Meiotic stability and genotype – phenotype correlation of the trinucleotide repeat in X–linked spinal and bulbar muscular atrophy

  title={Meiotic stability and genotype – phenotype correlation of the trinucleotide repeat in X–linked spinal and bulbar muscular atrophy},
  author={Albert R. La Spada and Daniel B. Roling and Anita E. Harding and Carolyn L. Warner and Roland Spiegel and Irena Hausmanowa-Petrusewicz and Woon Chee Yee and Kenneth H. Fischbeck},
  journal={Nature Genetics},
Expansion of the trinucleotide repeat (CAG)n in the first exon of the androgen receptor gene is associated with a rare motor neuron disorder, X–linked spinal and bulbar muscular atrophy. We have found that expanded (CAG)n alleles undergo alteration in length when transmitted from parent to offspring. Of 45 meioses examined, 12 (27%) demonstrated a change in CAG repeat number. Both expansions and contractions were observed, although their magnitude was small. There was a greater rate of… 
The mutation properties of spinal and bulbar muscular atrophy disease alleles
The results indicate that in SBMA, in contrast to sperm typing analysis of Huntington's disease, there is relative stability of the CAG repeat number during paternal transmissions and that the spectrum of mutations is narrow and suggest that anticipation may not be a significant feature of this disease.
Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1
There is a direct correlation between the size of the (CAG)n repeat expansion and the age–of–onset of SCA1, with larger alleles occurring in juvenile cases.
Mitotic and meiotic stability of the CAG repeat in the X‐linked spinal and bulbar muscular atrophy gene
It is demonstrated that the CAG repeat in SBMA is relatively stable in mitotic and meiotic processes, and there is a possibility that the lower mosaicism level of the carrier females compared with the SBMA patients is associated with X‐linked recessive inheritance.
The CAG/Polyglutamine Tract Diseases: Gene Products and Molecular Pathogenesis
In the past few years, a new type of genetic mutation, expansion of trinucleotide repeats, has been shown to cause neurologic disease and is found to be the causative mechanism in 10 other neurologic diseases.
Clinical Aspects of CAG Repeat Diseases
Seven neurodegenerative disorders are known to be caused by unstable expansions of the trinucleotide CAG within human genes, and more will be discovered in the coming years, which have unusual clinical genetic properties related to the dynamic nature of CAG repeat expansions.
Heritable trinucleotide repeats and neurological disorders
In the past 3 years, seven human neurological disorders have been found to be associated with an abnormal number of unstable trinucleotide repeats within exons or non-expressed regions of a gene.
Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I
Spinocerebellar ataxia type I (SCAI) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat on chromosome 6p. Normal alleles range from 19–36 repeats
Trinucleotide repeat length instability and age of onset in Huntington's disease
The initial observation of an expanded and unstable trinucleotide repeat in the Huntington's disease gene has now been confirmed and extended in 150 independent Huntington’s disease families and the analysis of the length and instability of individual repeats in members of these families has profound implications for presymptomatic diagnosis.
Trinucleotide repeat expansions and human genetic disease.
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The cloning of two regions at which chromosome breakage can be induced has in each case uncovered an unstable CG-rich triplet repeat which becomes methylated when fully expanded, suggesting a common basis to the observed phenotypes.


Moderate instability of the trinucleotide repeat in spino bulbar muscular atrophy.
Increased length of a protein-coding CAG repeat within the androgen receptor gene appears to be the only type of mutation responsible for spino-bulbal muscular atrophy (SBMA or Kennedy disease), and the mutant allele was unstable upon transmission from parent to child.
Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy
It is concluded that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of X-LINKED spinal and bulbar muscular atrophy.
Triplet repeat mutations in human disease.
This newly identified mechanism of mutation has been identified in two of the most common heritable disorders, fragile X syndrome and DM, and one rare disease, SBMA.
Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy
Infants with severe congenital DM, as well as their mothers, are shown to have on average a greater amplification of the CTG repeat than is seen in the noncongenital DM population, providing evidence for the existence of genetic anticipation in the transmission of DM.
Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene.
Increases in the size of the allele in patients with DM are now shown to be due to an increased number of trinucleotide CTG repeats in the 3' untranslated region of a DM candidate gene.
An unstable triplet repeat in a gene related to myotonic muscular dystrophy.
These studies suggest that the mutational mechanism leading to DM is triplet amplification, similar to that occurring in the fragile X syndrome.
Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy
A human genomic clone is isolated that detects novel restriction fragments specific to individuals with myotonic dystrophy, strongly supporting earlier results which indicated that most cases are descended from one original mutation.
Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy
The isolation of an expressed sequence is reported from this region which detects a DNA fragment that is larger in affected individuals than in normal siblings or unaffected controls, and it is postulated that this unstable DNA sequence is the molecular feature that underlies DM.