Editing Androgen insensitivity syndrome (section)

===Pathogenesis of AIS===
Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the [[Transcription (genetics)|transcriptional ability]] of the [[Protein dimer|dimerized]], androgen-AR complex.<ref name="1995 quigley 16" />  AIS can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the AR successfully and [[regulation of gene expression|regulate gene expression]].<ref name="1995 quigley 16" />  Exactly which steps a particular mutation will impair can be predicted, to some extent, by identifying the area of the AR in which the mutation resides.  This predictive ability is primarily retrospective in origin; the different [[protein domain|functional domains]] of the AR gene have been elucidated by analyzing the effects of specific mutations in different regions of the AR.<ref name="1995 quigley 16" />  For example, mutations in the steroid binding domain have been known to affect [[Ligand (biochemistry)#Receptor/ligand binding affinity|androgen binding affinity or retention]], mutations in the hinge region have been known to affect [[Protein targeting#Protein translocation|nuclear translocation]], mutations in the [[DNA-binding domain]] have been known to affect dimerization and binding to target DNA, and mutations in the [[transactivation]] domain have been known to affect target gene transcription regulation.<ref name="1995 quigley 16" /><ref name="2003 yong 9" />  Unfortunately, even when the affected functional domain is known, predicting the [[phenotype|phenotypical]] consequences of a particular mutation (see [[#Correlation of genotype and phenotype|Correlation of genotype and phenotype]]) is difficult.{{citation needed|date=September 2021}}

Some mutations can adversely impact more than one functional domain.  For example, a mutation in one functional domain can have deleterious effects on another by altering the way in which the domains interact.<ref name="2003 yong 9" />  A single mutation can affect all [[Upstream and downstream (DNA)|downstream]] functional domains if a [[nonsense mutation|premature stop codon]] or [[frameshift mutation|framing error]] results; such a mutation can result in a completely unusable (or unsynthesizable) androgen receptor protein.<ref name="1995 quigley 16" />  The steroid binding domain is particularly vulnerable to the effects of a premature stop codon or framing error, since it occurs at the end of the gene, and its information is thus more likely to be truncated or misinterpreted than other functional domains.<ref name="1995 quigley 16" />

Other, more complex relationships have been observed as a consequence of mutated ''AR''; some mutations associated with male phenotypes have been linked to [[male breast cancer]], [[prostate cancer]], or in the case of [[spinal and bulbar muscular atrophy]], disease of the [[central nervous system]].<ref name="2003 lund 79" /><ref name="2001 casella 58" /><ref name="1992 wooster 2" /><ref name="1996 evans 28" /><ref name="1993 lobaccaro 2" />  The form of breast cancer seen in some men with PAIS is caused by a mutation in the AR's DNA-binding domain.<ref name="1992 wooster 2" /><ref name="1993 lobaccaro 2" />  This mutation is thought to cause a disturbance of the AR's target gene interaction that allows it to act at certain additional targets, possibly in conjunction with the [[estrogen receptor]] protein, to cause [[neoplasm|cancerous growth]].<ref name="1995 quigley 16" /> The [[pathogenesis]] of spinal and bulbar muscular atrophy (SBMA) demonstrates that even the mutant AR protein itself can result in [[pathology]].  The [[trinucleotide repeat disorder|trinucleotide repeat expansion]] of the [[polyglutamine tract]] of the AR gene that is associated with SBMA results in the synthesis of a [[misfolded]] AR protein that the cell fails to [[Proteolysis|proteolyze]] and disperse properly.<ref name="1999 stenoien 8" />  These misfolded AR proteins form aggregates in the cell [[cytoplasm]] and [[Cell nucleus|nucleus]].<ref name="1999 stenoien 8" />  Over the course of 30 to 50 years, these aggregates accumulate and have a [[cytotoxicity|cytotoxic]] effect, eventually resulting in the [[neurodegeneration|neurodegenerative]] symptoms associated with SBMA.<ref name="1999 stenoien 8" />