Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset
Abstract Neurofilament heavy (NEFH) is one of the critical proteins required for the formation of the neuronal cytoskeleton and polymorphisms in NEFH are reported as a rare cause of sporadic ALS (sALS). In the current study, a candidate tetranucleotide (TTTA) repeat variant in NEFH was selected usin...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-18942-x |
| _version_ | 1811274924648562688 |
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| author | Frances Theunissen Ryan S. Anderton Frank L. Mastaglia Ian James Richard Bedlack P. Anthony Akkari |
| author_facet | Frances Theunissen Ryan S. Anderton Frank L. Mastaglia Ian James Richard Bedlack P. Anthony Akkari |
| author_sort | Frances Theunissen |
| collection | DOAJ |
| description | Abstract Neurofilament heavy (NEFH) is one of the critical proteins required for the formation of the neuronal cytoskeleton and polymorphisms in NEFH are reported as a rare cause of sporadic ALS (sALS). In the current study, a candidate tetranucleotide (TTTA) repeat variant in NEFH was selected using an in-silico short structural variant (SSV) evaluation algorithm and investigated in two cohorts of North American sALS patients, both separately and combined (Duke cohort n = 138, Coriell cohort n = 333; combined cohort n = 471), compared to a group of healthy controls from the Coriell Institute biobank (n = 496). Stratification according to site of disease onset revealed that the 9 TTTA allele was associated with reduced disease risk, specifically confined to spinal-onset sALS patients in the Duke cohort (p = 0.001). Furthermore, carriage of the 10 TTTA allele was associated with a 2.7 year later age of disease onset in the larger combined sALS cohort (p = 0.02). These results suggest that the 9 and 10 TTTA motif length may have a protective advantage for potentially lowering the risk of sALS and delaying the age of disease onset, however, these results need to be replicated in larger multicenter and multi-ethnic cohorts. |
| first_indexed | 2024-04-12T23:27:52Z |
| format | Article |
| id | doaj.art-1c62f08a480247a1b3de51c3ba7d123a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T23:27:52Z |
| publishDate | 2022-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1c62f08a480247a1b3de51c3ba7d123a2022-12-22T03:12:21ZengNature PortfolioScientific Reports2045-23222022-08-0112111010.1038/s41598-022-18942-xIntronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onsetFrances Theunissen0Ryan S. Anderton1Frank L. Mastaglia2Ian James3Richard Bedlack4P. Anthony Akkari5Perron Institute for Neurological and Translational SciencePerron Institute for Neurological and Translational SciencePerron Institute for Neurological and Translational ScienceInstitute for Immunology and Infectious Diseases, Murdoch UniversityDepartment of Neurology, Duke UniversityPerron Institute for Neurological and Translational ScienceAbstract Neurofilament heavy (NEFH) is one of the critical proteins required for the formation of the neuronal cytoskeleton and polymorphisms in NEFH are reported as a rare cause of sporadic ALS (sALS). In the current study, a candidate tetranucleotide (TTTA) repeat variant in NEFH was selected using an in-silico short structural variant (SSV) evaluation algorithm and investigated in two cohorts of North American sALS patients, both separately and combined (Duke cohort n = 138, Coriell cohort n = 333; combined cohort n = 471), compared to a group of healthy controls from the Coriell Institute biobank (n = 496). Stratification according to site of disease onset revealed that the 9 TTTA allele was associated with reduced disease risk, specifically confined to spinal-onset sALS patients in the Duke cohort (p = 0.001). Furthermore, carriage of the 10 TTTA allele was associated with a 2.7 year later age of disease onset in the larger combined sALS cohort (p = 0.02). These results suggest that the 9 and 10 TTTA motif length may have a protective advantage for potentially lowering the risk of sALS and delaying the age of disease onset, however, these results need to be replicated in larger multicenter and multi-ethnic cohorts.https://doi.org/10.1038/s41598-022-18942-x |
| spellingShingle | Frances Theunissen Ryan S. Anderton Frank L. Mastaglia Ian James Richard Bedlack P. Anthony Akkari Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset Scientific Reports |
| title | Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset |
| title_full | Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset |
| title_fullStr | Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset |
| title_full_unstemmed | Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset |
| title_short | Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset |
| title_sort | intronic nefh variant is associated with reduced risk for sporadic als and later age of disease onset |
| url | https://doi.org/10.1038/s41598-022-18942-x |
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