Dynamic mutation in Dutch Huntington's disease patients: increased paternal repeat instability extending to within the normal size range.

Rooij, Karien E. de; Gans, P. A. M. de Koning; Skraastad, M. I.; Belfroid, R. D. M.; Vlis, Maria Vegter-van der; Roos, Raymund A.C.; Bakker, Egbert; Ommen, G.J.B. van; Dunnen, Johan T. den; Losekoot, Monique

doi:10.1136/jmg.30.12.996

Cited by 50 publications

(30 citation statements)

References 17 publications

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“…Expanded CAG-tracts can be unstable and have a tendency to increase in size across generations, particularly when paternally transmitted. 13,14 New mutations for HD occur when the CAG-tract of a transmitted chromosome expands to 36 repeats or greater. The intermediate allele (IA; 27-35 CAG) class of chromosomes have a larger than normal CAG-tract in HTT.…”

Section: Introductionmentioning

confidence: 99%

HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia

et al. 2011

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Huntington disease (HD) results from CAG expansion in the huntingtin (HTT) gene. Although HD occurs worldwide, there are large geographic differences in its prevalence. The prevalence in populations derived from Europe is 10-100 times greater than in East Asia. The European general population chromosomes can be grouped into three major haplogroups (group of similar haplotypes): A, B and C. The majority of HD chromosomes in Europe are found on haplogroup A. However, in the East-Asian populations of China and Japan, we find the majority of HD chromosomes are associated with haplogroup C. The highest risk HD haplotypes (A1 and A2), are absent from the general and HD populations of China and Japan, and therefore provide an explanation for why HD prevalence is low in East Asia. Interestingly, both East-Asian and European populations share a similar low level of HD on haplogroup C. Our data are consistent with the hypothesis that different HTT haplotypes have different mutation rates, and geographic differences in HTT haplotypes explain the difference in HD prevalence. Further, the bias for expansion on haplogroup C in the East-Asian population cannot be explained by a higher average CAG size, as haplogroup C has a lower average CAG size in the general East-Asian population compared with other haplogroups. This finding suggests that CAG-tract size is not the only factor important for CAG instability. Instead, the expansion bias may be because of genetic cis-elements within the haplotype that influence CAG instability in HTT, possibly through different mutational mechanisms for the different haplogroups.

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Section: Introductionmentioning

confidence: 99%

HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia

et al. 2011

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“…[1][2][3][4] The mutation associated with this disorder is the expansion of a (CAG) n tract in the coding region of the MJD1 gene, 5 which in normal individuals contains from 12 to 41 repeat units and in expanded chromosomes from 61 to 86 repeat units. [5][6][7] Although the mechanisms of trinucleotide repeat instability are still not understood, a variety of factors have been implicated as modulating intergenerational repeat instability in the diseases associated with dynamic mutations, namely the sex of transmitter, [6][7][8][9][10][11][12][13][14][15][16][17][18] the expanded repeat size in the transmitting parent, [8][9][10][11][12][18][19][20] the presence or absence of an interruption of the repeat, 16,[21][22][23][24][25] and even the sex of the descendent. 26 We and others have previously shown that in MJD families the sex of the transmitting parent has a significant effect on intergenerational instability, 6,7,17 with male meiosis associated with larger variations, both contractions and expansions, of repeat size.…”

Section: Introductionmentioning

confidence: 99%

Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract

et al. 1999

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Intergenerational instability is one of the most important features of the disease-associated trinucleotide expansions, leading to variation in size of the repeat among and within families, which manifests as variable age at onset and severity, and is probably the basis for the occurrence of anticipation. Several factors are known to affect the degree of instability, namely the type of repeated sequence, its initial size, the presence or absence of interruptions in the repetitive tract and the gender of the transmitting parent. A recent study demonstrated the effect of an intragenic polymorphism (C 987 GG/G 987 GG) in the Machado-Joseph disease causative gene, immediately downstream of the CAG repeat, on the intergenerational instability of the expanded repeat. Surprisingly, there was an effect not only of the specific allele in cis to the disease chromosome, but also of the allele on the normal chromosome, suggesting the existence of an interaction between the normal and expanded alleles that affects the fidelity of replication of the (CAG) n tract. This effect could be a direct effect of the polymorphism studied or, alternatively, this polymorphism could be in disequilibrium with some other flanking sequence which affects the instability of the repetitive (CAG) n tract. In order to confirm the previous results in a different population and to distinguish between a direct and indirect effect of the CGG/GGG polymorphism, we typed 70 parent-progeny pairs for which the variation in the (CAG) n length in the MJD1 gene was known, for three intragenic polymorphisms: C European Journal of Human Genetics (1999) 7, 147-156 © 1999 Stockton Press All rights reserved 1018-4813/99 $12.00 t http://www.stockton-press.co.uk/ejhg suggestive of an instability-predisposing effect of the repeat-flanking sequences, which could have led to the origin of the MJD mutation in the human population. We confirmed the effect of the C 987 GG/G 987 GG polymorphism on intergenerational instability when present in trans. Our results suggest that this effect is restricted to a small region of the gene, immediately downstream of the CAG repeat, which includes this particular nucleotide substitution and the stop codon of the MJD1 cDNA, and is not a more widespread chromosomal effect. The lack of a significant association of any specific intragenic haplotype with larger CAG repeats in normal chromosomes, together with the absence of an effect of the intragenic haplotype in cis on the intergenerational instability of the expanded (CAG) n in MJD families does not indicate the existence of an instability-predisposing haplotype.

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“…Unaffected individuals carry up to 35 CAG repeats and affected individuals carry 36 or more CAG repeats Duyao et al, 1993;Hersch et al, 1994;Myers et al, 1993;Telenius et al, 19951. Intermediate alleles (IAs), which range from the larger sized normal length alleles to the smaller sized disease length alleles (29-38 repeats), appear to carry some level of instability and have been shown, in the unaffected parents of sporadic cases of HD, to antecede the disease length alleles [De Rooij et al, 1993;Goldberg et al, 199313, 1995;Myers et al, 19931. Molecular genetic characterization of HD uses the polymerase chain reaction (PCR) to amplify the region containing the CAG repeat and determine the number of CAG repeat units present Duyao et al, 1993;Goldberg et al, 199313;HD Collaborative Group, 1993;Myers et al, 19931. Molecular genetic analysis of HD is frequently utilized by neurologists for diagnostic confirmation of individuals with classical symptoms and a family history of HD as well as a differential diagnostic tool for suspected cases [Broholm et al, 1994;Hersch et al, 19941.…”

Section: Abstract: Huntington Disease Sporadicmentioning

confidence: 98%

“…Smaller IAs, between 29 t o 35 repeats, appear not to be associated with disease; however larger IAs, between 36 to 38 repeats have been shown, in some cases, to be associated with HD Duyao et al, 1993;Goldberg et al, 1995;Hersch et al, 1994;Myers et al, 1993;Telenius et al, 19951. In addition, the risk to future generations for inheritance of an affected length allele from a parent with an IA cannot be reliably determined at this time [Benjamin et al, 1994;Broholm et al, 1994;De Rooij et al, 1993;Goldberg et al, 1993aGoldberg et al, ,b,c, 1995Hersch et al, 1994;Kremer et al, 1995;Myers et al, 1993;Telenius et al, 1994, 19951. In our experience, sporadic cases of HD, caused by expansion of unstable intermediate alleles (IAs) to full mutations, represent the most challenging diagnostic and counseling situations for HD because the mechanism and frequency of new mutations at this locus is not clear at this time and risk for extended family members cannot be determined [Benjamin et al, 1994;Broholm et al, 1994;De Rooij et al, 1993;Goldberg et al, 1993aGoldberg et al, ,b,c, 1995Hersch et al, 1994;Kremer et al, 1995;Myers et al, 1993;Telenius et al, 1994, 19951. Little is known about the mechanism or frequency of CAG repeat expansion and contraction for intermediate length alleles at this locus.…”

Section: Genetic Counseling Of Sporadic Hd Familiesmentioning

confidence: 99%

“…In addition, the risk to future generations for inheritance of an affected length allele from a parent with an IA cannot be reliably determined at this time [Benjamin et al, 1994;Broholm et al, 1994;De Rooij et al, 1993;Goldberg et al, 1993aGoldberg et al, ,b,c, 1995Hersch et al, 1994;Kremer et al, 1995;Myers et al, 1993;Telenius et al, 1994, 19951. In our experience, sporadic cases of HD, caused by expansion of unstable intermediate alleles (IAs) to full mutations, represent the most challenging diagnostic and counseling situations for HD because the mechanism and frequency of new mutations at this locus is not clear at this time and risk for extended family members cannot be determined [Benjamin et al, 1994;Broholm et al, 1994;De Rooij et al, 1993;Goldberg et al, 1993aGoldberg et al, ,b,c, 1995Hersch et al, 1994;Kremer et al, 1995;Myers et al, 1993;Telenius et al, 1994, 19951. Little is known about the mechanism or frequency of CAG repeat expansion and contraction for intermediate length alleles at this locus. Recent studies suggest that intergenerational changes in repeat length of nor- [De Rooij et al, 1993;Goldberg et al, 1993bGoldberg et al, , 1995Myers et al, 19931. proband (individual 1-3) has a number of children and grandchildren whose concern for inheritance of an IA by asymptomatic relatives could cause considerable anxiety for these and future generations (Fig.…”

Section: Genetic Counseling Of Sporadic Hd Familiesmentioning

confidence: 99%

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Molecular detection of new mutations, resolution of ambiguous results and complex genetic counseling issues in Huntington disease

et al. 1996

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Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expansion of a variable length (CAG)n repeat in the 5' coding region of a novel gene on chromosome 4p16.3. We provide comprehensive molecular analysis of a sporadic case of HD in which a paternally derived normal length allele expanded to an affected length allele. Linkage analysis and paternity testing confirm the paternal origin of the expansion and demonstrate that unequal crossing over during meiosis is an unlikely mechanism for de novo expansion in HD. This case identifies a complex genetic counseling issue for the families of sporadic cases since calculations of recurrence risk are not possible at this time. In addition, we describe utilization of a combination of polymerase chain reaction (PCR) based assays for examination of both the CAG repeat and an adjacent variable length CCG repeat in the huntingtin gene. The combination of these assays can increase the accuracy of molecular diagnosis for HD and may clarify any ambiguous results obtained during molecular testing of HD families.

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Dynamic mutation in Dutch Huntington's disease patients: increased paternal repeat instability extending to within the normal size range.

Cited by 50 publications

References 17 publications

HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia

HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia

Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract

Molecular detection of new mutations, resolution of ambiguous results and complex genetic counseling issues in Huntington disease

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