FXTAS, SCA10, and SCA17 in American patients with movement disorders

Seixas, Ana I.; Maurer, Martin H.; Lin, Mark W.; Callahan, Colleen; Ahuja, Alka; Matsuura, Tetsuya; Ross, Christopher A.; Hisama, Fuki M.; Silveira, Isabel; Margolis, Russell L.

doi:10.1002/ajmg.a.30761

Cited by 36 publications

(24 citation statements)

References 24 publications

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“…Since then, several studies reporting a smaller contribution of FMR1 premutations to neurodegenerative phenotypes were published, where FMR1 premutation frequencies ranged from 0-5%. These data are shown in Table 1 (Garcia Arocena et al, 2004;Van Esch et al, 2004;Tan et al, 2004;Zühlke et al, 2004;Biancalana et al, 2005;Brussino et al, 2005;Seixas et al, 2005;Toft et al, 2005). Some issues in these reports deserve a closer scrutiny.…”

Section: Discussionmentioning

confidence: 95%

“…The contribution of FMR1 premutation to the phenotype ataxia-tremor-parkinsonism has been only seldom addressed. Discordant results on the contribution of FMR1 premutation to these phenotypes have been published and could be attributed to the relatively broad range of phenotypes included in FXTAS as well as to ascertainment bias (MacPherson et al, 2003;Tan et al, 2004;Van Esch et al, 2004;Zühlke et al, 2004;Brussino et al, 2005;Seixas et al, 2005). Correct diagnosis would contribute to genetic counseling of these families (Tan et al, 2004;Hall et al, 2005;Kamm and Gasser, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Frequency of FMR1 premutation in individuals with ataxia and/or tremorand/or parkinsonism

Reis

Ferreira²,

Gomes³

et al. 2008

Genet. Mol. Res.

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ABSTRACT.A late onset neurological syndrome in carriers of premutation in FMR1 gene was recently described. The condition was named fragile-X-associated tremor/ataxia syndrome (FXTAS) and includes intentional tremor, cerebellar ataxia, parkinsonism, and cognitive deficit. We ascertained the contribution of FMR1 premutation to the phenotypes ataxia, tremor and/or parkinsonism. Sixty-six men over 45 years old presenting these symptoms, isolated or combined, were tested. Also, 74 normal men, randomly chosen in the population, formed the control group. In the patient group, no premutation carrier was found, which is in agreement with other observed frequencies reported elsewhere (0-5% variation). 75Frequency of FMR1 in ataxia, tremor or parkinsonism No significant differences were found when comparing gray zone allele frequencies among target and control groups. The FXTAS contribution in patients with phenotypic manifestations of FXTAS was 15/748 (2%). The presence of gray zone alleles is not correlated with FXTAS occurrence.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Frequency of FMR1 premutation in individuals with ataxia and/or tremorand/or parkinsonism

Reis

Ferreira²,

Gomes³

et al. 2008

Genet. Mol. Res.

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“…Notably, alleles of 280-850 units show reduced penetrance in SCA10, and alleles of 33-280 repeats have not been observed. [41][42][43] DAB1 lies within the mapped SCA37 locus in chromosomal region 1p32 in a family originating from Spain. 20 The occurrence of multiple SCA gene mutations clustered in small genomic regions is rare and has been seen only in PDYN (MIM: 131340; associated with SCA23 [MIM: 610245]), NOP56 (associated with SCA36), and TGM6 (MIM: 613900; associated with SCA35 [MIM: 613908]), which are contained in a 750 kb region on human chromosomal arm 20p.…”

Section: Discussionmentioning

confidence: 99%

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia

Seixas

Loureiro

Costa

et al. 2017

The American Journal of Human Genetics

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118

173

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Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the noncoding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC) n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT) 7-400 ] and [(ATTTT) 60-79 (ATTTC) 31-75 (ATTTT) ], respectively. (ATTTC) n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC) n is located in 5 0 UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC) 58 insertion, but not (ATTTT) n , leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC) 58 insertion, but not (AUUUU) n , showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37.

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“…7,19 Screening studies have shown that fragile X tremor/ataxia syndrome could be a frequent genetic cause of late-onset sporadic ataxia. 20,21 Therefore, this method represents a useful tool especially in the case of screening of large population samples.…”

Section: Enhanced Pcr For Fmr1 Expansions 609mentioning

confidence: 99%

An Enhanced Polymerase Chain Reaction Assay to Detect Pre- and Full Mutation Alleles of the Fragile X Mental Retardation 1 Gene

Saluto¹,

Brussino²,

Tassone³

et al. 2005

The Journal of Molecular Diagnostics

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Several diagnostic strategies have been applied to the detection of FMR1 gene repeat expansions in fragile X syndrome. Here, we report a novel polymerase chain reaction-based strategy using the Expand Long Template PCR System (Roche Diagnostics, Mannheim, Germany) and the osmolyte betaine. Repeat expansions up to ϳ330 CGGs in males and up to at least ϳ160 CGGs in carrier women could be easily visualized on ethidium bromide agarose gels. We also demonstrated that fluorescence analysis of polymerase chain reaction products was a reliable tool to verify the presence of premutation and full mutation alleles both in males and in females. This technique, primarily designed to detect premutation alleles, can be used as a routine first screen for expanded FMR1 alleles. (J Mol Diagn 2005, 7:605-612)Fragile X syndrome is the most common inherited form of mental retardation. This syndrome is caused by the expansion of CGG repeats in the 5Ј-untranslated region of the fragile X mental retardation 1 (FMR1) gene and hypermethylation of its 5Ј upstream CpG island.1 The CGG repeat element is polymorphic, varying from 6 to 44 repeats in the normal range, from 45 to 54 repeats in the gray zone, and from 55 to 200 repeats in the premutation range.2 For alleles below the gray zone, the CGG repeat is generally stable in parent-to-offspring transmissions. However, CGG elements in the premutation range become increasingly unstable with increasing repeat number, and alleles exceeding ϳ59 CGG repeats can expand to a full mutation in a single generation, almost exclusively by transmission from mother to son. The FMR1 premutation is typically associated with specific clinical manifestations unique to the premutation range: premature ovarian failure has been observed in ϳ20% of women, 3-6 whereas the fragile X-associated tremor/ ataxia syndrome has been found in at least one-third of carrier males more than 50 years old.7-9 Individuals affected with fragile X syndrome have FMR1 alleles with a CGG repeat number greater than 200.At present, DNA analysis of the CGG expansion is primarily performed using Southern blot analysis, which is able to detect alleles spanning the range from normal to large full mutation alleles; however, this method lacks the resolution to accurately size alleles. An alternative approach, using polymerase chain reaction (PCR) amplification of the region spanning the CGG repeat, provides much greater resolution, although it suffers from the difficulty of amplifying CGG repeats greater than ϳ100 to 150 repeats, because of the high GC content of the sequence being amplified.Radioactive or chemiluminescent probing, or fluorescence PCR, can overcome most problems, at least in the premutation range. Several studies have already described a number of PCR techniques, which use diverse combinations of DNA polymerase, 7-deaza-dGTP, and co-solvents such as dimethyl sulfoxide (DMSO) and betaine. 10 -15 However, the largest allele that has been amplified to date is 250 CGG repeats, 13 and PCR results with alleles of greater than ϳ...

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FXTAS, SCA10, and SCA17 in American patients with movement disorders

Cited by 36 publications

References 24 publications

Frequency of FMR1 premutation in individuals with ataxia and/or tremorand/or parkinsonism

Frequency of FMR1 premutation in individuals with ataxia and/or tremorand/or parkinsonism

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia

An Enhanced Polymerase Chain Reaction Assay to Detect Pre- and Full Mutation Alleles of the Fragile X Mental Retardation 1 Gene

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