Different behavior in the paternally vs. maternally inherited mutated allele in Brazilian Machado-Joseph (MJD1) Families

Iughetti, Paula; Otto, Paulo Alberto; Zatz, Mayana; Bueno, Maria Rita Passos; Marie, Suely Kazue Nagahashi

doi:10.1002/(sici)1096-8628(19980518)77:3<246::aid-ajmg11>3.0.co;2-g

Cited by 14 publications

(7 citation statements)

References 27 publications

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“…Takiyama et al (1997), however, using the same approach as Grewal et al (1999), reported SRD favouring the expanded alleles (61%). In family studies, Ikeuchi et al(1996) and Iughetti et al(1998) identified SRD favouring the expanded alleles in paternal transmissions (73% and 59%, respectively), whereas Riess et al (1997) observed the same phenomenon but in maternal transmissions (72%). Issues related to criteria for family selection in these studies could at least partially explain the conflicting results.…”

Section: Discussionmentioning

confidence: 96%

“…An alternative hypothesis, which may also explain the high representation of the disease, could be the presence of segregation ratio distortion (SRD) in favour of the expanded alleles. Results concerning SRD in previous studies, based on different methodologies (Ikeuchi et al 1996;Riess et al 1997;Takiyama et al 1997;Iughetti et al 1998;Grewal et al 1999), are not consensual and therefore do not elucidate this possibility.…”

Section: Introductionmentioning

confidence: 89%

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Analysis of segregation patterns in Machado–Joseph disease pedigrees

et al. 2008

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Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder of late onset, which is considered the most common form of SCA worldwide. The main goal of this study was to investigate the presence of segregation ratio distortion (SRD) during transmissions of ATXN3 alleles by MJD patients, evaluating the putative role of SRD in the epidemiological representation of the disease. Sixty-two complete sibships, each with one clinically affected parent, totalling 330 transmissions were selected according to defined criteria and used for segregation analysis. Onset data from MJD patients with Azorean origin was used for residual risk estimates according to different ages. Residual risk values were applied to unaffected offspring to calculate the probability of inheriting the expanded allele. The proportion of offspring that received the expanded or the normal allele from the affected parent was calculated to determine the presence of SRD during transmissions of ATXN3 alleles by MJD patients. Segregation of ATXN3 alleles was in accordance with the expected Mendelian proportions (v 2 = 0.982, P = 0.322). However, there was a tendency favouring the transmission of the normal alleles. Thus, SRD is not a potential mechanism on the basis of MJD epidemiological representation.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 89%

Analysis of segregation patterns in Machado–Joseph disease pedigrees

et al. 2008

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“…1B). Although a Mendelian segregation distortion for the expanded CAG allele (with a higher transmission of the mutant allele) has been described by some authors in human MJD families (Ikeuchi et al, 1996;Iughetti et al, 1998;Riess et al, 1997;Takiyama et al, 1997), this is a controversial finding that, according to others, can be explained by observational bias in families selected for genetic lineage studies due to a large number of affected individuals (Grewal et al, 1999). Our analysis of the transmission of the CMVMJD94 and CMVMJD83 transgenic lineages excluded a "meiotic drive" effect of the expanded allele in these mice (Fig.…”

Section: Generation Of Mjd Transgenic Micementioning

confidence: 99%

Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products

Silva‐Fernandes

Costa

Duarte‐Silva

et al. 2010

Neurobiology of Disease

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Machado-Joseph disease (MJD) is a late-onset neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the ataxin-3 protein. We generated two transgenic mouse lineages expressing the expanded human ataxin-3 under the control of the CMV promoter: CMVMJD83 and CMVMJD94, carrying Q83 and Q94 stretches, respectively. Behavioral analysis revealed that the CMVMJD94 transgenic mice developed motor uncoordination, intergenerational instability of the CAG repeat and a tissue-specific increase in the somatic mosaicism of the repeat with aging. Histopathological analysis of MJD mice at early and late stages of the disease revealed neuronal atrophy and astrogliosis in several brain regions; however, we found no signs of microglial activation or neuroinflammatory response prior to the appearance of an overt phenotype. In our model, the appearance of MJD-like symptoms was also not associated with the presence of ataxin-3 cleavage products or intranuclear aggregates. We propose the transgenic CMVMJD94 mice as a useful model to study the early stages in the pathogenesis of MJD and to explore the molecular mechanisms involved in CAG repeat instability.

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“…Segregation distortion favoring the transmission of mutated or normal alleles during meiosis has been reported for both genes. (Ikeuchi et al, 1996;Riess et al, 1997;Iughetti et al, 1998). Rubinsztein and Leggo (1997) added to these observations, reporting the preferential transmission of alleles with smaller CAG repeats by normal females.…”

Section: Introductionmentioning

confidence: 99%

The SCA1 (Spinocerebellar ataxia type 1) and MJD (Machado-Joseph disease) CAG repeats in normal individuals: segregation analysis and allele frequencies

2003

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Spinocerebellar ataxia type 1 (SCA1) and Machado-Joseph disease (MJD/SCA3) are autosomal dominant neurodegenerative diseases caused by expansions of a CAG trinucleotide repeat in the SCA1 and MJD genes. These expanded sequences are unstable upon transmission, leading to an intergeneration increase in the number of repeats (dynamic mutation). The transmission of the CAG repeat was studied in normal mother-father-child trios, referred for paternity testing (SCA1, n = 367; MJD, n = 879). No segregation distortion was detected. The CAG allele frequencies were determined in 330 unrelated individuals (fathers from couples tested for paternity). The allele frequency distributions did not differ from those previously reported for European populations. The estimated values for the statistic parameters indicating diversity at the SCA1 locus did not differ much from those reported previously for other STRs in the Brazilian population, while those for the MJD locus were close to or higher than the maximum values of previous reports. This shows that SCA1 and MJD are highly informative loci for applications in genetic and population studies and for forensic analysis.

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Different behavior in the paternally vs. maternally inherited mutated allele in Brazilian Machado-Joseph (MJD1) Families

Cited by 14 publications

References 27 publications

Analysis of segregation patterns in Machado–Joseph disease pedigrees

Analysis of segregation patterns in Machado–Joseph disease pedigrees

Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products

The SCA1 (Spinocerebellar ataxia type 1) and MJD (Machado-Joseph disease) CAG repeats in normal individuals: segregation analysis and allele frequencies

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