FREM2

At least two mutations in the FREM2 gene have been found to cause Fraser syndrome; these mutations are involved in a small percentage of cases of this condition. Fraser syndrome affects development before birth and is characterized by eyes that are completely covered by skin (cryptophthalmos), fusion of the skin between the fingers and toes (cutaneous syndactyly), and abnormalities of the kidneys and other organs and tissues.

FREM2 gene mutations involved in Fraser syndrome lead to production of an abnormal FREM2 protein that likely does not function properly. As a result, the FRAS/FREM complex cannot form. Lack of the FRAS/FREM complex in the basement membrane of skin leads to detachment of the top layer of skin, causing blisters to form during development. These blisters likely prevent the proper formation of certain structures before birth, leading to cryptophthalmos and cutaneous syndactyly. It is unknown how lack of the FRAS/FREM complex leads to kidney abnormalities and other problems in Fraser syndrome.

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Mutations in the FREM2 gene have also been found in people with abnormalities of the kidneys and urinary tract but no other signs and symptoms of Fraser syndrome (described above). Such abnormalities are grouped together as congenital anomalies of the kidney and urinary tract (CAKUT). The FREM2 gene mutations involved in CAKUT typically change single protein building blocks (amino acids) in the FREM2 protein. Researchers speculate that the effects of these mutations are milder than those of mutations that cause Fraser syndrome; some FREM2 protein function may still remain. How these gene mutations affect the FRAS/FREM complex or lead to renal agenesis and other CAKUT is unknown.