Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia
Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal reces...
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MDPI AG
2022-03-01
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| author | Mariana Santos Joana Damásio Susana Carmona João Luís Neto Nadia Dehghani Leonor Correia Guedes Clara Barbot José Barros José Brás Jorge Sequeiros Rita Guerreiro |
| author_facet | Mariana Santos Joana Damásio Susana Carmona João Luís Neto Nadia Dehghani Leonor Correia Guedes Clara Barbot José Barros José Brás Jorge Sequeiros Rita Guerreiro |
| author_sort | Mariana Santos |
| collection | DOAJ |
| description | Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (<i>SACS</i> and <i>KIF1C</i>) and with ataxia and neuropathy or AOA (<i>PNKP</i>). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in <i>KIF1A</i>, <i>CACNA1A,</i> or <i>ATP1A3</i>, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration. |
| first_indexed | 2024-03-09T20:00:52Z |
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| language | English |
| last_indexed | 2024-03-09T20:00:52Z |
| publishDate | 2022-03-01 |
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| series | Cells |
| spelling | doaj.art-534e77106e9a4d248a700ba7784ccebc2023-11-24T00:44:11ZengMDPI AGCells2073-44092022-03-0111698110.3390/cells11060981Molecular Characterization of Portuguese Patients with Hereditary Cerebellar AtaxiaMariana Santos0Joana Damásio1Susana Carmona2João Luís Neto3Nadia Dehghani4Leonor Correia Guedes5Clara Barbot6José Barros7José Brás8Jorge Sequeiros9Rita Guerreiro10UnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalUnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalDepartment of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USAUnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalDepartment of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USADepartment of Neurosciences and Mental Health, Neurology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, 1649-028 Lisbon, PortugalCGPP-Centre for Predictive and Preventive Genetics, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalNeurology Department, Centro Hospitalar Universitário do Porto, 4099-001 Porto, PortugalDepartment of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USAUnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalDepartment of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USAHereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (<i>SACS</i> and <i>KIF1C</i>) and with ataxia and neuropathy or AOA (<i>PNKP</i>). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in <i>KIF1A</i>, <i>CACNA1A,</i> or <i>ATP1A3</i>, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.https://www.mdpi.com/2073-4409/11/6/981cerebellar ataxiarecessive ataxiaexome sequencingmolecular mechanismsde novo variant |
| spellingShingle | Mariana Santos Joana Damásio Susana Carmona João Luís Neto Nadia Dehghani Leonor Correia Guedes Clara Barbot José Barros José Brás Jorge Sequeiros Rita Guerreiro Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia Cells cerebellar ataxia recessive ataxia exome sequencing molecular mechanisms de novo variant |
| title | Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia |
| title_full | Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia |
| title_fullStr | Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia |
| title_full_unstemmed | Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia |
| title_short | Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia |
| title_sort | molecular characterization of portuguese patients with hereditary cerebellar ataxia |
| topic | cerebellar ataxia recessive ataxia exome sequencing molecular mechanisms de novo variant |
| url | https://www.mdpi.com/2073-4409/11/6/981 |
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