Deletion of the Steroid-Binding Domain of the Human Androgen Receptor Gene in One Family with Complete Androgen Insensitivity Syndrome: Evidence for Further Genetic Heterogeneity in this Syndrome

• Published in: Proceedings of the National Academy of Sciences - PNAS 1988-11, Vol.85 (21), p.8151-8155
• Main Authors: Brown, Terry R., Lubahn, Dennis B., Wilson, Elizabeth M., Joseph, David R., French, Frank S., Migeon, Claude J.
• Format: Article
• Language: English
• Subjects: 550401 - Genetics- Tracer Techniques; Androgen insensitivity syndrome; Androgen receptors; ANDROGENS; ANDROSTANES; ANIMAL CELLS; BASIC BIOLOGICAL SCIENCES; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; Biological and medical sciences; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; Blotting, Southern; BODY FLUIDS; CHROMOSOMAL ABERRATIONS; Chromosome Deletion; CHROMOSOMES; CLONING; Cloning, Molecular; Complementary DNA; CONNECTIVE TISSUE CELLS; DAYS LIVING RADIOISOTOPES; Deoxyribonuclease BamHI - metabolism; Deoxyribonuclease EcoRI - metabolism; DISEASES; Disorders of Sex Development - genetics; DNA; DNA - analysis; DNA HYBRIDIZATION; DNA probes; DNA-CLONING; ETIOLOGY; Female; FIBROBLASTS; GENES; Genetic mutation; Genitalia; GENOME MUTATIONS; Gynecology. Andrology. Obstetrics; HEREDITARY DISEASES; HETEROCHROMOSOMES; HORMONES; Humans; HYBRIDIZATION; ISOTOPES; Karyotyping; LEUKOCYTES; LIGHT NUCLEI; Male; Male and female genital diseases. Gonadal dysgenesis. Hermaphroditism. Sex hormones resistance; Male genital diseases; MATERIALS; Medical sciences; MEMBRANE PROTEINS; MUTATIONS; Non tumoral diseases; NUCLEI; NUCLEIC ACIDS; ODD-ODD NUCLEI; ORGANIC COMPOUNDS; PATIENTS; Pedigree; PHOSPHORUS 32; PHOSPHORUS ISOTOPES; PROTEINS; RADIOISOTOPES; RECEPTORS; Receptors, Androgen - genetics; RECOMBINANT DNA; SOMATIC CELLS; STEROID HORMONES; STEROIDS; X CHROMOSOME
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.85.21.8151

The cloning of a cDNA for the human androgen receptor gene has resulted in the availability of cDNA probes that span various parts of the gene, including the entire steroid-binding domain and part of the DNA-binding domain, as well as part of the 5′ region of the gene. The radiolabeled probes were used to screen for androgen receptor mutations on Southern blots prepared by restriction endonuclease digestion of genomic DNA from human subjects with complete androgen insensitivity syndrome (AIS). In this investigation, we considered only patients presenting complete AIS and with the androgen receptor (-) form as the most probable subjects to show a gene deletion. One subject from each of six unrelated families with the receptor (-) form of complete AIS and 10 normal subjects (6 females and 4 males) were studied. In the 10 normal subjects and in 5 of the 6 patients, identical DNA restriction fragment patterns were observed with EcoRI and BamHI. In one affected individual, a partial deletion of the androgen receptor gene involving the steroid-binding domain was detected. Analysis of other members of this family confirmed the apparent gene deletion. Our data provide direct proof that complete AIS in some families can result from a deletion of the androgen receptor structural gene. However, other families do not demonstrate such a deletion, suggesting that point mutations (or small, undetectable deletions) may also result in the receptor (-) form of complete AIS, adding further to the genetic heterogeneity of this syndrome.