The inner workings of the body are amazing. Through evolutionary time and random chance, proteins used in one area of the body become crucial in others. It would seem very unlikely that one enzyme would be responsible for proper brain function AND proper skin maintenance, because the two areas seem different in terms of function and composition. However, enzymes are associated with both of these areas. One of the enzymes linked to these two areas is steroid sulfatase. This enzyme is coded by the STS gene. A defect in this crucial protein can cause severe neurological and physical disorders, including some cancers. Several of the disorders associated with steroid sulfatase include autism, ADHD, X-linked ichthyosis, aggression, and breast cancer. While these disorders are seen in both males and females, one sex is especially more vulnerable to these disorders for understandable reasons. This paper will first look into the basic properties of steroid sulfatase and the conditions that steroid sulfatase can cause in order to gain a broad, yet adequately full, understanding of what the gene and the protein that it encodes are capable of doing. As it will soon be clear, many of the disorders associated are sexually dimorphic.
STS Location and Structure
The X-chromosome variant of the steroid sulfatase gene is the only significant variant. The X-chromosome STS gene is approximately 140 kb large, consists of 10 exons, and is located at band Xp22.3 (Ballabio et al., 1990). It is expressed in the cortex, thalamus, basal ganglia, and the cerebellum, but it is also present in the liver, adrenal, and the human placenta in an insoluble form (Nicolas et al., 2001a). In rats, this STS gene can only be found on the X-chromosome (Kopsida et al., 2009). In humans, the gene is present on both chromosomes, however, only the gene on the X-chromosome is functional (Kopsida et al., 2009). The human, Y-chromosome variant of STS is not expressed because many base substitutions, deletions, and insertions have inactivated the gene (Yen et al., 1988). The protein precursor is approximately 63 kilodaltons before being cleaved down to 61 kilodaltons during post-translational modification (Stengel et al., 2008). The STS gene is composed of 562 amino acids, and like the name “steroid sulfatase” suggests, it is classified as a hydrolase enzyme (Hernandez-Guzman et al., 2003). The structure of steroid sulfatase includes 2 antiparallel alpha helices that give the protein a mushroom-like shape (Hernandez-Guzman et al., 2003). These typical alpha helices are hydrophobic, suggesting that part of the steroid sulfatase structure is anchored inside a phospholipid bilayer, quite possibly the plasma membrane that belongs to the endoplasmic reticulum inside cells of the cortex, thalamus, basal ganglia, or the cerebellum. A study on mouse fetuses reveals the presence of steroid sulfatase mRNA in the hindbrain, cortex, and the thalamus on the final week of gestation (Compagnone et al., 1997). Additionally, an adult bovine brain reveals that steroid sulfatase is expressed in the midbrain and the hypothalamus (Park et al., 1997). These two pieces of evidence suggest that steroid sulfatase expression could vary throughout development and/or they could differ between species. One thing that is certain is that the differential expression of steroid sulfatase between the sexes can cause its own problems.
Sexually Dimorphic Characteristics
Recall back to any introductory genetics course and remember that males and females have different versions of the same types of chromosomes, except for one. Females and males have different sex chromosome complements: Females typically have 2 X-chromosomes, whereas men usually have 1 X-chromosome and 1 Y-chromosome. While this difference in sex chromosome complements between men and women is the basis for sex-linked disorders, it is also the basis for sexual dimorphic traits, since the gene products encoded by these sex chromosomes can affect the concentration of androgens and estrogens in the body which will have effects on skeletal and neurological developments.
The steroid sulfatase gene is associated with sexually dimorphic traits. As previously mentioned, the gene is present on both X- and Y-chromosome in humans, but the Y-chromosome variant is not functional due to the many changes to its nucleotide sequence. In rats, the STS gene is completely gone on the Y-chromosome (Yen et al., 1988). Moreover, it has been shown that STS is not subjected to X-inactivation, suggesting that women would most likely have more steroid sulfatase in circulation compared to men if the gene expression of STS between men and women are identical (Kopsida et al., 2009). And if so, depending on the processes that require steroid sulfatase and its products, it would make logical sense that the different amounts of these two compounds could lead to sexually dimorphic responses. However, while women do have twice as many STS genes as men do and both genes are capable of being expressed in females, current research have concluded that women do not have twice the level of STS activity compared to men (Kopsida et al., 2009). There is not twice as much STS activity, like neurotransmitter receptor modulation, DHEA production and other mechanisms that will be discussed below, in female tissues than there are in male tissues.
Depending on the mammal, the function and mechanism through which steroid sulfatase acts can be different. The general mechanism for steroid sulfatase consists of the cleavage of sulfate groups from various steroid precursors, the product of which modulate neurons by acting as modulators for different types of neurotransmitter receptors (Davies 2014). These steroids affect the receptors for gamma-aminobutyric acid (GABA), N-methyl-D-aspartic acid (NMDA), and sigma-1 receptors. One of the most notable products of steroid sulfatase is dehydroepiandrosterone (DHEA), which is converted from dehydroepiandrosterone sulfate (DHEAS) (Davies 2014). As previously noted, the STS gene is expressed in the cortex, thalamus, basal ganglia, and the cerebellum. All of these areas are associated with ADHD in mice and in humans (Davies 2014). A deficiency in STS results in increased levels of DHEAS, which could cause problems for whoever possesses it, be it man or mouse.
In mice, steroid sulfatase is needed to convert DHEAS to DHEA. This reaction controls sexually dimorphic behavior such as male aggression to other male mice within the same species (Nicolas et al., 2001b). It was suggested that steroid sulfatase may also have a role in regulating the immune response. A study using mice DHEA in vitro was able to conclude that DHEA (and not DHEAS) can suppress the release of Th2 cytokines, which causes an enhanced Th1 (Type 1 helper T cell) response (Daynes et al., 1993). A decrease in the gene expression of STS or the lack of steroid sulfatase causes an increase in DHEAS which is found to be correlated with an increase in male aggression higher than those of the control group (Nicolas et al., 2001b). In addition to that, mice with unusually low amounts of steroid sulfatase show symptoms similar to those with ADHD, such as hyperactivity, aggression (as previously mentioned), increased emotional reactivity, and atypical striatal and hippocampal neurochemistry (Trent et al., 2012). However, inhibition of STS has been shown to cause improvement in spatial learning for mice (Johnson et al., 2000). From the data gather on experimentation in mice, it would seem that there are pros and cons with having a deficiency in the expression of STS gene: a mouse could be quick at learning, but he would also become more aggressive and emotional towards his fellow male mice.
In humans, steroid sulfatase is largely distributed throughout the body (Purohit et al., 2008). During pregnancy, steroid sulfatase produces androgens and estrogens from sulfated steroid precursors in the placenta. These steroids are crucial for fetal development (Compagnone et al., 1997). Data gathered suggest that steroid sulfatase is able to promote tumor growth, and because of that, steroid sulfatase is now of interest to those working in cancer research. Breast tumors require estrogen to grow and survive in postmenopausal women. These tumors highly express STS in order to get the estrogen they require to sustain themselves (Nussbaumer and Billich 2005). And because women carry two copies of the gene, it becomes easier for the breast tumors to survive in women.
Like previously mentioned briefly, ADHD and X-linked Ichthyosis are both disorders caused by the dysfunction of STS. Within males, like it is in mice, attention deficit hyperactivity disorder is diagnosed 4 to 6 times more often, most likely due to the fact that males need to have their one and only copy of STS on their X-chromosome function properly, whereas women have two STS genes to rely upon for normal function (Trent et al., 2012). Also previously mentioned, STS is a modulator for GABA receptors. Specifically speaking, DHEAS is a negative modulator for GABA receptors and GABA is a neurotransmitter that reduces neuronal excitability, producing a calming effect (Yadid et al., 2010). In patients with dysfunctional steroid sulfatase, there is an abundance of DHEAS, which negatively affects the GABA receptors. Negative modulation of GABA receptors will prevent GABA from binding onto the receptors, and because GABA is a calming neurotransmitter, the individual with a low functional STS gene will suffer from hyperactivity due to reduced GABA receptor functionality (Yadid et al., 2010). A reduction in the calming effect that GABA receptors provide will also increase the emotional reactivity of the individual with ADHD, much like in male mice.
In humans, a common X-linked skin disorder known as X-linked ichthyosis can occur due to deficiencies in steroid sulfatase or a mutation in the STS gene. The symptoms of X-linked ichthyosis include dry, scaly skin, typically on the neck, torso, and the lower extremities (Basler et al., 1992). Since females have two active copies of the STS genes (one on each of their sex chromosomes) and both escapes x-inactivation, X-linked ichthyosis is more likely to occur in males, because unlike females, males only have one copy of the steroid sulfatase gene (Ballabio et al., 1990). For females, the presence of a defective STS gene is often compensated by the presence of a normal STS gene on the other X-chromosome. The cause of the appearance of dry, scaly skin is due to the accumulation of cholesterol sulfate (CSO4) in the epidermis. Steroid sulfatase is densely concentrated in the lamellar bodies, and it stays there until it is secreted to the subcorneal interstices (Elias et al., 2004). Steroid sulfatase typically degrades cholesterol sulfate to free up cholesterol for use in the skin barrier. CSO4 is also a serine protease inhibitor, and a decline in its concentration due to STS allows the protease to degrade corneodesmosomes, permitting normal desquamation (skin peeling) to occur (Elias et al., 2004). A deficiency in steroid sulfatase leads to an accumulation of CSO4 that could work in two ways to cause symptoms in X-linked ichthyosis. The first way is that CSO4 could further separate the spaces between the atypical skin barrier and the corneocytes (Elias et al., 2004). The second way is that CSO4, while in the stratum corneum, can delay corneodesmosome degradation, leading to non-normal desquamation (Elias et al., 2004).
In this mini review, steroid sulfatase has proven to be an essential hydrolase enzyme that is associated with several sexually dimorphic disorders. It has roles in processes affecting everything from the brain to the skin. Currently, there is more research being conducted to learn more about the functions of steroid sulfatase and its steroid products. Knowledge for future cancer treatments could be potentially heightened if a better understanding of steroid sulfatase is had, as shown in the discovery that steroid sulfatase is needed for the growth of tumors in breast cancer patients. But like most cancers, it’s difficult to target one pathway, shut it down, and expect all other pathways to cooperate as if nothing has changed within the body. Take out steroid sulfatase to treat breast cancer and the patient might end up with flaky skin, aggression, and hyperactiveness even though she will be able to retain short-term information much more easily. Hopefully, this review has shed light on some of the basic knowledge for steroid sulfatase and how its differential expression between males and females can explain the higher prevalence of certain disorders in one sex over the other. Although the focus of this paper is to provide knowledge of steroid sulfatase, the information provided in this paper only scratches the surface of the total knowledge researchers have on this enzyme. More aspects of this enzyme can be learned and discovered with more time.
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David Nguyen | CSU-Long Beach, Department of Natural Science and Mathematics | May 5, 2015