# Expansion of a trinucleotide repeat causes X-linked spinal and bulbar muscular atrophy: Discovery of the expansion and genetic analysis of the repeat

#### Abstract

X-linked spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease associated with signs of androgen insensitivity. Evaluation of the androgen receptor (AR) gene as a candidate gene for this disorder led to discovery of an association between expansion of a tandem trinucleotide repeat, (CAG)$\sb{\rm n},$ and the disease phenotype. The (CAG)$\sb{\rm n}$ expansion segregated with the disease in 15 families, with no recombination in 61 meioses, yielding a maximum log likelihood ratio (lod score) of 13.2 with no recombination. Variation in clinical course and in (CAG)$\sb{\rm n}$ expansion length between unrelated SBMA patients led to investigation of genotype-phenotype correlation. A significant correlation between disease severity and repeat length was found, but there were exceptions. My results support the conclusion that repeat length is an important factor in disease severity, although other factors contribute, as well. Stability of the (CAG)$\sb{\rm n}$ repeat was studied by tracking its inheritance in normal and SBMA families. This work showed that expanded repeats change in length when transmitted from parent to offspring. Of 53 meioses, 12 (23%) had a change in repeat number. Both expansions and contractions were observed, although size alterations were small. There was a greater rate of instability when the (CAG)$\sb{\rm n}$ repeat was paternally transmitted than maternally transmitted. This work indicates that (CAG)$\sb{\rm n}$ expansion in the first exon of the AR gene causes SBMA. Fragile X syndrome, myotonic dystrophy and Huntington's disease have also been associated with expanded repeats, further substantiating trinucleotide repeat expansion as a mechanism of mutation in genetic disease. Unlike the trinucleotide repeats in fragile X syndrome and myotonic dystrophy, the (CAG)$\sb{\rm n}$ repeats in SBMA and in Huntington's disease fall within the coding domain and exhibit a narrower range of expansion. Thus, the (CAG)$\sb{\rm n}$ repeat in SBMA has greatest similarity to the (CAG)$\sb{\rm n}$ repeat in Huntington's disease.

#### Subject Area

Molecular biology|Neurology|Pathology

#### Recommended Citation

La Spada, Albert Russell, "Expansion of a trinucleotide repeat causes X-linked spinal and bulbar muscular atrophy: Discovery of the expansion and genetic analysis of the repeat" (1993). Dissertations available from ProQuest. AAI9321424.
https://repository.upenn.edu/dissertations/AAI9321424

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