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French Machado-Joseph disease patients do not exhibit gametic segregation distortion: a sperm typing analysis
R P Grewal1, G Cancel, E P Leeflang
1Program in Molecular Biology, SHS 172, 835 West 37th Street, University of Southern California, Los Angeles, CA 90089-1340, USA.
Abstract:
Segregation distortion has been reported to occur in a number of the trinucleotide repeat disorders. On the basis of a sperm typing study performed in patients of Japanese descent with Machado-Joseph disease (MJD), it was reported that disease alleles are preferentially transmitted during meiosis. We performed a sperm typing study of five MJD patients of French descent and analysis of the pooled data shows a ratio of mutant to normal alleles of 379:436 (46.5:53.5%), which does not support meiotic segregation distortion. To confirm these results, sperm typing analysis was also performed using a polymorphic marker, D14S1050, closely linked to the MJD1 gene. Among 910 sperm analyzed, the allele linked to the disease chromosome was detected in 50.3% of the samples and the allele linked to the normal chromosome was found in 49.6% of the sperm. The difference in frequency of these two alleles is not significant ( P = 0.8423). Likelihood-based analysis of segregation distortion in the single sperm data using the SPERMSEG program also showed no support for segregation distortion at the gamete level in this patient population. The previous report on the Japanese patients also suggested that disease allele stability may be influenced by a trans effect of an intragenic polymorphism (987 G/C) in the wild-type allele. All of the French patients were heterozygous for this polymorphism. However, analysis of the variance in repeat number in sperm from the French MJD patients overlapped significantly with the variance in repeat number observed in the C/C homozygous Japanese patients.
Insights
Segregation distortion, a phenomenon in trinucleotide repeat disorders like Machado-Joseph disease (MJD), was investigated in French patients. Sperm typing revealed no significant evidence of preferential transmission of disease alleles during meiosis in this population.
Area of Science:
- Genetics
- Molecular Biology
- Neurology
Background:
- Segregation distortion, the unequal inheritance of alleles, has been observed in trinucleotide repeat disorders.
- Previous studies on Japanese Machado-Joseph disease (MJD) patients suggested preferential transmission of disease alleles during meiosis.
Purpose of the Study:
- To investigate meiotic segregation distortion in French patients with Machado-Joseph disease (MJD).
- To determine if allele transmission patterns in French MJD patients differ from those reported in Japanese patients.
- To assess the influence of intragenic polymorphisms on MJD allele stability.
Main Methods:
- Sperm typing analysis was performed on five French MJD patients.
- Allele frequencies of mutant and normal MJD alleles were quantified.
- Analysis included a polymorphic marker (D14S1050) closely linked to the MJD1 gene.
- SPERMSEG program was used for likelihood-based analysis of segregation distortion.
Main Results:
- The ratio of mutant to normal alleles in French MJD patients was 46.5:53.5%, not supporting segregation distortion.
- Analysis of the linked marker D14S1050 showed no significant difference in allele frequencies (50.3% vs. 49.6%).
- Likelihood-based analysis confirmed no significant segregation distortion at the gamete level in the French MJD patient population.
- Variance in repeat number in French MJD patients overlapped with Japanese patients homozygous for a specific polymorphism.
Conclusions:
- Meiotic segregation distortion does not appear to significantly influence Machado-Joseph disease allele transmission in French patients.
- The intragenic polymorphism (987 G/C) may not be the sole factor affecting MJD allele stability across different populations.
- Further research is needed to understand the genetic factors governing MJD allele stability.