Which are the causes of Androgen Insensitivity Syndrome?

Androgen Insensitivity Syndrome (AIS) is a rare genetic disorder that affects sexual development in individuals with XY chromosomes. It is primarily caused by mutations in the androgen receptor gene (AR), which is located on the X chromosome. These mutations result in the body's inability to respond to androgens, the male sex hormones, leading to incomplete or absent masculinization of the external genitalia and other related developmental issues.

1. Genetic Mutations: The most common cause of AIS is the presence of mutations in the AR gene. These mutations can vary in their severity, with some completely impairing the function of the androgen receptor and others partially affecting its activity. The AR gene provides instructions for producing the androgen receptor protein, which is crucial for the normal development of male sexual characteristics. Mutations in this gene disrupt the receptor's ability to bind to androgens, resulting in a range of phenotypic variations in affected individuals.

2. X-Linked Inheritance: AIS follows an X-linked recessive pattern of inheritance. Since the AR gene is located on the X chromosome, males have only one copy of this gene, while females have two. If a male inherits a mutated copy of the AR gene from his carrier mother, he will develop AIS. On the other hand, females need to inherit two mutated copies (one from each parent) to exhibit the symptoms of AIS. This is why AIS is more commonly observed in individuals assigned female at birth.

3. De Novo Mutations: In some cases, individuals with AIS may have no family history of the condition. This is because de novo mutations can occur spontaneously during the formation of reproductive cells or early embryonic development. These new mutations in the AR gene can lead to the development of AIS in individuals without any prior family history of the disorder.

4. Genetic Mosaicism: Another possible cause of AIS is genetic mosaicism. This occurs when there is a mutation in the AR gene during early embryonic development, resulting in two distinct cell populations within an individual's body. One population carries the mutated AR gene, leading to AIS, while the other population has a normal AR gene. This genetic mosaicism can result in varying degrees of androgen insensitivity and phenotypic differences among affected individuals.

5. Other Genetic Factors: While mutations in the AR gene are the primary cause of AIS, other genetic factors may also contribute to the development and severity of the condition. Modifier genes, which can interact with the AR gene, may influence the expression of AIS and account for the variability in its clinical presentation. Additionally, variations in other genes involved in sexual development and hormone signaling pathways may impact the overall phenotype of individuals with AIS.

It is important to note that AIS is a complex condition with a wide range of clinical manifestations. The severity of androgen insensitivity can vary greatly among affected individuals, leading to differences in external genitalia, internal reproductive structures, and secondary sexual characteristics. Genetic counseling and testing are crucial for accurate diagnosis and management of AIS, as it can have significant implications for an individual's physical and psychological well-being.