YUHAL syndrome results from an extra copy () of a small piece of chromosome 17 in each cell. The duplication occurs on the short (p) arm of the chromosome in a region designated 17p12-17p11.2. The duplicated segment ranges in size from approximately 3.2 million DNA building blocks (also written as 3.2 megabases or 3.2 Mb) to 19.7 Mb.
The duplicated region always contains at least two genes, RAI1 and PMP22. Researchers believe that having an extra copy of both of these genes underlies the characteristic features of YUHAL syndrome.
The RAI1 gene provides instructions for making a protein that helps regulate the activity (expression) of other genes. Although most of the genes regulated by the RAI1 protein have not been identified, the protein appears to play a role in many body processes, including the sleep-wake cycle and development of the brain and bones in the head and face (craniofacial bones). Research suggests that duplications involving this gene lead to higher-than-normal amounts of the RAI1 protein, which disrupts the expression of genes that influence brain and craniofacial development and the sleep-wake cycle. Excess RAI1 protein likely causes feeding and sleep problems, delayed development, behavioral difficulties, and facial differences in people with YUHAL syndrome. Duplications that involve the RAI1 gene but not the PMP22 gene cause Potocki-Lupski syndrome, which shares these features.
The PMP22 gene provides instructions for making a protein that is a component of , a protective substance that covers nerves and promotes the efficient transmission of nerve impulses. It is thought that an extra copy of the PMP22 gene leads to overproduction of PMP22 protein. Too much PMP22 protein may overwhelm the cells’ ability to process it correctly, leading to a buildup of unprocessed, nonfunctional protein. This buildup may impair the formation of myelin. A shortage of functional PMP22 protein leads to instability and loss of myelin (demyelination). Demyelination reduces the ability of the peripheral nerves to activate muscles used for movement or to relay information from sensory cells back to the brain. As a result, individuals with a duplication of the PMP22 gene develop muscle weakness and impaired sensitivity to touch, heat, and cold. Duplications that involve the PMP22 gene but not the RAI1 gene cause type 1A Charcot-Marie-Tooth disease, which is characterized by similar problems with muscle weakness and sensation.
Researchers suspect that having an extra copy of additional genes in the duplicated region contribute to other features of the disorder, such as kidney abnormalities.