening nuclear translocation ribonucleolytic activity |
| title | Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analyses |
| title_full | Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analyses |
| title_fullStr | Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analyses |
| title_full_unstemmed | Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analyses |
| title_short | Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analyses |
| title_sort | angiogenin mutations in hungarian patients with amyotrophic lateral sclerosis clinical genetic computational and functional analyses |
| topic | amyotrophic lateral sclerosis angiogenin molecular dynamics mutation screening nuclear translocation ribonucleolytic activity |
| url | https://doi.org/10.1002/brb3.1293 |
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