Single sperm analysis of the CAG repeats in the gene for Machado-Joseph disease (MJD1): evidence for non-Mendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability
Abstract
To investigate the mechanism of the meiotic instability of expanded CAG repeats in the gene for Machado-Joseph disease (MJD1), we analyzed the CAG repeat sizes of 1036 single sperm from six individuals with Machado-Joseph disease (MJD). The segregation ratio between single sperm with an expanded allele and those with a normal allele is significantly different (P <0.0001) from the expected 1:1 segregation ratio, which demonstrates segregation distortion of expanded alleles in male meiosis. In single sperm from individuals with the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] genotype, significantly greater instability of the CAG repeat was observed compared with single sperm from individuals with the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] genotype (F-test, P <0.001). These findings in single sperm confirm non-Mendelian transmission of the MJD1 gene and the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability of the CAG repeats in the MJD1 gene, which have been observed in clinical and genetic studies. Our results indicate similarities and dissimilarities between MJD and Huntington's disease or myotonic dystrophy in terms of the inter-allelic interaction, segregation distortions and size distribution of trinucleotide repeats in mutant alleles. Further study is required to determine whether there is a common mechanism underlying the instability of the triplet repeats in 'triplet repeat diseases'.
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Preferential transmission of premutated or expanded repeats to unaffected, subclinical, and affected individuals occurs in many repeat diseases.
“Preferential transmission of premutated or expanded repeats to unaffected, subclinical, and affected individuals has been observed in many different repeat-related diseases42–44.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [43]
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Genome-wide detection of tandem DNA repeats that are expanded in autism
Trost, B., Engchuan, W., Nguyen, C. M., Thiruvahindrapuram, B., Dolzhenko, E., Backstrom, I., Mirceta, M., Mojarad, B. A., Yin, Y., Dov, A., et al. (2020) · Nature · doi:10.1038/s41586-020-2579-z · Cited by 238 · see citing works
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- Authors
- Takiyama, Y.
- Affiliations
- Jichi Medical University (JP)
- Corresponding author
- Takiyama, Y
- ORCID
- Takiyama, Y
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1997-07-01
- Volume
- 6
- Issue
- 7
- Pages
- 1063-1068
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2113041268
- Cited by
- 66
- References
- 26
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2020: 3 · 2019: 1 · 2018: 1 · 2016: 1 · 2015: 2 · 2013: 1 · 2012: 3
- FWCI
- 3.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Research Committee for Ataxic Disease
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- spinocerebellar ataxia type 3, CAG repeat expansion, trinucleotide repeat instability, segregation distortion, triplet repeat diseases, Huntington's disease, myotonic dystrophy, meiotic instability
- MeSH terms
- Ataxin-3, Alleles, Gene Frequency, Humans, Leukocytes, Male, Meiosis, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Polymorphism, Genetic, Repressor Proteins, Spermatozoa, Machado-Joseph Disease, Trinucleotide Repeats
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