by Kevin C Zebari
A rare autosomal recessive disorder of genetic (XY) males leads to ambiguous
external genitalia and often to an initial misdetermination of sex. This
disorder is classified as Psuedohermaphroditism and it can have significant
biological and social impact on the individual. It is characterized by a
clitoris-like phallus, bifid scrotum, and urogenital sinus with a blind
vaginal pouch (Davis, 1992, p.1216). The testes are undescended pre-pubescently,
and are usually located in the abdomen, inguinal canals, or scrotal folds.
The position of the urethra on these males is located near the location
of the normal female urethra (Herdt, 1990, p.436). Psuedohermaphroditism
has a high incidence in the Dominican Republic, the focus of many studies
to understand and characterize this disease. Implicated in this disorder
is a deficiency in the activity of the steroid enzyme, 5-alpha reductase,
which converts testosterone to dihydrotestosterone (DHT), an androgen responsible
for external male development (Behrman, 1992, p.1468). At fault in this
deficiency is a single base-pair substitution in the DNA encoding this enzyme.
Internally, affected males have internal male development; testes, wolffian
ducts, vas deferens, epididymis and seminal vesicles are all present. At
puberty, further male development occurs including enlargement of the penis,
descension of the testicles, and a deeper voice (Diamond, 1992, p.76).
The high incidence of the condition in the Dominican Republic kindred, 47
affected males over seven generations, has made them the target of research
to further characterize this disorder. The formation of an accurate pedigree
to analyze the inheritance pattern of the disease posed difficulty due to
its non-expression in females. The fact that all carriers could be traced
back to a single female carrier accounts for this conditions high incidence
in this small, isolated population (Davis, 1992, p.1217). Phenotypically,
affected males were found to have less facial and body hair than normal
males, and less acne as well. Two isotypes of the gene encoding the 5-alpha
reductase enzyme have been located. The first type is found on chromosome
5 and is usually not present in very significant concentrations in androgen-sensitive
tissues. The second isotype is present in androgen-sensitive tissues at
higher concentrations than the first type. The second isotype was the target
of the substitution and ultimately, the deficiency. Electrophoretic DNA
migration patterns of heterozygous parents and their homozygous sons revealed
patterns of migration that differed between heterozygous and homozygous
(Davis, 1992, p.1218). Various social aspects of the kindred contributed
to the prevalence of the disease. The people are socially isolated and marriage
between relatives, which serve to amplify expression of rare recessive conditions,
are not uncommon (Herdt, 1990, p.435).
The locus of this mutation is on exon 5 of chromosome 2. Using PCR and site-directed
mutagenesis, it was determined that the mutation is a substituion of thymidine
in place of cytosine that correlates to the production of tryptophan, a
bulky, hydrophobic amino acid, instead of arginine, a highly basic amino
acid . This results in the deficient activity of the enzyme. Further testing
revealed that this mutation was indeed responsible and present in all cases.
It appears that the single base substitution of cytosine-guanosine dinucleotides
are not uncommon to the human genome. It is usually the result of methylation-induced
deamination of 5-methylated cytosine residues. The 246th position of exon
5 encoding the 5-alpha reductase may be a site of high frequency of mutation
(Davis, 1992, p.1218-19).
The effects of this base change were determined with biochemical characterization
and comparison of the mutants and the normal, wild-type strain. It was determined
that the mutant enzyme functioned optimally at a more alkaline pH (5.3 -
5.5) than the wild-type (4.8 - 4.9). The mutant enzyme also failed to reach
the velocity of the wild-type enzyme. An important co-factor in the ability
of this enzyme, NADPH, is utilized by the normal enzyme at relatively low
concentrations (Km = 8 - 13 umol/L) while the mutant type enzyme requires
much greater concentrations (Km = 600 - 650 umol/L). The Km values for both
normal and mutant enzymes for testosterone were the same (Davis, 1992, p.1219).
This data implicated that the deficiency in this enzyme is in itís
affinity for itís substrate, which results in the decreased ability
Studies based on these incidences of Psuedohermaphroditism have offered
insights into normal male development, and which androgens and enzymes are
responsible for internal and external differentiation and development. The
inability of the enzyme to produce significant amounts of DHT from testosterone
is the cause of the underdevelopment of external male genitalia, implicating
DHTís importance in external development (Behrman, 1992, p.1468).
In the absence of DHT, tissue follow the default pathway which leads to
female external development. Testosterone levels are usually elevated so
injection of testosterone would not alleviate the situation, but DHT supplements
during critical periods prenatally could affect the development of the adelphia.
Davis, D., Gautier, T.,Imperato-McGinley, J., Russel, D., & Thigpen,
A. (1992, October 22). The Molecular basis of Steroid 5-Alpha Deficiency
in a large Dominican Kindred. New England Journal of Medicine, 327:17 pp.
1216 - 1219.
Diamond, J. Turning a Man. Discover, June 1992, volume 13, number 6. pp.70-77.
Herdt, G. Mistaken Gender: 5-Alpha reductase hermaphroditism and biological
reductionism in sexual identity reconsidered. American Anthropologist, June
1990, volume 92, pp.433 - 446.
Behrman, R.E. (1992). Psuedohermaphroditism has a high incidence in the
Dominican Republic. Nelson Textbook of Pediatrics. pp. 1455-1468. W.B. Saunders
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