A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis
ABSTRACT Background Heterozygous variants of sequestosome‐1 gene (SQSTM1) have been reported in patients with various neurological disorders, whereas biallelic pathogenic variants of SQSTM1 can cause child‐onset and multisystem neurodegeneration, including cerebellar ataxia, dystonia, and vertical g...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-11-01
|
| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.70044 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850146059984044032 |
|---|---|
| author | Shinji Masuko Mitsuto Sato Katsuya Nakamura Kohei Hamanaka Satoko Miyatake Yuji Inaba Tomoki Kosho Naomichi Matsumoto Yoshiki Sekijima |
| author_facet | Shinji Masuko Mitsuto Sato Katsuya Nakamura Kohei Hamanaka Satoko Miyatake Yuji Inaba Tomoki Kosho Naomichi Matsumoto Yoshiki Sekijima |
| author_sort | Shinji Masuko |
| collection | DOAJ |
| description | ABSTRACT Background Heterozygous variants of sequestosome‐1 gene (SQSTM1) have been reported in patients with various neurological disorders, whereas biallelic pathogenic variants of SQSTM1 can cause child‐onset and multisystem neurodegeneration, including cerebellar ataxia, dystonia, and vertical gaze palsy (NADGP). Here, we describe two cases of NADGP in a Japanese family. Methods We performed clinical and genetic laboratory evaluations of the two patients and their healthy parents. Results By whole‐exome sequencing, we identified compound heterozygous variants in SQSTM1(NM_003900.5): c.1A>G p.(Met1?) in the initial codon, and c.969G>A, located at the 3′ end of exon 6, which is novel and seemingly a synonymous but is actually a truncating variant causing aberrant splicing. An SQSTM1 protein expression assay using urine‐derived cells (UDCs) demonstrated that both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of premessenger RNA. Cerebellar ataxia is a characteristic manifestation of this disorder; however, brain magnetic resonance imaging studies have not shown significant cerebellar atrophy. Our patients experienced chorea during adolescence. Conclusions Only a few reports have highlighted the presence of chorea; however, our findings suggest that NADGP should be considered as a differential diagnosis of hereditary chorea. This study also demonstrates the utility of UDCs, obtained using noninvasive approaches, in functionally analyzing genetic diseases. |
| format | Article |
| id | doaj-art-687cbdd84de047abbf4ec9978d2ca909 |
| institution | OA Journals |
| issn | 2324-9269 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj-art-687cbdd84de047abbf4ec9978d2ca9092025-08-20T02:27:57ZengWileyMolecular Genetics & Genomic Medicine2324-92692024-11-011211n/an/a10.1002/mgg3.70044A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional AnalysisShinji Masuko0Mitsuto Sato1Katsuya Nakamura2Kohei Hamanaka3Satoko Miyatake4Yuji Inaba5Tomoki Kosho6Naomichi Matsumoto7Yoshiki Sekijima8Department of Medicine (Neurology & Rheumatology) Shinshu University School of Medicine Matsumoto JapanDepartment of Medicine (Neurology & Rheumatology) Shinshu University School of Medicine Matsumoto JapanDepartment of Medicine (Neurology & Rheumatology) Shinshu University School of Medicine Matsumoto JapanDepartment of Human Genetics Yokohama City University Graduate School of Medicine Yokohama JapanDepartment of Human Genetics Yokohama City University Graduate School of Medicine Yokohama JapanDivision of Neuropediatrics Nagano Children's Hospital Azumino JapanCenter for Medical Genetics Shinshu University Hospital Matsumoto JapanDepartment of Human Genetics Yokohama City University Graduate School of Medicine Yokohama JapanDepartment of Medicine (Neurology & Rheumatology) Shinshu University School of Medicine Matsumoto JapanABSTRACT Background Heterozygous variants of sequestosome‐1 gene (SQSTM1) have been reported in patients with various neurological disorders, whereas biallelic pathogenic variants of SQSTM1 can cause child‐onset and multisystem neurodegeneration, including cerebellar ataxia, dystonia, and vertical gaze palsy (NADGP). Here, we describe two cases of NADGP in a Japanese family. Methods We performed clinical and genetic laboratory evaluations of the two patients and their healthy parents. Results By whole‐exome sequencing, we identified compound heterozygous variants in SQSTM1(NM_003900.5): c.1A>G p.(Met1?) in the initial codon, and c.969G>A, located at the 3′ end of exon 6, which is novel and seemingly a synonymous but is actually a truncating variant causing aberrant splicing. An SQSTM1 protein expression assay using urine‐derived cells (UDCs) demonstrated that both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of premessenger RNA. Cerebellar ataxia is a characteristic manifestation of this disorder; however, brain magnetic resonance imaging studies have not shown significant cerebellar atrophy. Our patients experienced chorea during adolescence. Conclusions Only a few reports have highlighted the presence of chorea; however, our findings suggest that NADGP should be considered as a differential diagnosis of hereditary chorea. This study also demonstrates the utility of UDCs, obtained using noninvasive approaches, in functionally analyzing genetic diseases.https://doi.org/10.1002/mgg3.70044GC‐AT intronNADGPSQSTM1UDCurine‐derived cell |
| spellingShingle | Shinji Masuko Mitsuto Sato Katsuya Nakamura Kohei Hamanaka Satoko Miyatake Yuji Inaba Tomoki Kosho Naomichi Matsumoto Yoshiki Sekijima A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis Molecular Genetics & Genomic Medicine GC‐AT intron NADGP SQSTM1 UDC urine‐derived cell |
| title | A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis |
| title_full | A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis |
| title_fullStr | A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis |
| title_full_unstemmed | A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis |
| title_short | A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis |
| title_sort | novel synonymous variant in sqstm1 causes neurodegeneration with ataxia dystonia and gaze palsy revealed by urine derived cells based functional analysis |
| topic | GC‐AT intron NADGP SQSTM1 UDC urine‐derived cell |
| url | https://doi.org/10.1002/mgg3.70044 |
| work_keys_str_mv | AT shinjimasuko anovelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT mitsutosato anovelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT katsuyanakamura anovelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT koheihamanaka anovelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT satokomiyatake anovelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT yujiinaba anovelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT tomokikosho anovelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT naomichimatsumoto anovelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT yoshikisekijima anovelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT shinjimasuko novelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT mitsutosato novelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT katsuyanakamura novelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT koheihamanaka novelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT satokomiyatake novelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT yujiinaba novelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT tomokikosho novelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT naomichimatsumoto novelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis AT yoshikisekijima novelsynonymousvariantinsqstm1causesneurodegenerationwithataxiadystoniaandgazepalsyrevealedbyurinederivedcellsbasedfunctionalanalysis |