DiagnosisClinical DiagnosisAndrogen insensitivity syndrome (AIS) can be subdivided into three phenotypes: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS) (Table 1).The clinical findings that permit a presumptive diagnosis of AIS include the following: Absence of extragenital abnormalities Two nondysplastic testes Absent or rudimentary müllerian structures (i.e., fallopian tubes, uterus, and cervix) and the presence of a short vagina Undermasculinization of the external genitalia at birth Impaired spermatogenesis and/or somatic virilization at pubertyTable 1. Classification of AIS PhenotypesView in own windowType External Genitalia (Synonyms) Findings CAIS Female (“testicular feminization”)Absent or rudimentary wolffian duct derivatives
Absence or presence of epididymides and/or vas deferens
Inguinal, labial, or abdominal testes
Short blind-ending vagina
Scant or absent pubic and/or axillary hair PAIS Predominantly female (“incomplete AIS”) Inguinal or labial testes
Clitoromegaly and labial fusion
Distinct urethral and vaginal openings or a urogenital sinus Ambiguous Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum
Descended or undescended testes
Perineoscrotal hypospadias or urogenital sinus
Gynecomastia (development of breasts) in puberty Predominantly male Simple (glandular or penile) or severe (perineal) “isolated” hypospadias with a normal-sized penis and descended testes or severe hypospadias with micropenis, bifid scrotum, and either descended or undescended testes
Gynecomastia in puberty MAIS Male (“undervirilized male syndrome”)Impaired spermatogenesis and/or impaired pubertal virilization
Gynecomastia in puberty Adapted from Sinnecker et al [1997]The diagnosis of CAIS is usually made on clinical findings and laboratory evaluations alone.The diagnosis of PAIS and MAIS may also require a family history consistent with X-linked inheritance, as laboratory findings useful in establishing the diagnosis may not be present in all affected individuals [Gottlieb et al 1999a].TestingThe laboratory findings required for the diagnosis of AIS may include the following: Normal 46,XY karyotype Evidence of normal or increased synthesis of testosterone (T) by the testes Evidence of normal conversion of testosterone to dihydrotestosterone (DHT) Identification of a disease-causing AR mutationEvidence of normal or increased luteinizing hormone (LH) production by the pituitary gland In CAIS, but not in PAIS: possible reduction in postnatal (0-3 months) surge in serum LH and serum T concentrations [Bouvattier et al 2002] Evidence of deficient or defective androgen binding activity of genital skin fibroblast. Family history. The diagnosis of CAIS can be established by clinical and laboratory findings alone; however, the diagnosis of PAIS and MAIS may require a family history of other affected individuals related to each other in a pattern consistent with X-linked recessive inheritance. “Other affected family members” refers to: Affected 46,XY individuals Manifesting female (46, XX) carriers. About 10% of carrier females are manifesting carriers with asymmetric distribution and sparse or delayed growth of pubic and/or axillary hair. Additional findings in affected individuals with no family history of the syndrome that substantiate the apparent diagnosis of PAIS in an individual with the “predominantly male” phenotype (Table 1): Impaired development of the prostate and of the wolffian duct derivatives demonstrated by ultrasonography or genitourography Less-than-normal decline of sex hormone-binding globulin (SHBG) in response to a standard dose of the anabolic androgen, stanozolol [Sinnecker et al 1997] Higher-than-normal levels of anti-müllerian hormone (AMH) during the first year of life or after puberty has begun Molecular Genetic Testing Gene. AR is the only gene in which mutations are known to cause androgen insensitivity syndrome. Clinical testing Sequence analysis. A recent informal survey of AIS databases in Canada, United States, and Great Britain showed that AR mutation detection frequency ranged from 65% to 95% in individuals with CAIS and from 40% to 45% in those with PAIS. The AIS database at the Lady Davis Institute for Medical Research (Montreal, Canada) which includes 138 patients with CAIS or PAIS (www.androgendb.mcgill.ca/ldi.pdf), reflects this variable detection rate [Author, unpublished data]. AR mutation detection frequency in individuals with MAIS is more difficult to assess because of the assumption that MAIS diagnoses are often missed: In the presence of deficient or defective androgen binding activity in genital skin fibroblasts in an XY individual with clinical findings of CAIS and PAIS, the likelihood of finding a mutation in the androgen binding domain of AR approached 40% [Weidemann et al 1996]. In the presence of normal androgen binding in genital skin fibroblasts in an XY individual with clinical findings of PAIS, the likelihood of finding an AIS-causing AR mutation is 10% or less, even when exon 1 is screened and/or sequenced in its entirety. [Author, personal observation].Because the presence of an AR mutation, not abnormal androgen binding, is now the primary diagnostic criterion for AIS, defective androgen binding activity in an XY individual with clinical findings of CAIS, PAIS, or MAIS who does not have an AR mutation may be inappropriately precluded from the above diagnostic categories [Author, personal observation]. Deletion/duplication analysisAffected individuals. Deletion/duplication analysis can detect the less common exonic, multiexonic, and gross deletions or rare duplications in AR in affected individuals. Note: deletions/duplications in AR that result in AIS are rare [Gottlieb et al 2004b].Carrier testing. Deletion/duplication analysis (e.g., multiplex ligation-dependent probe amplification [MLPA]) can detect the less common exonic, multiexonic, and gross deletions and rare duplications in AR in at-risk relatives who have an XX karyotype. Table 2. Summary of Molecular Genetic Testing Used in Androgen Insensitivity SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityAffected Individuals 2Carrier Females ARSequence analysisSequence variants 3 CAIS: 65%-95% 4, 5Unknown 6ClinicalPAIS: <50% 4, 5MAIS: UnknownDuplication / deletion analysis 7Deletion / duplication of one or more exons or of the whole geneUnknownUnknownCAIS = complete androgen insensitivity syndromePAIS = partial androgen insensitivity syndromeMAIS = mild androgen insensitivity syndrome1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Individuals with a 46,XY karyotype3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome in affected individuals with a 46,XY karyotype; confirmation may require additional testing by deletion/duplication analysis. 5. Includes the mutation detection frequency using deletion/duplication analysis6. Sequence analysis of genomic DNA cannot detect exonic or whole-gene deletions on the X chromosome in carrier females.7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results In some cases failure to detect an AR mutation in individuals with decreased or defective androgen binding activity may be explained as follows:Mutations in regulatory or deep intronic portions of AR are not identifiable with the clinically available tests [Gottlieb et al 1999b];
ORA “timing” problem exists in an individual in whom AR is normal; that is, the acquisition of normal testosterone synthesis or normal androgen responsiveness is delayed beyond the critical periods for normal external and/or internal male genital differentiation. Mutations may be present in genes whose products either collaborate with AR or are subject to androgenic control [Cheung-Flynn et al 2005] (see Differential Diagnosis).Somatic mosaicism could result in a population of cells with an AR mutation in genital skin but not in peripheral blood cells [Gottlieb et al 2001b]. For other issues to consider in interpretation of sequence analysis results, click here. Testing StrategyTo confirm/establish the diagnosis in a proband1.Perform sequence analysis of AR on DNA extracted from a blood sample from the affected individual. 2.If no AR mutation is identified by sequence analysis, deletion/duplication analysis may be considered, particularly if other family members are known or thought to be affected. Note: Deletions/duplications in AR that result in AIS are rare. 3.If a deletion/duplication is not identified, test a biopsy of genital skin for defective androgen binding. Carrier testing for at-risk female relatives requires prior identification of the disease-causing mutations in the family.Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersExpansion of the polymorphic CAG repeat within AR causes spinobulbar muscular atrophy (SBMA; Kennedy disease). Other disease conditions associated with somatic alterations to AR [Gottlieb et al 2004a] include the following:Prostate cancer Male breast cancer Laryngeal cancer Liver cancerTesticular cancer}

Natural HistoryComplete androgen insensitivity syndrome (CAIS, testicular feminization, Tfm). Individuals with CAIS have normal female external genitalia with absence of female internal genitalia. They typically present either before puberty with masses in the inguinal canal that are subsequently identified as testes or at puberty with primary amenorrhea and sparse to absent pubic or axillary hair. Breasts and female adiposity develop normally. Sexual identity and orientation are typically female and heterosexual. CAIS almost always runs true in families; that is, affected XY relatives usually have normal female external genitalia and seldom have any sign of external genital masculinization, such as clitoromegaly or posterior labial fusion [Boehmer et al 2001]. On occasion, wolffian duct development is observed [Hannema et al 2004].Partial AIS (PAIS) with predominantly female external genitalia (Table 1) presents in a manner similar to CAIS; however, affected individuals have signs of external genital masculinization including clitoromegaly or posterior labial fusion. Partial AIS with ambiguous genitalia or predominantly male genitalia (PAIS, Reifenstein syndrome). Determining the sex of rearing may be an issue for children with frank genital ambiguity. In families with PAIS, phenotypic disparity may warrant male sex of rearing in one affected sib and female sex of rearing in another affected sib [Rodien et al 1996, Evans et al 1997, Boehmer et al 2001]. Individuals with PAIS and predominantly male genitalia are raised as males. Gynecomastia at puberty and impaired spermatogenesis occur in all individuals with PAIS. Pubic hair is usually moderate; facial, body, and axillary hair are often reduced. Mild AIS (MAIS, undervirilized male syndrome). The external genitalia of affected individuals are unambiguously male. They usually present with gynecomastia at puberty. They may have undermasculinization that includes sparse facial and body hair and small penis. Impotence may be a complaint. Spermatogenesis may or may not be impaired. In some instances, the only observed abnormality appears to be male infertility [Gottlieb et al 2005]; therefore, MAIS could explain some cases of idiopathic male infertility. MAIS almost always runs true in families.

Genotype-Phenotype CorrelationsA correlation does exist among certain missense AR mutations, their functional consequences, and external genital development, particularly in the case of CAIS (see the Androgen Receptor Gene Mutations Database). The correlation is much less clear in PAIS, in which interfamilial phenotypic variation is observed [Brinkmann & Trapman 2000, Boehmer et al 2001, Deeb et al 2005]. The Androgen Receptor Gene Mutations Database includes 34 instances in which identical AR mutations produce different AIS phenotypes [Gottlieb et al 2001a]. See androgendb.mcgill.ca/variable.pdf.In some instances, the variable expressivity associated with a number of point mutations may be attributed to somatic mosaicism rather than to the modifying influence of “background” genetic factors [Boehmer et al 1997, Holterhus et al 1997, Holterhus et al 2001, Kohler et al 2005]. See Gottlieb et al [2001b] for a detailed discussion of the possible role of somatic mosaicism as a cause of variable expressivity.It remains to be determined whether specific missense mutations can be correlated with normal or impaired spermatogenesis and with absence or presence of localized expressions of undervirilization (e.g., gynecomastia, high-pitched voice, impotence). Although specific mutations associated with azoospermia have been reported [Zuccarello et al 2008, Mirfakhraie et al 2011], only a more extensive analysis of more cases of idiopathic male infertility is likely to identify definitive correlations. Recently, Melo et al [2010] noted that infertile males who do not produce sperm have a higher number of AR mutations than do males with impaired sperm production.In addition to causing different forms of AIS, AR somatic mutations as opposed to germline mutations have also been associated with cancers − prostate cancer in particular [Gottlieb et al 2004a]. See Genetically Related Disorders. The allelic variants associated with cancer, however, appear to result in a gain of function rather than the loss of function seen in AIS.

Differential DiagnosisMayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is diagnosed in phenotypic females who exhibit amenorrhea and have a partial or complete absence of the cervix, uterus, and vagina. Individuals with MRKH can be distinguished from those with CAIS by confirmation of a 46,XX karyotype [Sultan et al 2009].Hypospadias that results from an AR mutation (and thus a part of the spectrum of PAIS) cannot be distinguished from hypospadias resulting from other (largely undefined) causes by the examination of the genitalia alone. AR mutations associated with hypospadias are likely rare.MAIS caused by point mutations of AR [Wang et al 1998] may be clinically indistinguishable from MAIS caused by expansion of the polymorphic CAG repeat in AR [Tut et al 1997]. Pathologic expansion of this triplet repeat is the cause of spinobulbar muscular atrophy (SBMA), also known as Kennedy disease. Undermasculinization of the external genitalia and pubertal undervirilization are components of many different syndromes that have no etiologic relation to AR. They may or may not have a pathogenic relation to the androgen receptor protein. The one exception is a contiguous gene deletion syndrome that includes the AR locus and results in intellectual disability and genital abnormalities [Davies et al 1997]. A recent survey of the Androgen Receptor Gene Mutations Database (see www.androgendb.mcgill.ca/ldi.pdf), suggests that AIS may be attributable to factors other than the presence of AR mutations. Findings that suggest the presence of other identifiable diagnoses in 46,XY individuals with predominantly female, ambiguous, or predominantly male genitalia include the following: Elevated levels of testosterone precursors caused by a partial testosterone biosynthetic defect in which compensatory serum LH concentrations stimulate a normal plasma testosterone concentration The presence of müllerian duct derivatives as a result of a testicular organogenesis defect with impaired Sertoli cell production of anti-müllerian hormone The presence of wolffian duct-derived internal male reproductive structures that differentiate in response to testosterone, suggesting 5-α-reductase deficiency, a partial testosterone biosynthetic defect, or PAIS. 5-α-reductase deficiency is the result of mutations in SRD5A2, which encodes the enzyme 5-α-reductase. The enzyme converts testosterone to dihydrotestosterone (DHT), which is primarily responsible for the development of the external genitalia before birth.Issues to consider in individuals with some, but not all, of the clinical features of AIS: Normal serum concentrations of T, DHT, and LH after birth do not prove that the concentration was normal during the critical period of fetal genital masculinization. Normal responsiveness to androgen after birth does not prove that it was normal before birth. That is, in utero delay in the acquisition of normal androgen biosynthesis or normal androgen sensitivity may lead to features consistent with androgen insensitivity.Subnormal sensitivity to androgen after birth may involve components of the overall androgen response system (AR-interacting proteins) beyond the androgen receptor itself. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Complete androgen insensitivity syndrome (CAIS)Partial androgen insensitivity syndrome (PAIS)

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and the needs of an individual diagnosed with androgen insensitivity syndrome, a complete evaluation by specialists in disorders of sex development (DSD), which can include specialists in endocrinology, urology, medical genetics, psychology/psychiatry [Hughes et al 2006, Parisi et al 2007, Douglas et al 2010], is ideal.Evaluation of androgen receptor-binding properties (i.e., binding and dissociation of specific ligands) of genital skin can help predict the likely outcome of hormone treatments (see PAIS with ambiguous genitalia).Treatment of ManifestationsA number of clinicians have sought to establish a consensus statement on management of disorders of sex development including AIS [Hughes & Deeb 2006]. A number of publications have subsequently discussed best management of these disorders [Diamond & Beh 2008 (click for full text), Douglas et al 2010 (click ), Pasterski et al 2010 (click ; registration or institutional access required), Wiesemann et al 2010 (click )]. Gender assignment. The issue of sex assignment in infancy when the child is being evaluated for ambiguous genitalia is paramount. It requires informed decision making by parents and healthcare personnel and should be resolved as early as possible, after a multidisciplinary evaluation has been completed. However, even in CAIS this may not always be so easy in light of a study that looked at the effects of gender assignment. After following 29 individuals with CAIS, it was recommended that gonads be kept at least until the completion of spontaneous puberty and the possibility of virilization be evaluated before management decisions are made [Cheikhelard et al 2008]. Psychological counseling and use of support groups can be of benefit [Cul & Simmonds 2010].CAISA critical consideration of any surgical intervention is the nature and timing of such intervention; thus surgeons need to be involved with the affected individuals and pediatrician in any such decisions [Purves et al 2008, Munoz & Swan 2010]. Recently, Vidal et al [2010] reviewed the evolution of surgical techniques for ‘feminization’ and ‘masculinization’ and their possible outcomes.A common practice is to remove the testes after puberty when feminization of the affected individual is complete, since feminization occurs partly by testicular estrogen and partly by peripheral conversion of androgen to estrogen. The rationale for postpubertal gonadectomy is that testicular malignancy, which develops at the usual rate for cryptorchid testes, seldom occurs before puberty [Hannema et al 2006]. Prepubertal gonadectomy is now only considered if inguinal testes are physically or esthetically uncomfortable, and if inguinal herniorrhaphy is necessary. In this event, estrogen replacement therapy is necessary to initiate puberty, maintain feminization, and avoid osteoporosis. However, the issue of gonadectomy is controversial. Some have argued that the true risk for malignant transformation of the gonads is small and have suggested postpubertal gonad biopsy as opposed to removal [Hughes et al 2006, Parisi et al 2007], which would allow affected individuals to retain a natural source of androgen production and avoid exogenous hormone replacement.Vaginal dilatation to augment vaginal length and to avoid dyspareunia is typically the treatment of choice for those with short vaginal length. If this method fails, new treatments of blind vagina have been proposed, including autologous buccal mucosal graft vaginoplasty and enhanced balloon vaginoplasty [Zhoa et al 2009, El Saman et al 2011]. Surgical reconstruction frequently requires maintenance vaginal dilatation to decrease the likelihood of future stricture. The question of how much and when to disclose the diagnosis of CAIS to an affected individual has not been resolved uniformly; however, it has become obvious that explanation of the diagnosis in an empathic setting is much preferable to systematic concealment or self-discovery of the diagnosis in an environment devoid of support from family, professionals, and other affected individuals [Conn et al 2005].PAIS with predominantly female genitalia (incomplete AIS)The issues are similar to those discussed under CAIS, except prepubertal gonadectomy helps avoid the emotional discomfort of increasing clitoromegaly at the time of puberty. In instances in which the diagnosis of PAIS is difficult to establish because of the presence of somatic mosaicism, a change of sex assignment can result in concomitant problems [Kohler et al 2005]. PAIS with ambiguous genitalia or predominantly male genitaliaThe assignment of sex in an infant with ambiguous genitalia is a complex process that requires timely assessment by a multidisciplinary team in consultation with the family and should be resolved as early as possible. Aside from purely anatomical and surgical considerations, the choice of a male sex-of-rearing demands a therapeutic trial with pharmacologic doses of androgen to try to predict potential androgen responsiveness at puberty. Furthermore, appreciable phallic growth in response to administered androgen facilitates reconstructive surgery. In instances in which maximum information is being gathered on an infant with no family history of AIS before sex is assigned, sequence analysis of AR may be considered; however, the lower probability of detecting an AR mutation in individuals with the PAIS phenotype and the poor positive predictive value of any given mutation regarding AIS phenotype need to be considered when making decisions about sex assignment. It has also been reported that the length of the AR exon 1 CAG repeat can influence the efficacy of testosterone treatments: individuals with shorter repeat lengths are more likely to respond to hormonal treatments [Zitzmann 2009]. However, the efficacy of CAG repeat length as a possible marker to assess hormonal treatment must await further studies. Based on experience with a small number of individuals, the role of long-term androgen pharmacotherapy in individuals with PAIS who are raised as males remains unclear. Response to androgen treatment may be substantial in individuals with certain missense mutations in the DNA-binding domain of the androgen receptor [Weidemann et al 1998]; however, it is still difficult to accurately predict the efficacy of androgen treatment. Thus, considerable caution should be exercised with regard to androgen treatment [Werner et al 2010], in particular because special hormonal profiles to androgen insensitivity have often not been acknowledged in replacement strategies.Gynecomastia that develops in puberty eventually requires reduction mammoplasty.Those individuals with PAIS who are raised as females and who have gonadectomy after puberty may need combined estrogen and androgen replacement therapy, the latter to maintain libido. MAISMen with MAIS often require reduction mammoplasty for treatment of gynecomastia. A trial of androgen pharmacotherapy is recommended to attempt to improve virilization [Loy & Yong 2001]. Prevention of Primary ManifestationsThe efficacy of androgen therapy in preventing manifestations such as gynecomastia is not clear.Prevention of Secondary ManifestationsWomen with CAIS have decreased bone mineral density, regardless of timing of gonadectomy [Oakes et al 2008]. In addition to estrogen replacement therapy, supplemental calcium and vitamin D are recommended. Regular weight-bearing exercises are encouraged to maintain bone health. Bisphosphonate therapy may be indicated for those individuals with evidence of decreased bone mineral density and/or multiple fractures.SurveillanceAppropriate measures include the following:Monitoring of postnatal development of genitalia that were ambiguous at birth for changes that could lead to reconsideration of the assigned sexFor individuals assigned a male sex, evaluation during puberty for signs of gynecomastiaIn adults, monitoring of bone mineral density through DEXA (dual-emission x-ray absorptiometry) scanning [Oakes et al 2008]Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Androgen Insensitivity Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDARXq12Androgen receptorThe Androgen Receptor Gene Mutations Database
AR @ LOVD
alsod/AR genetic mutationsARData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Androgen Insensitivity Syndrome (View All in OMIM) View in own window 300068ANDROGEN INSENSITIVITY SYNDROME; AIS 313700ANDROGEN RECEPTOR; ARMolecular Genetic PathogenesisOther possible gene involvementRecently, Chen et al [2010] noted that Fkbp52 regulates AR transactivation activity and male urethra morphogenesis, suggesting that AR mutations may require other genetic factors to produce hypospadias.Apolipoprotein D (APOD) is a possible biomarker of AR function in AIS [Appari et al 2009].Normal allelic variants. AR comprises nine exons. Nucleotide numbering varies depending on three principal factors: Variable length of the polyglutamine and polyglycine repeats Nucleotide at which the opening reading frame startsComplementary DNA sequence used as the reference sequenceCoincidentally, two major species of AR mRNA (10-11 kb; ~7 kb) result from alternative splicing of a very long 3'-UTR. Two forms of the androgen receptor protein (A and B) exist. Their size difference suggests that the short form (B) represents translation initiation at the internal Met190 residue.The issue of different forms of androgen receptor is somewhat confusing as a number of mutations that delete either whole exons or a substantial part of an exon, or affect splice sites, have been identified. In almost all cases when an attempt has been made to test these variant forms of androgen receptor protein, they have been found to be nonfunctional. Note: The Androgen Receptor Gene Mutations Database has recently changed its nucleotide and amino acid numbering scheme to conform to the HGVS standards, which are based on NCBI cDNA reference sequence NM_000044.2:A trinucleotide repeat tract (CAG)_nCAA with n=7-37 CAG repeats starting at nucleotide 1288 encodes a polyglutamine tract (Table 3). Another polymorphic tract (GGT)₃ GGG(GGT)_2-4 GGC_(n), with n=12-29 starting at nucleotide 2466 encodes a polyglycine repeat [Lumbroso et al 1997].A silent c.1754G>A variant in the coding region (at the third position of codon 213 in exon 1) is referred to as c.709G>A in Hiort et al [1994], c.995G>A in Batch et al [1992], and c.1152G>A in Chang et al [1988]. A HindIII restriction fragment length polymorphism (RFLP) is detectable by a 0.7-kb fragment of the AR cDNA that extends from near the 5' border of exon 2 to about the middle of exon 7. Pathologic allelic variants. More than 450 point mutations in AR have been found to cause AIS (see Androgen Receptor Gene Mutations Database). The great majority are missense mutations that impair DNA or androgen binding and cause CAIS or PAIS; a small number have been proven to cause MAIS. Point mutations in exon 1 are relatively uncommon; the majority of mutations are either nonsense or small deletions or insertions that result in a frameshift; thus, they almost always cause CAIS. Thus, PAIS is seldom the result of exon 1 mutations [Choong et al 1996]. On the other hand, the number of point mutations identified in exon 1 has increased over the past few years with a considerable number having the MAIS phenotype see Androgen Receptor Gene Mutations Database). A small number of major AR deletions and intronic alterations have also been described (see Table A). Expansion of the trinucleotide repeat tract (CAG)_nCAA that encodes a polyglutamine tract to more than 38 results in Kennedy disease (spinobulbar muscular atrophy) with some findings of MAIS, which are likely the result of the reduced transactivation of AR with long CAG repeat tracts of androgen receptor proteins that contain expanded polyglutamine tracts.In addition, variations in length of CAG repeat in AR have been associated with the following conditions. Cancers:ProstateHead & neckColonFemale breastEndometrial Abnormalities of:Platelet activityBone & mineral densityAlzheimer diseaseMale infertilityHypertensionArthritisEndometriosisAutismNote: (1) A complete list of CAG repeat length associated conditions is available at the Androgen Receptor Gene Mutations Database. (2) These data involve small increases and decreases in CAG repeat length as a possible risk factor. These conditions are not related to SBMA, as SBMA is caused by having more than 38 CAG [p.Gln58(>38)] repeats. Table 3. Selected AR Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change Protein Amino Acid ChangeReference SequencesNormalc.1288CAG(7-37)p.Gln58(7-37)NM_000044​.2Complex trinucleotide repeat beginning at position 2466p.Gly451(12-29)c.(1754G>A) ^{1p.= 2Pathologicc.1288CAG(>38) 3p.Gln58(>37)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant has different numbering systems; see Normal allelic variants.2. p.= designates that protein has not been analyzed, but no change is expected.3. Pathologic allelic variant associated with SBMANormal gene product. Androgen receptor. The entire N-terminal portion of the androgen receptor (~538 aa) is encoded by exon 1, the DNA-binding domain (amino acid residues 558-617) by exons 2 and 3, the bipartite nuclear localization signal (amino acid residues 618-637) by exons 3 and 4, and the androgen-binding domain (residues 646-920) by exons 4-8. Two polyA-addition signals occur about 220 nucleotides apart. Coincidentally, two major species of AR mRNA (10-11 kb; ~7 kb) result from alternative splicing of a very long 3'-UTR. Two forms of the androgen receptor protein (A and B) exist. Their size difference suggests that the short form (B) represents translation initiation at the internal Met190 residue.The different forms of the androgen receptor are somewhat confusing: a number of mutations that either delete whole exons or a substantial part of an exon, or affect splice sites, have been identified. When the functionality of these variant forms of androgen receptor protein is tested, almost all have been found to be nonfunctional. The androgen receptor is a well-defined transcriptional regulatory factor. Once activated by binding to androgen, it collaborates with other co-regulatory proteins (some involve DNA binding, others do not) to achieve control over the rate of transcription of an androgen target gene that is under the influence of a nearby promoter. A large number of AR-associated proteins have now been identified [Heinlein & Chang 2002, Gottlieb et al 2004b]; for latest listing see the Androgen Receptor Gene Mutations Database.Abnormal gene product. Nearly all point mutations in the androgen-binding domain impair androgen binding and, therefore, affect transactivation by the AR. Some decrease only the apparent equilibrium affinity constant; some increase only the non-equilibrium dissociation rate; others do both, either with all androgens or selectively with certain androgens. Still others are thermolabile or degrade excessively in the presence of androgen. Point mutations in the zinc fingers or α-helical portions of the DNA-binding domain impair binding to a sequence of regulatory nucleotides known as an androgen response element. Such binding is essential for the androgen receptor to exert transcriptional regulatory control over most of its target genes. The polyglutamine-expanded androgen receptor causes the spinobulbar muscular atrophy component of Kennedy disease by a gain of function that is selectively motor neuronotoxic. The precise mechanism of its neuronotoxicity has not been determined, although there are clearly many contributing mechanisms [Beitel et al 2005, Jordan & Lieberman 2008, Ranganathyan & Fishbeck 2010, Sau et al 2011]. Further, the MAIS component of Kennedy disease may be caused by decreased transcriptional regulatory activity of the polyglutamine-expanded androgen receptor or its decreased synthesis [Beitel et al 2005]. Insight into the relationship between mutations and their possible effects on the functionality of the actual androgen receptor protein has been obtained by creating molecular models of the receptor using molecular dynamic modeling based on the x-ray crystal structure [Matias et al 2000]. This technique has produced dynamic models that have successfully simulated the effects of particular mutations on the ligand-binding properties of mutant androgen receptors [Elhaji et al 2004, Wu et al 2004, Elhaji et al 2006]. It is hoped that this technique may eventually lead to treatments that return to normal the ligand-binding capacity of mutant androgen receptors.}