Summary OBJECTIVE Partial androgen Insensitivity syndromes are the cause of genital ambiguity that is at times quite severe; there is, therefore, a high demand for prenatal diagnosis in families already afflicted with this syndrome. When the mutation has not been identified, the diagnosis can be made by the study of the polymorphisms of the androgen receptor gene. To perform molecular prenatal diagnosis in a family with partial androgen insensitivity syndrome, we studied the Hind III polymorphism of the androgen receptor gene on the trophoblastic DNA. The use of this restriction fragment length polymorphism tracked maternal X chromosome segregation and established prenatal diagnosis although the mutation had not yet been identified in this family. FAMILY The mother had been previously described as heterozygous for the Hind III polymorphism and chromosomal segregation analysis showed that the affected allele was associated with the 6.7‐kb Hind III fragment. MEASUREMENTS Hind III RFLP with an androgen receptor gene cDNA probe was realized on the trophoblastic DNA, along with measurement of androgen binding activity on the trophoblastic cells. RESULTS We detected the presence of the 6.7‐kb fragment In the DNA of the trophoblastic cells suggesting the fetus was affected. Partial androgen insensitivity syndrome was confirmed by a considerable decrease in androgen binding activity on the trophoblastic cells and by sonography of the fetus. After a therapeutic abortion requested by the parents, the diagnosis was confirmed by clinical examination of the fetus, biochemical analyses of the fetal androgen receptor, and molecular studies of the fetal DNA. CONCLUSIONS When the mutation of the androgen receptor gene has not been identified, Hind III polymorphism of the trophoblastic DNA is useful in the prenatal diagnosis of androgen insensitivity syndrome in high‐risk families.
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.
Cholesterol is essential for mammalian cell functions and integrity. It is an important structural component maintaining the permeability and fluidity of the cell membrane. The balance between synthesis and catabolism of cholesterol should be tightly regulated to ensure normal cellular processes. Male reproductive function has been demonstrated to be dependent on cholesterol homeostasis. Here we review data highlighting the impacts of cholesterol homeostasis on male fertility and the molecular mecanisms implicated through the signaling pathways of some nuclear receptors.
