Limited somatic mosaicism for Friedreich's ataxia GAA triplet repeat expansions identified by small pool PCR in blood leukocytes

Hellenbroich, Yorck; Schwinger, E.; Zühlke, C.

doi:10.1034/j.1600-0404.2001.103003188.x

Cited by 19 publications

(14 citation statements)

References 16 publications

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“…Incontinentia pigmenti can lead to atrophy of the cortex and cerebellum, with some cases due to somatic mutation in the gene encoding the inhibitor of kappa light polypeptide gene enhancer in β cells, kinase gamma (IKBKG, also known as NEMO ) (53). Some neurodegenerative diseases—such as Friedrich’s ataxia, dentatorubral-pallidoluysian atrophy, and Huntington’s disease—are caused by inheritance of expanded microsatellite repeats that are highly mutable; these loci can exhibit marked somatic heterogeneity in repeat lengths across brain regions and tissues of affected individuals (54–60). Age-related (postdevelopmental) somatic mutation, known to play a role in cancer, has also been widely postulated as playing a role in normal aging processes as well as in neurodegeneration (61, 62), but a full consideration of such age-related somatic mutation is beyond the scope of this Review.…”

Section: How Do Somatic Mutations Manifest As Neurological Disease?mentioning

confidence: 99%

Somatic Mutation, Genomic Variation, and Neurological Disease

Poduri

Evrony

Cai

et al. 2013

Science

536

446

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Genetic mutations causing human disease are conventionally thought to be inherited through the germ line from one’s parents and present in all somatic (body) cells, except for most cancer mutations, which arise somatically. Increasingly, somatic mutations are being identified in diseases other than cancer, including neurodevelopmental diseases. Somatic mutations can arise during the course of prenatal brain development and cause neurological disease—even when present at low levels of mosaicism, for example—resulting in brain malformations associated with epilepsy and intellectual disability. Novel, highly sensitive technologies will allow more accurate evaluation of somatic mutations in neurodevelopmental disorders and during normal brain development.

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Section: How Do Somatic Mutations Manifest As Neurological Disease?mentioning

confidence: 99%

Somatic Mutation, Genomic Variation, and Neurological Disease

Poduri

Evrony

Cai

et al. 2013

Science

536

446

View full text Add to dashboard Cite

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“…Not surprisingly, therefore, long (GAA) n runs are very unstable in length and are prone to both expansions and contractions. Long tracts of GAA repeats are also particularly unstable in somatic tissues (22), with contractions more common than expansions (23,24). It was hypothesized that the instability of GAA repeats is due to their ability to form an intramolecular DNA triplex, also known as H-DNA (25,26).…”

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confidence: 99%

Large-scale contractions of Friedreich’s ataxia GAA repeats in yeast occur during DNA replication due to their triplex-forming ability

Khristich

Armenia

Matera

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Friedreich’s ataxia (FRDA) is a human hereditary disease caused by the presence of expanded (GAA)n repeats in the first intron of the FXN gene [V. Campuzano et al., Science 271, 1423–1427 (1996)]. In somatic tissues of FRDA patients, (GAA)n repeat tracts are highly unstable, with contractions more common than expansions [R. Sharma et al., Hum. Mol. Genet. 11, 2175–2187 (2002)]. Here we describe an experimental system to characterize GAA repeat contractions in yeast and to conduct a genetic analysis of this process. We found that large-scale contraction is a one-step process, resulting in a median loss of ∼60 triplet repeats. Our genetic analysis revealed that contractions occur during DNA replication, rather than by various DNA repair pathways. Repeats contract in the course of lagging-strand synthesis: The processivity subunit of DNA polymerase δ, Pol32, and the catalytic domain of Rev1, a translesion polymerase, act together in the same pathway to counteract contractions. Accumulation of single-stranded DNA (ssDNA) in the lagging-strand template greatly increases the probability that (GAA)n repeats contract, which in turn promotes repeat instability in rfa1, rad27, and dna2 mutants. Finally, by comparing contraction rates for homopurine-homopyrimidine repeats differing in their mirror symmetry, we found that contractions depend on a repeat’s triplex-forming ability. We propose that accumulation of ssDNA in the lagging-strand template fosters the formation of a triplex between the nascent and fold-back template strands of the repeat. Occasional jumps of DNA polymerase through this triplex hurdle, result in repeat contractions in the nascent lagging strand.

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“…The allele size may be dependent on the age of the person at sampling, meaning that a progression of the expansion size heterogeneity due to the age of the patient may influence results of correlation studies. 40 In conclusion, our family demonstrated marked intrafamilial phenotypic variability, including spastic paraplegia, in the presence of similar midsize homozygous expansions of the FRDA1 gene. Our study confirms that predictions on disease presentation and progression in any individual FA patient are not possible based solely on expansion sizes in leucocytes.…”

Section: Discussionmentioning

confidence: 51%

Striking intrafamilial phenotypic variability and spastic paraplegia in the presence of similar homozygous expansions of the FRDA1 gene

et al. 2004

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We report on a Friedreich's ataxia (FA) family with 3 affected siblings with markedly different phenotypic presentations, including one with spastic paraplegia. Molecular analysis showed midsize GAA repeat expansion sizes in all 3 individuals. Gait spasticity in FA, although rare, has been described in a few patients who are compound heterozygotes for a point mutation, or who had GAA expansions of less than 200 repeats. The occurrence of spastic paraplegia in our family, in the presence of homozygous midsize GAA repeat expansions, is an unusual finding. Spasticity can be the main feature in both sporadic and familial patients with FA, either as an isolated finding, or in addition to other neurological abnormalities, and should be included as a rare feature in the clinical spectrum of FA. This family also demonstrates that in FA, marked intrafamilial phenotypic variability can arise in the presence of similar GAA expansion sizes. Therefore, in familial FA, the disease course in relatives therefore cannot be predicted solely from repeat length. Factors such as somatic mosaicism, repeat interruptions, modifying mutations and environmental factors must also be considered.

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Limited somatic mosaicism for Friedreich's ataxia GAA triplet repeat expansions identified by small pool PCR in blood leukocytes

Cited by 19 publications

References 16 publications

Somatic Mutation, Genomic Variation, and Neurological Disease

Somatic Mutation, Genomic Variation, and Neurological Disease

Large-scale contractions of Friedreich’s ataxia GAA repeats in yeast occur during DNA replication due to their triplex-forming ability

Striking intrafamilial phenotypic variability and spastic paraplegia in the presence of similar homozygous expansions of the FRDA1 gene

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