AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 89:210–217 (1999) ARTICLE

Androgen Insensitivity

BRUCE GOTTLIEB,* LEONARD PINSKY, LENORE K. BEITEL, AND MARK TRIFIRO

The androgen receptor (AR) protein regulates transcription of certain genes. Usually, this activity depends upon a central DNA-binding domain that permits the binding of androgen–AR complexes to regulatory DNA sequences near or in a target gene. The AR also has a C-terminal androgen-binding domain (ABD) and an N-terminal modulatory domain. These domains interact among themselves and with coregulatory, nonreceptor proteins to determine vector control over a gene’s transcription rate. The precise roles of these proteins are active research areas. Severe X-linked androgen receptor gene (AR) mutations cause complete androgen insensitivity, mild ones impair virilization with or without infertility, and moderate ones some- times yield a wide phenotypic spectrum among sibs. Different expressivity may reflect variability of AR- interactive proteins. The family history must identify heterozygous XX females with sparse, delayed, or asymmetric pubic/axillary hair or delayed menarche and infertile XY maternal aunts or uncles. Mutation type and density vary along the length of the AR. N-terminal polyglutamine tract expansion limits AR transactivation, causing a form of mild androgen insensitivity. Analysis of ABD mutations that do not impair androgen binding or impair it selectively will illuminate its intradomain properties. For partial androgen insensitivity and mild androgen insensitivity, pharmacotherapy with certain androgens or other steroids may overcome some dysfunction of certain mutant ARs. Experience with this approach is limited; outcomes have been generally disappointing. Am. J. Med. Genet. (Semin. Med. Genet.) 89:210–217, 1999. ᮊ 2000 Wiley-Liss, Inc.

KEY WORDS: androgen insensitivity; androgen receptor; gene mutations; pharmacotherapy

mosomal locus Xq11-q12) is currently Bruce Gottlieb, Ph.D., is a geneticist/ INTRODUCTION molecular biologist who is the curator of available on a research basis only. AIS the Androgen Receptor Gene Mutations can be subdivided into three pheno- database and is particularly interested in The X-linked intracellular androgen types: complete androgen insensitivity the development of gene mutation da- receptor (AR) is essential for androgen tabases. He is a senior scientist at the syndrome (CAIS), partial androgen in- action, whether of testosterone (T) or Lady Davis Institute for Medical Re- sensitivity syndrome (PAIS), and mild search, Sir Mortimer B. Davis–Jewish of its 5␣-reduced derivative, 5␣-dihy- androgen insensitivity syndrome General Hospital, and professor of biol- drotestosterone (DHT). Hence, the ogy at John Abbott College, Montreal. (MAIS). The diagnosis of CAIS usually Leonard Pinsky, M.D., was a staff in- AR is essential for normal primary male is made on clinical findings and labora- vestigator 1969–1999 and director of the sexual development before birth (mas- androgen receptor lab 1974–1999 at the tory evaluations alone. The diagnosis of culinization) and for normal secondary Lady Davis Institute for Medical Re- PAIS and MAIS may require, in addi- search. At McGill University, Montreal, male sexual development around pu- he was director of the Center for Human tion, a family history consistent with X- berty (virilization). AR dysfunctions in Genetics 1979–1999 and professor of linked inheritance. medicine and pediatrics and chairman, XY individuals result in androgen in- Department of Human Genetics, from sensitivity syndromes (AIS). Androgens 1994. He is now retired. Lenore K. Beitel, Ph.D., is a bio- also participate in female sexual devel- chemist/molecular biologist who is inter- opment around puberty and in adult fe- ested in many aspects of the structure/ Mutation analysis of the function relationship of the androgen male sexual function. Therefore, an- receptor and, in particular, androgen re- drogens are involved in male and AR gene (chromosomal ceptor–interacting proteins. She is a re- search scientist at the Lady Davis Insti- female reproduction, and AR muta- locus Xq11-q12) is tute for Medical Research. tions may interfere with reproduction currently available on a Mark Trifiro, M.D., is a clinical and in either sex, albeit much more subtly research molecular endocrinologist and heads the Molecular Endocrinology in females. research basis only. Laboratory at the Lady Davis Institute for Medical Research. He is an associate pro- fessor of medicine at McGill University. Contract grant sponsor: Medical Re- BASIC DIAGNOSIS OF search Council, Canada; Contract grant The clinical findings that permit a sponsor: Fonds de la Recherche en Sante´, ANDROGEN presumptive diagnosis of AIS include Que´ bec; Contract grant sponsor: Fonds INSENSITIVITY the following: absence of extragenital pour la Formation de Chercheurs et SYNDROMES l’Aide a` la Recherche, Que´ bec. abnormalities, two nondysplastic testes, *Correspondence to: Lady Davis In- absent or rudimentary mu¨llerian struc- stitute for Medical Research, Sir Mor- timer B. Davis–Jewish General Hospital, The diagnosis of AIS is based on clinical tures (i.e., no fallopian tubes, uterus, or 3755 Cote Ste. Catherine Road, Montre- findings, endocrine evaluation, and, cervix) and presence of a short vagina, al, Que´ bec, Canada H3T 2E1. E-mail: [email protected] whenever possible, family history. Mu- undermasculinization of the external tation analysis of the AR gene (chro- genitalia at birth, and impaired sper- © 2000 Wiley-Liss, Inc. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 211 matogenesis and/or somatic virilization their mutant alleles should represent be normal male in morphologically but at puberty. The laboratory findings re- new mutations. A recent report on small, or there may be simple coronal quired for the diagnosis of AIS include single-case families with CAI or partial hypospadias or a prominent midline ra- the following: 46,XY karyotype, nor- androgen insensitivity (PAI) gene mu- phe of the scrotum. Between these ex- mal or increased synthesis of T by the tations [Hiort et al., 1998a] found a de tremes are all grades of frank external testes, normal conversion of T to DHT, novo AR mutation rate of close to 30% genital ambiguity that require delicate normal or increased luteinizing hor- (eight of 30), thereby affirming the decision making in order to choose a mone production by the pituitary theoretical expectation of 33% for an sex of rearing that is compatible with gland, and deficient or defective andro- X-linked recessive genetic lethal [Hal- surgical, anatomical constraints and gen-binding activity of genital skin dane, 1935]. Thus, two-thirds of moth- with some predictive information con- fibroblasts. ers of CAI subjects are heterozygous cerning the probable balance between carriers of the mutant allele. Further- virilization and feminization at puberty. more, because of random X-chromo- MAI takes two phenotypic forms SPECIAL DIAGNOSTIC some inactivation, such carriers may at puberty: in one, spermatogenesis and CHARACTERISTICS OF express their heterozygosity clinically fertility are impaired [Migeon et al., ANDROGEN by delayed, diminished, or asymmetric 1984; Cundy et al., 1986]; in the other, INSENSITIVITY pubic and/or axillary hair and by de- spermatogenesis is normal or sufficient SYNDROMES layed menarche [Kaufman et al., 1976]. to preserve fertility [Pinsky et al., 1989; The reason for delayed menarche is not Tsukada et al., 1994; Grino et al., AR mutations that severely impair the entirely clear, but it has been recog- 1988]. In both, gynecomastia, high- amount, structure, or function of the nized that females homozygous for 5␣- AR cause the phenotype of complete reductase type 2 deficiency also have androgen insensitivity (CAI). Standard delayed menarche [Katz et al., 1995]. Mild androgen insensitivity references quote rates of two to five per Since 5␣-reductase type 2 is responsible takes two phenotypic forms 100,000 for CAI. These estimates are for an important fraction of T→DHT derived from the number of otherwise conversion in some parts of the body, it at puberty: in one, normal girls whose inguinal hernias are follows that DHT deficiency or T ex- spermatogenesis and discovered to contain normal testes. cess or both contribute to delayed men- Subjects are born appearing unambigu- arche. However, the effect of DHT de- fertility are impaired; in the ously female because DHT-dependent ficiency can be mimicked by DHT other, spermatogenesis is masculinization of the external genital resistance. Furthermore, by aromatiza- normal or sufficient to primordia is totally absent. They are tion, T excess can generate estrogen ex- typically not suspected of being abnor- cess. The latter mimics an androgen- preserve fertility. mal until the onset of puberty, when resistant state. Thus, pubertal resetting breast development is normal, but pu- of the gonadostat in heterozygous fe- bic and axillary hair development is not. males may be delayed directly by DHT pitched voice, sparse sex hair, and im- Menarche, initially considered late, resistance or indirectly by an increased potence may be noted. In the form never occurs. Mu¨llerian duct regres- ratio of estrogen/androgen action. where fertility is preserved, one pre- sion, being androgen independent, is sumes that the dysfunction of the mu- normal. Hence, these patients usually tant AR is sufficiently mild that it can lack a uterus, oviducts, and the cervix. Because all XY subjects be overcome by collaboration with the In theory, they also should lack the up- set of coregulatory proteins that is ac- per, Mu¨llerian duct–derived portion of with CAI are sterile, tive in Sertoli cells. Such collaboration the vagina; however, many patients one-third of their mutant would permit the target genes necessary with CAI have satisfactory coitus with- alleles should represent new for spermatogenesis to be regulated out dyspareunia. Since Wolffian duct properly. In the form where fertility is differentiation is T dependent, these mutations. not preserved, one must conclude that subjects should lack vasa deferentia, ep- the mutant AR is competent to mascu- ididymides, seminal vesicles, and ejacu- linize or virilize most targets of andro- latory ducts. Occasionally, however, Family history becomes even more gen action and that its incompetence rudimentary segments of the Mu¨llerian crucial when one is concerned with with regard to spermatogenesis cannot duct or the Wolffian duct or both are various degrees of PAI. In one form, be rectified by collaboration with those found by ultrasonography or laparoto- the external genitalia may be nearly coregulatory proteins that compose the my. Their testes may or may not be normal female, except for clitoro- transcriptional regulatory environment inguinal. megaly and/or posterior labial fusion. of Sertoli cells. Because all XY subjects with CAI At the other extreme (mild androgen The great majority of families with are sterile (genetic lethals), one-third of insensitivity, or MAI), the genitalia may CAI “breed true”; in other words, ef- 212 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE fected individuals depart little from the bind to a sequence of regulatory PHENOTYPE–GENOTYPE textbook phenotype of “complete tes- nucleotides (nts) (a bipartite “androgen- CORRELATION OF AR ticular feminization” (as it used to be response element”), and interact with MUTATION known). upstream and downstream coregulatory Figure 3 depicts all AR point mutations In families with PAI, on the other proteins (some also DNA binding). and small deletions or insertions that hand, it is not uncommon for affected These interactions, and those with basal have been reported to cause CAI, PAI, individuals to have frankly ambiguous transcription factors and core promoter or MAI [Gottlieb et al., 1999]. The external genitalia that are, nonetheless, elements, determine vector control present version of the Androgen Re- predominantly masculine or predomi- over the transcriptional expression of a ceptor Gene Mutations Database (avail- nantly feminine. As may be expected, given androgen target gene. Some of able at www.mcgill.ca/androgendb) this can lead to opposite sexes of rearing the coregulatory proteins that are able contains 311 entries of mutations caus- [Rodien et al., 1996]. Indeed, for some to interact with certain portions of the ing AIS (Table I), representing more mutations in the androgen-binding do- AR, under certain conditions, are than 230 different AR mutations (Fig. main (ABD), such variable expressivity shown in Figure 1 with their code 3) from more than 440 patients with may be the rule, not the exception names. AIS, and demonstrates an unequal dis- [Pinsky et al., 1996]. Furthermore, in tribution of these mutations along the rare families with PAI, the expressivity The AR gene is about 90,000 nts ∼ length of the AR. It has been suggested may vary markedly, from near-normal long (90 kb), but only 2,750 of them, that these mutation-dense regions are male to near-normal female. divided into eight exons, code for hot spots that reflect the high density of Although experience with MAI amino acids (aa). The variable length of mutable CpG sites in the region [Got- families is limited, they appear to harbor the AR reflects the fact that its amino- tlieb et al., 1996]. It is also apparent that relatively little phenotypic disparity. terminal transregulation modulatory the types of mutations differ along the Nonetheless, between or among fami- portion (∼537 aa) contains two homo- length of the AR. In particular, nearly lies, the same mutation may be respon- polymeric aa repeats that are polymor- all mutations in exon 1 (Fig. 3) cause sible for MAI or PAI. These consider- phic in size (Fig. 2). One is polygluta- CAI, and nearly all are of the premature ations of variable expressivity within or mine, and its repeat size varies from translation termination variety, whether among families have great import for nine to 36 [Andrew et al., 1997]; the by direct mutation to a stop codon or taking a sophisticated family history. other, polyglycine, varies from 10 to 31 indirectly, by frameshifting after small For instance, in the early differential di- [Lumbroso et al., 1997]. Expansion of deletions or insertions. agnosis of androgen resistance (insensi- the polyglutamine tract beyond 38 is tivity) as a cause of apparently isolated the cause of Kennedy syndrome [La hypospadias or azoospermia (no sperm Spada et al., 1991], a motor neuronopa- More than 200 different production), it would be very helpful to thy associated with MAI that is dis- mutations associated with know whether any maternally related cussed later herein. females had delayed menarche, primary There are three additional primary AIS have been found in amenorrhea, delayed and reduced or structure/function domains of the AR. absent sex hair (symmetrically or asym- exons 2–8, but only 23 Centrally, there is a DNA-binding metrically), or even clitoromegaly with domain (DBD), ∼557–616 aa, encoded have been found in exon 1. or without posterior labial fusion. Of by exons 2 and 3. Adjacent to the course, the reciprocal would be true in DBD, C-terminally, there is a bipar- the early differential diagnosis of phe- Some mutations in the DBD cause tite nuclear localization signal (617– notypic females with any of these pre- CAI, but at least as many mutations senting signs. 636 aa) encoded by exons 3 and 4. Fi- cause PAI, and none cause MAI. To ∼ nally, there is a C-terminal 250-aa date, relatively few mutations have ABD encoded by exons 4–8. In addi- been reported in exon 1 of the AR in STRUCTURE/FUNCTION tion to their principal functions, the RELATIONSHIPS OF THE patients suffering from some form of ABD, DBD, and N-terminal domains AIS—and even fewer in splicing and ANDROGEN RECEPTOR embody subsidiary functions that PROTEIN AND GENE untranslated regions of the AR gene affect dimerization, nuclear localiza- (Fig. 3). More than 200 different mu- Once transformed by binding an andro- tion, and transcriptional regulation tations associated with AIS have been gen molecule, the AR acquires the (Fig. 2). Thus, the trimodular (do- found in exons 2–8, but only 23 have ability to regulate the rate of transcrip- main) concept of AR function is a sim- been found in exon 1, despite the fact tion of genes whose expression is sub- plification; instead, domain interaction that it encodes more than half of the ject to androgenic control. To exert and interaction with coregulatory pro- AR protein [Gottlieb et al., 1998]. A such regulation, a complex of an andro- teins hold the secrets to a full under- number of recent studies have analyzed gen and an androgen receptor (an standing of AR structure/function various possible functions of the N-ter- A-AR) must do three things: dimerize, properties. minal region encoded by exon 1 of the ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 213

Figure 1. A sample of coregulatory proteins that interact with different portions of the androgen receptor (AR) positively (coacti- vators), negatively (corepressors), or in an uncertain way (other proteins). The crosshatched rectangles in the left half of the AR represent the polyglutamine and polyglycine tracts in its N-terminal transactivation domain. The portion of the AR devoted to DNA binding is darkly stippled; that devoted to ligand binding is finely hatched. (An updated, referenced list of these coregulatory proteins, including novel AR interaction sites, is available from the authors by E-mail at [email protected] or at the AR Gene Mutations Database Website: www.mcgill.ca/androgendb.) human AR. Among these functional three of the eight patients with de novo affected individuals, however, a rela- assignments are a set of transactivation mutations had the mutation in only a tively mild clinical outcome could re- domains [Jenster et al., 1991,1995; fraction of the somatic cells [Hiort et flect back-mutation of an inherited mu- Chamberlain et al., 1996] and two pu- al., 1998a]. The simplest origin of such tation to a normal allele. tative dimerization zones [Langley et mosaicism would be forward mutation Kennedy syndrome is a spinobul- al., 1995]. of an inherited normal allele to a mu- bar motor neuronopathy associated In the ABD there is a striking pre- tant allele in a subject with a negative with MAI. It is caused by expansion of ponderance of missense mutations and family history. In a family with multiple the glutamine-coding (CAG)8–35 CAA an equally striking concentration of them in and around those exons that putatively contribute to the androgen- binding pocket of the ABD (Fig. 3). In addition, a number of mutations have been reported that exhibit variable expressivity (i.e., mutations R855H and V866H in Fig. 3). The traditional ex- planation for such variable expressivity of an AR mutation is that the level or competence of coregulatory proteins acts as a genetic “background” factor in determining the overall clinical out- come [Pinsky et al., 1996; Rodien et al., 1996; Boehmer et al., 1997]. Re- cently, however, it has been appreci- ated that somatic mosaicism (more or Figure 2. A linear rendition of the major structure/function domains and putative subdomains of the androgen receptor. The solid portions of the interrupted lines below less covert) may account for some vari- the androgen-binding domain indicate the most likely location of a given functional able expressivity [Boehmer et al., 1997; subdomain. Holterhus et al., 1997]. In one study, Figure 3. Structure of the AR indicating the location of all exon and intron androgen insensitivity syndrome mutations. ᭝, 1–4 bp deleted; ᭞, 1–4 bp inserted; X, a termination codon at the site of the mutation or at the frameshifted codon identified by the number that follows; 0, a codon deletion; *, mutations in male breast cancer tissue. Mutations in normal type indicate complete androgen insensitivity (CAI). Mutations in italics indicate partial androgen insensitivity (PAI). Mutations in outline denote mild androgen insensitivity (MAI). Mutations that are underlined cause both CAI and PAI. Mutations in outline and underlined cause both PAI and MAI. Mutations in italic and underlined occur in both normal individuals and those with PAI. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 215

Brooks et al., 1997], or it may be both, TABLE I.. AIS mutations in the Database* depending on the cell type. Gynecomastia is the single most Type Phenotype Mutation common sign of MAI in spinobulbar Single base mutations muscular atrophy, and it is frequently Amino acid substitution Complete AIS 134 the first [Beitel et al., 1998]. Decreased Partial AIS 104 libido and impotence usually appear Mild AIS 10 next. Testicular atrophy and infertility Normal 4 typically are last. Testicular atrophy Multiple amino acid substitution Complete AIS 2 represents impaired spermatogenesis Splice junction substitution Complete AIS 5 and corresponds to oligospermia (re- Partial AIS 1 duced sperm production) or azoosper- Splice junction insertion Complete AIS 1 mia on semen analysis. Because impo- Intron substitution Complete AIS 1 tence, reduced libido, and impaired Premature termination codons Complete AIS 22 spermatogenesis appear relatively late, Partial AIS 1 often between 40 and 50 years of age Total 285 [Guidetti et al., 1986], males affected Structural defects with Kennedy syndrome are usually Complete gene deletions Complete AIS 3 fertile. In fact, in the cases summarized Partial gene deletions (6–30 bp, 1–7 exons) Complete AIS 8 by Warner et al. [1990], 72% had chil- Mild AIS 1 dren. In Singapore, otherwise normal 1- to 4-bp deletions Complete AIS 6 males with 28 or more CAG repeats in Intron deletion Partial AIS 1 their AR have been reported to have Splice junction deletion Complete AIS 1 more than a fourfold increased risk of Insertions Complete AIS 4 impaired spermatogenesis, and the Insertions (variable) Kennedy syndrome 1 more severe the spermatogenic defect, Bp duplications Complete AIS 1 the greater the number with a long re- Total 26 peat [Tut et al., 1997]. It will be inter- Grand total 311 esting to see if a similar observation can be made studying different ethnic *AIS, androgen insensitivity syndrome. populations. Recently, infertility was reported to be associated with two different “si- tract in exon 1 of the AR to a total of Ն may be intrinsic [Mhatre et al., 1993; lent” single nt polymorphisms [Hiort et 38 (Fig. 4) [Andrew et al., 1997]. The Chamberlain et al., 1994; Kazemi- al., 1998b; Wang et al., 1998]. Whether MAI component reflects a loss of AR Esfarjani et al., 1995; McPhaul et al., the association of each single nt alter- transcriptional regulatory activity by 1997], it may reflect diminished intra- ation with male infertility is causal or virtue of a pathologically expanded cellular steady-state levels of polygln- coincidental remains to be defined. A polyglutamine (polygln) tract. This loss expanded AR [Choong et al., 1996; third silent AR mutation now has been found in an individual with PAIS [Nor- denskjo¨ld et al., 1999]. In a recent re- port [Lumbroso et al., 1999], we have noted that missense mutations in the ABD region coding aa 785–800 are dis- proportionately associated with MAI and display distinctive ligand kinetics. Other mutation hot spots associated with specific AI phenotypes must be sought. PROSPECTS FOR THE THERAPY AND Figure 4. Expansion of the trinucleotide repeat encoding polyglutamine (starting at MANAGEMENT OF residue 58 of the AR) is the cause of Kennedy syndrome (a form of spinobulbar ANDROGEN motorneuronopathy associated with mild androgen insensitivity). The normal number (n) of repeats varies polymorphically from nine to 36. Kennedy syndrome occurs when INSENSITIVITY n Ն 38. As elaborated later herein, it is possible, in theory, to overcome the functional 216 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE defects of certain mutant ARs by phar- et al., 1984; McPhaul et al., 1991; Hiort drogens and progesterone. Mol Endocrinol macotherapy with appropriate andro- et al., 1993]. This is notably disappoint- 7:1541–1550. Cundy TF, Rees M, Evans BAJ, Hughes IA, But- gens or other steroids. It may even be ing, especially when laboratory studies ler J, Wheeler MJ. 1986. Mild androgen possible to increase the concentration of indicate that a particular ABD mutation insensitivity presenting with sexual dysfunc- deficient, but otherwise normal ARs, decreases androgen-binding affinity in a tion. Fertil Steril 46:721–723. Gottlieb B, Beitel LK, Lumbroso R, Pinsky L, simply by increasing the rate of synthe- manner that theoretically should be Trifiro M. 1999. Update of the androgen sis or decreasing the rate of degradation. normalized simply by provision of ex- receptor gene mutations database. Hum These statements are irrelevant for cess androgen. Failure of this therapeu- Mutat 14:103–114. tic strategy implies that occupancy of Gottlieb B, Lehvaslaiho H, Beitel LK, Lumbroso those with CAI or incomplete AI, who R, Pinsky L, Trifiro M. 1998. The andro- are irremediably infertile. the ABD by the androgen is only a su- gen receptor gene mutations database. Some missense AR mutations ex- perficial expression of mutant AR dys- Nucleic Acids Res 26:234–238. press androgen-binding defects that are function: its core dysfunction is its fail- Gottlieb B, Trifiro M, Lumbroso R, Vasiliou DM, Pinsky L. 1996. The androgen recep- conditional on being exposed to a par- ure to be activated to a competent tor gene mutations database. Nucleic Acids ticular type of androgen [Pinsky et al., transcriptional regulatory protein even Res 24:151–154. 1984; Pinsky et al., 1985; Kaufman et when the androgen-binding pocket of Grino PB, Griffin JE, Cushard WG Jr, Wilson JD. 1988. A mutation of the androgen receptor al., 1990]. It follows that it may be pos- the mutant AR is fully occupied. associated with partial androgen resistance, sible to find, or design, a type of andro- familial gynecomastia, and fertility. 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