Expansion of the (CAG)<sub>n</sub> repeat causing Huntington's disease in 352 patients of German origin

Zühlke, Christine; Rieß, Olaf; Schröder, Karsten; Siedlaczck, I; Epplen, Jörg T.; Engel, W. King; Thies, Ulrike

doi:10.1093/hmg/2.9.1467

Cited by 41 publications

(9 citation statements)

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“…Age of onset is inversely correlated with the CAG repeat length, such that a longer repeat in a patient is associated with a younger age of onset (8)(9)(10)(11)(12)(13)(14)(15). Analysis of 42 juvenile onset probands revealed that the anticipation observed in these families is closely correlated with an intergenerational expansion of the repeat, from the adult onset parent to the juvenile onset child (16).…”

Section: Huntington Disease (Hd) Is a Neurodegenerative Disorder Inhementioning

confidence: 99%

Somatic mosaicism in sperm is associated with intergenerational (CAG)_n changes in Huntington disease

Telenius

Almqvist

Kremer³

et al. 1995

Hum Mol Genet

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We have analysed the CAG repeat in the Huntington disease (HD) gene in sperm and blood from 20 unrelated HD patients. Although the CAG repeat displayed significant mosaicism in sperm from all individuals, there were marked differences in the degree of repeat instability. Individuals who had either inherited or transmitted an expanded CAG repeat displayed the highest levels of repeat mosaicism, whereas individuals who had inherited or transmitted a contracted repeat had very limited CAG mosaicism in sperm. A strong association between intergenerational change in CAG allele size and the level of sperm repeat mosaicism was determined (P = 0.019). In contrast, neither blood CAG size nor repeat mosaicism in blood, were significantly associated with intergenerational CAG changes. These data suggest the presence of a cis-acting factor, separate from CAG size, that strongly influences the intergenerational behaviour of the CAG repeat. Additional studies are needed to determine whether analysis of CAG mosaicism in sperm is useful for assessing an individual's risk for transmitting large expansions or contractions to his offspring.

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Section: Huntington Disease (Hd) Is a Neurodegenerative Disorder Inhementioning

confidence: 99%

Somatic mosaicism in sperm is associated with intergenerational (CAG)_n changes in Huntington disease

Telenius

Almqvist

Kremer³

et al. 1995

Hum Mol Genet

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“…CAG repeat sizes were determined by polymerase chain reaction of the number of CAG trinucleotide repeats responsible for the HD gene [HDCRG, 1993], using a modified protocol which eliminated an adjacent proline (CCG) repeat [Barron et al, 1993;Zü hlke et al, 1993]. Cases with 36 or more repeats, were designated HD gene carriers in accordance with published associations with disease expression [Myers et al, 1998].…”

Section: Cag Repeat Size Determinationmentioning

confidence: 99%

Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease

Djoussé

Knowlton

Hayden

et al. 2003

American J of Med Genetics Pt A

152

120

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Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.

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“…The underlying cause is an expanded CAG repeat of more than 35 units in the HD gene encoding huntingtin, which leads to manifestation of the symptoms commonly at the age of 35-50 years (Hayden 1981;The Huntington's Disease Collaborative Research Group 1993). The length of the translated polyglutamine (polyQ) tract is inversely correlated with the age at onset (AAO) of the disease (Andrew et al 1993;Duyao et al 1993;Snell et al 1993;Zühlke et al 1993) and accounts for up to 73% of the variance in the AAO depending on the respective population (Brinkman et al 1997;Lucotte et al 1995). Similar to other neurodegenerative diseases, the disease-causing gene alone does not determine the AAO and the course of the disease.…”

Section: Introductionmentioning

confidence: 99%

Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7

et al. 2010

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Huntington's disease (HD) is caused by an expansion of a polyglutamine repeat of more than 35 units in the huntingtin protein. The expanded repeat length is inversely correlated with the age at onset (AAO); however, additional genetic factors apart from the expanded CAG repeat length can modify the course and the AAO in HD. Aberrations in macroautophagy have been observed in Huntington, Alzheimer, Parkinson, motor neuron and prion diseases. Therefore, we hypothesized that polymorphisms in autophagy-related (Atg) genes might contribute to the variation in the AAO. We initially tested eight single nucleotide polymorphisms in five Atg genes (Atg3, Atg5, Atg7, Atg16L1 and Beclin-1) for their frequency of ≥1%. Subsequently, we investigated the polymorphisms Atg7 V471A and Atg16L1 T281A for a disease-modifying effect in more than 900 European HD patients (including 2 populations consisting of 346 German patients and 327 patients of Italian descent). One polymorphism in the Atg7 gene that substitutes alanine for valine (V471A) showed a significant effect on the AAO (P=0.0050) and was associated with an earlier disease onset of 4 years. Our results further support the important pathophysiological role of autophagy in HD.

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Expansion of the (CAG)_n repeat causing Huntington's disease in 352 patients of German origin

Cited by 41 publications

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Somatic mosaicism in sperm is associated with intergenerational (CAG)_n changes in Huntington disease

Somatic mosaicism in sperm is associated with intergenerational (CAG)_n changes in Huntington disease

Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease

Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7

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Expansion of the (CAG)n repeat causing Huntington's disease in 352 patients of German origin

Cited by 41 publications

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Somatic mosaicism in sperm is associated with intergenerational (CAG)n changes in Huntington disease

Somatic mosaicism in sperm is associated with intergenerational (CAG)n changes in Huntington disease

Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease

Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7

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Expansion of the (CAG)_n repeat causing Huntington's disease in 352 patients of German origin

Somatic mosaicism in sperm is associated with intergenerational (CAG)_n changes in Huntington disease

Somatic mosaicism in sperm is associated with intergenerational (CAG)_n changes in Huntington disease