Introduction to the Androgen Receptor Gene Mutations Database
Constitutional mutations in the androgen receptor gene (AR ) impair androgen - dependent male sexual differentiation to various degrees . Somatic mutations in the AR have been found in metastatic prostate cancer . Severe constitutional androgen insensitivity (AI) yields an external female phenotype. Partial constitutional AI yields a range of external genital phenotypes that vary from near - normal female to normal or near - normal male, with or without gynecomastia and other relatively "mild" signs of undervirilization. Some have suggested that clinical severity of AI be divided into three degrees: complete, partial, (when there is appreciable external genital ambiguity) and mild (for the least severe forms). Others have graded severity into seven degrees . The current version of the AR mutation database retains the complete / partial bifurcation of the original database , but provides additional information on the external genitalia and on sex - of - rearing . When external genital ambiguity is appreciable, the sex - of - rearing implies that the external genitalia were predominately male or female. Because different clinical degrees of AI are sometimes seen within families or between those with the same mutation, the new version of the database has an entry for family history.
There are various ways to characterize the androgen - binding activity of a mutant AR. In addition to Bmax and Kd, the new version of the database provides for k, the off - rate of androgen from A-R complexes, and for thermolability of A-R complex formation. Each of these values may be abnormal when the other three are normal.
Ultimately, it is essential to prove that a given AR mutation is causally related to an AI or prostate cancer phenotype. Usually this is done by recreating the mutation in a AR cDNA and demonstrating an AR abnormality after transfection into AR - free host cells. Therefore, the new version of the database has an entry to show if pathogenicity has been proven.
This version of the database has several structural alterations to improve user friendliness. For instance, the mutations are listed in a simple 5' - 3' sequence regardless of their type, and 1- 3 - base pair changes are indicated in codon context. The previous version first lumped particular types of mutations, and then listed them sequentially. It also gave single - base changes out of codon context, in order to visualize CpG sites directly. This version has a separate entry for CpG sites.