Phenotypic Variation in a Family with Partial Androgen Insensitivity Syndrome Explained by Differences in 5  Dihydrotestosterone Availability

Abstract

Mutations in the androgen receptor (AR) gene result in a wide range of phenotypes of the androgen insensitivity syndrome (AIS). Inter- and intrafamilial differences in the phenotypic expression of identical AR mutations are known, suggesting modifying factors in establishing the phenotype. Two 46,XY siblings with partial AIS sharing the same AR gene mutation, R846H, but showing very different phenotypes are studied. Their parents are first cousins. One sibling with grade 5 AIS was raised as a girl; the other sibling with grade 3 AIS was raised as a boy. In both siblings serum levels of hormones were measured; a sex hormone-binding globulin (SHBG) suppression test was completed; and mutation analysis of the AR gene, Scatchard, and SDS-PAGE analysis of the AR protein was performed. Furthermore, 5alpha-reductase 2 expression and activity in genital skin fibroblasts were investigated, and the 5alpha-reductase 2 gene was sequenced. The decrease in SHBG serum levels in a SHBG suppression test did not suggest differences in androgen sensitivity as the cause of the phenotypic variation. Also, androgen binding characteristics of the AR, AR expression levels, and the phosphorylation pattern of the AR on hormone binding were identical in both siblings. However, 5alpha-reductase 2 activity was normal in genital skin fibroblasts from the phenotypic male patient but undetectable in genital skin fibroblasts from the phenotypic female patient. The lack of 5alpha-reductase 2 activity was due to absent or reduced expression of 5alpha-reductase 2 in genital skin fibroblasts from the phenotypic female patient. Exon and flanking intron sequences of the 5alpha-reductase 2 gene showed no mutations in either sibling. Additional intragenic polymorphic marker analysis gave no evidence for different inherited alleles for the 5alpha-reductase 2 gene in the two siblings. Therefore, the absent or reduced expression of 5alpha-reductase 2 is likely to be additional to the AIS. Distinct phenotypic variation in this family was caused by 5alpha-reductase 2 deficiency, additional to AIS. This 5alpha-reductase deficiency is due to absence of expression of the 5alpha-reductase iso-enzyme 2 as shown by molecular studies. The distinct phenotypic variation in AIS here is explained by differences in the availability of 5alpha-dihydrotestosterone during embryonic sex differentiation.

Homosexuality as a Consequence of Epigenetically Canalized Sexual Development

“…Boehmer et al (2001) review evidence that strongly supports the conclusion that this sex-specific difference in gene expression is not androgen-induced via a feed-forward process (i.e., due to changes induced by higher T in XY fetuses during earlier development). Higher conversion of T to DHT would permit XY fetuses to develop male traits even when T levels overlap (to a limited degree) with XX female fetuses, thereby promoting phallus development despite low circulating T. Similarly, lower 5-␣-reductase production in XX females would prevent or reduce masculinization of the vulva when T levels overlapped (to a limited degree) with those of XY males.…”

Androgen insensitivity syndrome: clinical features and molecular defects

“…52 Boehmer et al 78 analysed the genotype-phenotype relationship in AIS and the possible causes of phenotypic variations in families with many affected individuals. Intrafamilial phenotypic variation was observed for mutations R846H and M771I.…”

“…85 Discrepancies of phenotype-genotype can also be caused by splice site mutations due to alternative splicing, 81,87 or by differences in 5alpha-reductase 2 activity and thus in adequate DHT availability. 78 The length of polyglutamine repeats in exon 1 is also a candidate factor leading to diverse phenotypes. 88 In a recent report, Werner et al 89 documented experimentally the contradictory effect of the combination of a short polyglycine (PolyG) repeat with the rare mutation of the hinge region A645D, resulting in seriously reduced AR activity when paired with a long polyglutamine (PolyQ) repeat and in almost wild-type AR activity when paired with a short PolyQ repeat.…”

5-alpha-reductase deficiency: a case report

“…2,12 Phenotypic findings in a newborn are limited to the genitalia. Most commonly, the external genitalia exhibit labial appearance to the labioscrotal folds with some mild rugation or pigmentation, clitoris-like phallus, perineoscrotal hypospadia, and pseudovagina blind ending introitus.…”

“…3,4,12,20,21 Basal testosterone to DHT ratio in healthy prepubertal children is 3, and at puberty is 12. 22 The normal level of testosterone in breast development.…”