Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson’s disease
Abstract Biallelic intronic pentanucleotide repeat expansions, mainly (AAGGG)exp and/or (ACAGG)exp in RFC1, are detected in cerebellar ataxia, neuropathy and vestibular areflexia syndrome, late-onset ataxia, and in a wide disease spectrum including Charcot-Marie-Tooth disease, multiple system atroph...
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Nature Portfolio
2025-01-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-025-00868-6 |
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| author | Peng Liu Fan Zhang Xinhui Chen Xiaosheng Zheng Miao Chen Zhiru Lin Shuqi Chen Lebo Wang Xinchen Wang Nan Jin Chenxin Ying Fei Xie Bo Wang Sheng Wu Zhidong Cen Wei Luo |
| author_facet | Peng Liu Fan Zhang Xinhui Chen Xiaosheng Zheng Miao Chen Zhiru Lin Shuqi Chen Lebo Wang Xinchen Wang Nan Jin Chenxin Ying Fei Xie Bo Wang Sheng Wu Zhidong Cen Wei Luo |
| author_sort | Peng Liu |
| collection | DOAJ |
| description | Abstract Biallelic intronic pentanucleotide repeat expansions, mainly (AAGGG)exp and/or (ACAGG)exp in RFC1, are detected in cerebellar ataxia, neuropathy and vestibular areflexia syndrome, late-onset ataxia, and in a wide disease spectrum including Charcot-Marie-Tooth disease, multiple system atrophy, and Parkinson’s disease (PD). However, the genotype-phenotype correlation and underlying mechanism are mostly unknown. We screened RFC1-repeat expansions in 1445 patients with parkinsonism. Comprehensive genetic and clinical, and pathological assessments were performed. We report two early-onset patients with PD carrying complex biallelic pentanucleotide repeat expansions in RFC1. Long-read sequencing revealed a novel repeat configuration of (AGGGG)exp(AAGGG)14 and a possible somatic variant of (AAGGG)exp(AATGG)exp(AAGGG)exp in the (AAGGG)exp alleles in two RFC1-related PD patients. RNA foci were detected in the (AGGGG)exp-expressed HEK293T cell line as well as (AAGGG)exp and (ACAGG)exp, supporting (AGGGG)exp as a novel pathogenic repeat motif. This work revealed complex genotypes with novel repeat configuration of (AGGGG)exp and possible somatic (AATGG)exp insertion in RFC1-related PD. |
| format | Article |
| id | doaj-art-990b3ae2b8564310a72055b6b4ad267f |
| institution | Kabale University |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-990b3ae2b8564310a72055b6b4ad267f2025-01-26T12:21:29ZengNature Portfolionpj Parkinson's Disease2373-80572025-01-011111810.1038/s41531-025-00868-6Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson’s diseasePeng Liu0Fan Zhang1Xinhui Chen2Xiaosheng Zheng3Miao Chen4Zhiru Lin5Shuqi Chen6Lebo Wang7Xinchen Wang8Nan Jin9Chenxin Ying10Fei Xie11Bo Wang12Sheng Wu13Zhidong Cen14Wei Luo15Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineAbstract Biallelic intronic pentanucleotide repeat expansions, mainly (AAGGG)exp and/or (ACAGG)exp in RFC1, are detected in cerebellar ataxia, neuropathy and vestibular areflexia syndrome, late-onset ataxia, and in a wide disease spectrum including Charcot-Marie-Tooth disease, multiple system atrophy, and Parkinson’s disease (PD). However, the genotype-phenotype correlation and underlying mechanism are mostly unknown. We screened RFC1-repeat expansions in 1445 patients with parkinsonism. Comprehensive genetic and clinical, and pathological assessments were performed. We report two early-onset patients with PD carrying complex biallelic pentanucleotide repeat expansions in RFC1. Long-read sequencing revealed a novel repeat configuration of (AGGGG)exp(AAGGG)14 and a possible somatic variant of (AAGGG)exp(AATGG)exp(AAGGG)exp in the (AAGGG)exp alleles in two RFC1-related PD patients. RNA foci were detected in the (AGGGG)exp-expressed HEK293T cell line as well as (AAGGG)exp and (ACAGG)exp, supporting (AGGGG)exp as a novel pathogenic repeat motif. This work revealed complex genotypes with novel repeat configuration of (AGGGG)exp and possible somatic (AATGG)exp insertion in RFC1-related PD.https://doi.org/10.1038/s41531-025-00868-6 |
| spellingShingle | Peng Liu Fan Zhang Xinhui Chen Xiaosheng Zheng Miao Chen Zhiru Lin Shuqi Chen Lebo Wang Xinchen Wang Nan Jin Chenxin Ying Fei Xie Bo Wang Sheng Wu Zhidong Cen Wei Luo Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson’s disease npj Parkinson's Disease |
| title | Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson’s disease |
| title_full | Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson’s disease |
| title_fullStr | Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson’s disease |
| title_full_unstemmed | Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson’s disease |
| title_short | Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson’s disease |
| title_sort | long read sequencing revealed complex biallelic pentanucleotide repeat expansions in rfc1 related parkinson s disease |
| url | https://doi.org/10.1038/s41531-025-00868-6 |
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