Fraser syndrome is caused by changes (mutations) in the FRAS1, FREM1, FREM2 or GRIP1 genes). More specifically, Fraser syndrome 1 (FRASRS1) is caused by mutations in the Fraser extracellular matrix complex subunit 1 (FRAS1) gene. Fraser syndrome 2 (FRASRS2) is caused by mutations in the FRAS1-related extracellular matrix protein 2 (FREM2) gene. Fraser syndrome 3 (FRASRS3) is caused by mutations in the glutamate receptor-interacting protein 1 (GRIP1) gene. FRAS1 gene mutations are the most common cause for Fraser syndrome, representing approximately half of the FS cases; whereas FREM2 gene and GRIP1 gene mutations account for a smaller percentage of cases.
Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The FRAS1 and FREM2 genes produce proteins (FRAS1 and FREM2 proteins, respectively) that work together as part of the FRAS/FREM complex. One of the FRAS/FREM complex’s functions is to connect the different layers of skin together, one on top of the other, to essentially form the skin. Its function is important during the embryonic period before birth. This group of proteins play a role in the proper development of the skin, internal organs including kidneys and other tissues. Therefore, a mutation in the FRAS1 or FREM2 gene causes its respective protein to be faulty, thus the FRAS/FREM complex cannot function properly and therefore leading to improper development of the skin, internal organs and other tissues. This improper development ultimately causes signs and symptoms such as cryptophthalmos, cutaneous syndactyly and renal agenesis. The GRIP1 gene produces the GRIP1 protein that ensures that FRAS1 and FREM2 proteins get to their correct location within the cell to carry out their function. Mutations in the GRIP1 gene prevent normal function of the FRAS1 and FREM2 proteins, causing an improper development of the skin, internal organs and other tissues.
Fraser syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal/mutated gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.