Just a quick preface: I am NOT a licensed physician. I am a high school student who enjoys researching interesting medical phenomena. These posts are just a summary of my research and the answers to questions I had while conducting it!! This was my hardest article to write by far as it required the most specialized background knowledge to understand. I tried my best to condense the information and concepts into ways that people can easily understand.
Adams-Oliver syndrome is a rare genetic disorder characterized by the presence of both aplasia cuitis congenita of the scalp, which is basically the absence of certain layers of the skin which leaves the affected area covered by a thin translucent membrane, and the simultaneous presence of limb malformation. So what causes AOS? Well, AOS can be caused by a mutation in one of six genes that play a vital role in embryonic development. The six genes, in particular, are called ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, and RBPJ. In order to understand the impact that these mutations have on the embryonic development process, it is crucial to understand what each of these genes is responsible for. I like to break these genes up into three groups. In the first group of genes, we have the GTPase regulating genes. The ARHGAP gene provides instructions to make GAPs or RHoGTpase activating proteins. GAPs are responsible for deactivating or terminating the signaling to enzymes called GTPases. GTPases are the key intermediates within signaling pathways that control cell-cycle progression, morphogenesis, which is the process in which a developing organism develops its shape, and gene expression that is responsible for the development of the limbs, skull, and heart. The "opposite" of the ARHGAP gene is the DOCK 6 gene, which provides the instructions to make GEFs or Guanine nucleotide exchange factor. GEFs are the direct opposite of GAPs as GEFs are responsible for initiating or turning on the signaling to the GTPase enzymes. These genes are responsible for regulating GTPase activity, as the ARHGAP makes GAPs which turn off signaling to the GTPase enzymes and the DOCK6 gene makes GEFs that turn on the signaling to the GTPase enzymes. In order to understand the function or role of the next set of genes, we need to look at what the NOTCH signaling pathway is and its function. So the NOTCH signaling pathway is a conserved method of signaling that is crucial in cellular differentiation. So how does the NOTCH signaling pathway work? The signal sending cell extends a protein through its cytoplasm and cellular membrane into the extracellular space. The
signal receiving cell has a protein on the surface of the cell called a
delta ligand which interacts with the NOTCH protein of the signal-receiving cell which is located inside the cell membrane. The protein from the first cell interacts with the delta ligand which then interacts with the NOTCH protein inside the cell. A portion of the NOTCH protein then changes shape and is cleaved from the rest of the protein and is then sent to the nucleus. This triggers a myriad of reactions between molecules and proteins that activate or repress the transcriptions of certain genes; one such example of a protein responsible for this is the RBP-J protein. It is the choice of which genes to transcribe that ultimately drives cellular differentiation. Now that we have a basic understanding of the process and function of the NOTCH signaling pathway we can begin to learn about the genes that facilitate this process. In the second group of genes, we have the NOTCH signaling pathway regulating genes. The DLL4 gene provides instructions for making a protein that initiates the NOTCH signaling pathway. The NOTCH1 gene is responsible for providing the instructions to make NOTCH1 proteins that bind to ligand proteins, then change shape, are cleaved off, and are sent to the nucleus during the operation of the NOTCH signaling pathway. The RBPJ gene is responsible for providing the instructions for making the RBP-J protein which is integral in the NOTCH pathway as the signal generated by the NOTCH signaling pathway stimulates the RBP-J protein to bind to specific regions of DNA and then is tasked with controlling the activation of genes that are crucial in cellular development. Finally, we have the EOGT gene which is in a group of its own as it affects the general process of DNA transcription. The EOGT gene is tasked with providing the instructions for making a protein that modifies other proteins by transferring the molecule called N-acetylglucosamine to them. This process is called an O-GlcNAc modification. The O-GlcNAc modification is responsible for regulating protein stability, regulating cellular signaling, and protein production. Unfortunately, little is known about the effect that the O-GlcNAc modification has on the proteins altered by it. Some studies do suggest that the O-GlcNAc modification may modify NOTCH proteins. Now that we have a good understanding of the roles and functions of the genes that have mutations in patients with AOS, we can start to dissect how these mutations are passed on to offspring. A mutation is essentially a change in the nucleotide sequence of a genome. Mutations that are passed on to offspring occur in a germline cell which is a cell that gives rise to the gametes or sex cells. AOS is hereditary, so we know that the mutations are passed down in two scenarios through a dominant or recessive gene. When AOS is caused by mutations in one of the ARHGAP31, DLL4, NOTCH1, or RBPJ genes the condition is inherited in an autosomal dominant pattern. Meaning that the individual has one copy of a mutated gene and one normal gene on a pair of non-sex chromosomes. Essentially, only one copy of the mutated gene is necessary to cause the disorder. In mutations on the DOCK6 or EOGT genes, AOS is inherited in a autosomal recessive pattern. Meaning that both of the individual’s copies of the gene have the mutation. If both parents are carriers of the recessive gene, meaning that the mutated gene is not expressed but the parents carry the mutated gene, then their offspring will have a 25% chance of having AOS and have a 50% chance of being carriers of the mutation like their parents. Patients may have AOS through de novo or new mutations as well. In cases where the NOTCH1 gene is mutated, people with no family history of AOS have contracted the disease. So what are the symptoms of patients who get AOS? The trademark symptoms used for diagnosis of the condition are aplasia cutis congenita of the scalp and transverse limb defects including the hands, feet, legs, and arms. The other symptoms include vascular abnormalities like cutis marmorata telangiectatica congenita, which is characterized by the presence of dilated blood surface blood vessels resulting in the discoloration of patches of skin. The dilation of blood vessels can lead to muscle tissue loss, elevated fluid pressure within the eye (glaucoma), and under grown limbs. More potential vascular symptoms include pulmonary hypertension, portal hypertension, and retinal hypovascularization. Congenital heart defects are estimated to occur in 20% of cases. There is a plethora of potential symptoms for patients with AOS
and a lot of it depends on which six of your genes have the mutation. My biggest question after all of this research and learning was are there treatments? What I found made sense… since there are so many potential symptoms, the treatments for the condition vary depending on the specific symptoms of each patient. In terms of the trademark symptoms, being the aplasia cutius congenita of the scalp, the treatments range from nothing, as the scalp can heal on its own with in the first couple of months of being born, to cranial surgery depending on the severity. Skin grafting is also an option in order to replace the layers of skin that don’t develop. In terms of the other trademark symptoms, the malformation or development of limbs, many patients receive prosthetic or artificial limbs to help correct the defect. With such a large array of symptoms ranging in terms of severity, the prognosis for some may be a normal life while for others the condition can be very severe. The rarity for AOS is 1 in 225,000, so while not as rare as other conditions we have covered in the past, it is still considered very rare.
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