Molecular Analysis of the Androgen Receptor Gene in Kennedy’s Disease

Abstract

We have performed a molecular analysis of the androgen receptor gene in two families with suspected Kennedy’s disease (spinal and bulbar muscular atrophy, SBMA) with the aim of making a firm diagnosis of the disease. The 2 patients studied were sporadic cases. Both presented clinical signs compatible with the diagnosis of SBMA: limb and facial muscular weakness of adult onset progressing toward muscular atrophy. Clinical signs of partial androgen insensitivity syndrome usually observed in SBMA were present only in patient 2. Enzymatic amplification of the CAG repeat region of exon 1 of the androgen receptor gene was performed on genomic DNA. PCR products were submitted to agarose or acrylamide electrophoresis for size evaluation. Precise determination of the CAG number was performed by direct sequencing of purified amplification products. Androgen receptor gene analysis was also performed in 2 sisters of patient 1 and in the mother, sisters and daughter of patient 2. Androgen receptor-binding activity was also determined on cultured genital skin fibroblasts of patient 1. Analysis of PCR products showed in both patients a single band that was much larger in size than the control. The expansion of the CAG repeat number was confirmed by direct sequencing: the exact number of CAG was 47 in patient 1 and 42 in patient 2 (n = 12-32). The 2 studied sisters of patient 1 did not present the abnormal fragment, demonstrating they are not carriers for the disease. Conversely, the mother, sisters and daughter of patient 2 presented both normal and mutated alleles. The migration of the labelled PCR products on a sequencing gel revealed a meiotic instability of expanded CAG repeat in family 2. Moreover, patient 1 had a decreased androgen-binding capacity on cultured genital skin fibroblasts. In both families, analysis of the androgen receptor gene permitted us to diagnose SBMA in the patients and to establish the carrier status in siblings. These results correspond to the literature data and confirm the usefulness of CAG repeat evaluation in the diagnosis of Kennedy’s disease. They highlight the relationship between the androgen receptor and motoneuron growth, development and regeneration.

Androgen Receptor (AR) Gene (CAG)n and (GGN)n Length Polymorphisms and Symptoms in Young Males With Long-Lasting Adverse Effects After Finasteride Use Against Androgenic Alopecia

“…In our study, (CAG)n repeats spanned from 9 to 37; therefore, none of the subjects had at least 40 repeats, a high value typically found in Kennedy disease. 20 In our patients with PFS, short (CAG)n repeats showed a greater decrease in sexual desire and libido (AMS item 17) than medium repeats, whereas long (CAG)n repeats were associated with worse orgasm satisfaction (ASEX item 5) than short repeats.…”

“… 18 CAG expanded repeats of at least 40 have been found in Kennedy disease, a neurodegenerative syndrome also characterized by androgen insensitivity. 18 , 19 , 20 Long (CAG)n repeats have been associated with male infertility, 21 although studies have been inconsistent. 17 , 18 , 21 In contrast, a meta-analysis suggested that a shorter (CAG)n repeat polymorphism in Caucasians and Asians might increase the risk of prostate cancer compared with the longer (CAG)n repeat.…”