Gender Should Be Considered When Treating Angelman, Mouse Study Suggests

Sex-dependent behavioral and sensory symptoms in Angelman syndrome support the involvement of sex hormones in disease development and suggest that gender should be considered when treating patients, according to a study of mice.

The study, “Sex-Dependent Sensory Phenotypes and Related Transcriptomic Expression Profiles Are Differentially Affected by Angelman Syndrome,” was published in Molecular Neurobiology.

Angelman syndrome is a genetic disorder that causes delayed mental and physical development. The disease is caused by mutations in the UBE3A gene, also known as the Angelman gene. That gene holds the instructions to produce ubiquitin protein ligase E3A (Ube3a), which plays a critical role in the normal development and function of the nervous system.

The condition occurs with similar frequency among men and women, but there are not many studies addressing whether the sex of an individual affects disease development and its manifestations.

Scientists at the University of Haifa, Israel, used a mouse model of Angelman syndrome and compared different neuronal phenotypes (observable  characteristics of the disease) to those of non-affected animals, focusing on the differences between males and females.

They found that, overall, non-affected mice interact more with new objects than Angelman mice. However, while non-affected males are more curious than non-affected females, Angelman females are more curious than Angelman males. Additionally, non-affected males are more attracted to new odors than non-affected females, but this sex-related difference is not seen among Angelman mice.

Regarding pain response, Angelman male mice were more sensitive than Angelman females. This trend was inverted in non-affected animals.

“Several [Angelman syndrome] phenotypes were differentially affected by sex compared to the [non-affected] littermates. The main sex-dependent modifications were observed in the sensory phenotypes,” researchers wrote.

“This intriguing inversion of male-female phenotype raises questions about the role of sex hormones in neurodevelopment and why these are reversed in [Angleman syndrome] mice. A possible answer could be that Ube3a interacts directly or indirectly with sex hormones functioning and thus affects the neurodevelopment of specific pathways, in which this sex-dependent phenotype inversion is recognized,” they added.

Angelman mice had reduced motor capacity and coordination, and showed more anxious behavior, when compared to non-affected mice, but there were no sex-related differences in these phenotypes.

To understand whether the observed sex-related sensorial manifestations (sensory symptoms) were related to differences in gene expression in males and females, the team studied the genes that were expressed in the hippocampus of Angleman mice. The hippocampus is a central brain structure related to cognitive, emotional, and stress-related learning processes, that is affected in Angelman syndrome. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

Researchers identified various genes that were differentially expressed among the sexes. The most relevant were pain-related (43 differential genes), estrogen-dependent (64 differential genes), and androgen-dependent genes (eight differential genes). Among the genes that were expressed differentially between males and females, seven were both pain- and androgen-dependent.

Estrogen and androgen are two sex hormones that promote the development and maintenance of female and male characteristics, respectively.

The fact that genes related to estrogen and androgen show specific patterns of expression in Angelman syndrome supports the involvement of sex hormones in this disorder. Further studies focusing on these newly found differentially expressed genes could help understand the mechanisms of disease progression and manifestation, the study states.

“[N]onpharmacological therapies such as occupational therapy (OT) should be tailored also in accordance with sex,” researchers concluded.