Most ATP2A2 mutations are haploinsufficiency mutations, which means that only having only one functional copy of the functional gene results in a reduced level of protein expression that is not sufficient for wild type function for making enough of the coded protein for the cell to function properly. However, there is significant variability in disease severity in how the mutations are expressed even within families that have the same mutation. It is currently unclear in the current research why a reduction in SERCA2 expression/activity causes clinical symptoms restricted to the epidermis. One hypothesis that some researchers have given is that other cell types express additional “back-up” Ca2+ pumps that can compensate for the reduced function or expression of the SERCA2 protein, while skin cells rely exclusively on the SERCA2 gene for calcium sequestration, meaning only they are affected by its reduction in expression.As mentioned above, some cases of DAR result from somatic mutations to ATP2A2 in epidermal stem cells. These cases are referred to as instances of "linear" Dariers disease. Such individuals display phenotypic mosaicism, where the Dariers phenotype only affects the subset of epidermal tissue arising from the mutated progenitor cell. Somatic mutations are not inherited by the offspring of such individuals. Diagnosis
Diagnosis of Darier disease is often made by the appearance of the skin, family history, or genetic testing for the mutation in the ATP2A2 gene. However, many individuals affected by this disorder are never diagnosed, due to the mildness of symptoms in most cases.
Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of achondroplasia.The most common side effects include injection site reactions (such as swelling, redness, itching, or pain), vomiting, and decreased blood pressure.Achondroplasia is a genetic condition that causes severely short stature and disproportionate growth. The average height of an adult with achondroplasia is approximately four feet. People with achondroplasia have a genetic mutation that causes a certain growth regulation gene called fibroblast growth factor receptor 3 to be overly active, which prevents normal bone growth. Vosoritide works by binding to a specific receptor called natriuretic peptide receptor-B that reduces the growth regulation genes activity and stimulates bone growth.Vosoritide was approved for medical use in the European Union in August 2021, and in the United States in November 2021. Medical uses
In the European Union, vosoritide is indicated for the treatment of achondroplasia in people two years of age and older whose epiphyses are not closed.In the United States, vosoritide is indicated to increase growth in children five years of age and older with achondroplasia and open epiphyses (growth plates). Mechanism of action
Vosoritide works by binding to a receptor (target) called natriuretic peptide receptor type B (NPR-B), which reduces the activity of fibroblast growth factor receptor 3 (FGFR3). FGFR3 is a receptor that normally down-regulates cartilage and bone growth when activated by one of the proteins known as acidic and basic fibroblast growth factor.