Very Large (CAG)n DNA Repeat Expansions in the Sperm of Two Spinocerebellar Ataxia Type 7 Males

Monckton, Darren G.; Cayuela, María Luz; Gould, Fiona K.; Brock, Graham; Silva, Rajith de; Ashizawa, Tetsuo

doi:10.1093/hmg/8.13.2473

Cited by 66 publications

(41 citation statements)

References 33 publications

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“…A later study of 182 families from two particular Long QT syndromes did not find the same distortion to the expected 50:50 Mendelian transmission. 10 Diseases caused by expansion of CAG repeats, such as Machado-Joseph disease 11,12 and spinocerebellar ataxia 7 13 are suggested to show a prevalence of transmission of the mutant allele, but again have conflicting reports. Investigating transmission at two CAG disease repeat loci, TRD was noted in male meioses in live-born offspring 11 and in sperm typing from MJD patients 14 and preferentially transmitted to live-born offspring by female carriers.…”

Section: Introductionmentioning

confidence: 99%

Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation?

et al. 2012

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Intellectual disability is common. Aristaless-related homeobox (ARX) gene is one of the most frequently mutated and pleiotropic genes, implicated in 10 different phenotypes. More than half of B100 reported cases with ARX mutations are due to a recurrent duplication of 24 bp, c.429_452dup, which leads to polyalanine tract expansion. The excess of affected males among the offspring of the obligate carrier females raised the possibility of transmission ratio distortion for the c.429_452dup mutation. We found a significant deviation from the expected Mendelian 1:1 ratio of transmission in favour of the c.429_452dup ARX mutation. We hypothesise that the preferential transmission of the c.429_452dup mutation may be due to asymmetry of meiosis in the oocyte. Our findings may have implications for genetic counselling of families segregating the c.429_452dup mutation and allude to putative role of ARX in oocyte biology.

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Section: Introductionmentioning

confidence: 99%

Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation?

et al. 2012

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“…A high level of mosaicism was commonly observed in sperm, with this mosaicism overlapping the sizes inherited by the offspring, suggesting that intergenerational instability results mainly from germinal instability in the father (8,12,25,34,38,52,53). However, several studies, including one on fragile X fetuses and one on transmission in Friedreich ataxia families, suggested that intergenerational length changes could also involve a postzygotic instability event (13,14,37).…”

mentioning

confidence: 99%

MSH2-Dependent Germinal CTG Repeat Expansions Are Produced Continuously in Spermatogonia from DM1 Transgenic Mice

Savouret

Cordier

Mégret

et al. 2004

Molecular and Cellular Biology

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Myotonic dystrophy type 1 is a neuromuscular affection associated with the expansion of an unstable CTG repeat in the DM protein kinase gene. The disease is characterized by somatic tissue-specific mosaicism and very high intergenerational instability with a strong bias towards expansions. We used transgenic mice carrying more than 300 unstable CTG repeats within their large human genomic environment to investigate the dynamics of CTG repeat germinal mosaicism in males. Germinal mosaicism towards expansions was already present in spermatozoa at 7 weeks of age and continued to increase with age, suggesting that expansions are continuously produced throughout life. To determine the precise stage at which germinal expansions occur during spermatogenesis, we sorted and collected the different germ cell types produced during spermatogenesis from males of different ages and analyzed the CTG repeat mosaicism in each fraction. Strong mosaicisms towards expansions were already observed in spermatogonia before meiosis. In transgenic Msh2-deficient mice, germinal instability of the CTG repeats (only contractions) also occurs premeiotically. No significant difference in mosaicism was detected between spermatogonia and spermatozoa, arguing against continued expansions during postmeiotic stages. This indicates that germinal expansions are produced at the beginning of spermatogenesis, in spermatogonia, by a meiosis-independent mechanism involving MSH2.Myotonic dystrophy type 1 (DM1) is associated with the expansion of a CTG trinucleotide repeat located in the 3Ј untranslated region of the DM protein kinase (DMPK) gene at 19q13. 3 (3, 7, 17, 27). In normal subjects, there are usually between 5 and 37 copies of this repeat, which remains stable following intergenerational transmissions. In DM1 patients, more than 50 CTG repeats are typically present, and the repeat is highly unstable and increases with each generation. The number of CTG repeats is positively correlated with the severity of symptoms and is negatively correlated with age at onset, resulting in an anticipation phenomenon that is particularly obvious in DM1 (19). The behavior of the CTG repeat between generations appears to depend on the sex of the transmitting parent. Paternal transmissions lead to larger expansions for Ͻ100 CTG repeats, whereas maternal transmissions lead to larger expansions when the CTG repeat tract contains Ͼ500 repeats in the transmitting parent (2, 24). In between, both paternal and maternal alleles expand. In addition to intergenerational instability, somatic CTG repeat-length mosaicism is also found in DM1 patients. Inter-and intratissue mosaicisms increasing with age are observed, with a strong bias towards expansions (1,22). DM1 is one of the growing group of diseases caused by dynamic mutations. This group currently comprises more than a dozen diseases, including Huntington's disease (HD), spinocerebellar ataxias, and fragile X syndrome, which are generally associated with CNG trinucleotide repeats (11, 46). The dynamics of the different...

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“…CAG repeat instability has previously been described in a number of polyQ diseases as germ-line instability or intergenerational variations in repeat size. 4,5,7,9,10 However, to our knowledge, analyses of germ-line instability have not been investigated in SCA2. Out of 18 single spermatozoa with the expanded ATXN2 allele, 4 (22%) showed an expansion beyond the 45 CAG repeats detected in somatic cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, in SCA1 and SCA3 the longest gains reported were by 12 and 24 CAG repeats, 7,11,12 respectively, whereas much longer gains have been reported for SCA7 and DRPLA. 9,10 Exactly why CAG repeats in some genes are gaining more repeats than others remains obscure, but it seems that within a given disease longer repeats tend to be more unstable, as do pure CAG repeats, compared with repeats interrupted by CAA codons. 2,3 The extreme expansion observed in the girl was surprising, given the fact that her father's pathogenic allele of 45 glutamine codons was interrupted by a CAA codon at position 37.…”

Section: Discussionmentioning

confidence: 99%

Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

Vinther-Jensen

Dunø

et al. 2012

Eur J Hum Genet

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The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective genes leading to pathogenic expansions of polyglutamine stretches in the encoded proteins. In general, unstable CAG repeats have an uninterrupted CAG repeat, whereas stable CAG repeats are either short or interrupted by CAA codons, which -like CAG codons -code for glutamine. Here we report on an infantile SCA2 patient who, due to germ-line CAG repeat instability in her father, inherited an extremely expanded CAG repeat in the SCA2 locus. Surprisingly, the expanded allele of the father was an interrupted CAG repeat sequence. Furthermore, analyses of single spermatozoa showed a high frequency of paternal germ-line repeat sequence instability of the expanded SCA2 locus.

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Very Large (CAG)n DNA Repeat Expansions in the Sperm of Two Spinocerebellar Ataxia Type 7 Males

Cited by 66 publications

References 33 publications

Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation?

Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation?

MSH2-Dependent Germinal CTG Repeat Expansions Are Produced Continuously in Spermatogonia from DM1 Transgenic Mice

Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

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