Using Knockout Mice to Learn about Eye and Skin Disorders

Albinism is the best known of a group of rare genetic disorders that can affect both the eyes and the skin. Some genes have been identified that are linked to these conditions, but many remain mysterious. In a study published today in Scientific Reports, researchers have identified dozens of these genetic mutations in a screen of knockout mice.

“This mouse data may be of interest to clinicians, especially for patients with no known genetic cause for their condition,” says senior author Ala Moshiri of UC Davis.

Skin, eyes, and nerve tissue are linked because they all develop from the same early embryonic tissue. When animals or people have albinism, they lack pigment in their hair, skin, and eyes. The degree of pigment loss varies, likely depending on the genetic change responsible. Another group of rare eye and skin disorders distinct from albinism, called phakomatoses, are also genetic in nature.

For the study, the team searched the public database of gene knockout mice created by the International Mouse Phenotyping Consortium (IMPC) for animals with skin, hair, or pigmentation abnormalities. They then crosschecked for those that also had eye defects. The search produced a list of 52 genes that affect both skin and eye organ systems, 35 of which were previously unknown.

“I expect the majority of these genes will cause similar problems in humans,” Moshiri says.

The IMPC is an international effort including the Mouse Biology Program at UC Davis. The IMPC collaborators create mice with targeted deletions of a single gene (“knockout” mice) and examine the effects. So far, the consortium has produced lines of knockout mice for about 6,000 genes, of which more than 5,000 have been characterized across eleven body systems.

Identifying mouse genes related to a specific disorder can help identify the equivalent genes in humans. Sequencing an entire human genome is relatively easy in 2019, but working out which genetic change is tied to a specific disease or disorder is much harder because humans are so genetically variable. Laboratory mice, on the other hand, are inbred on a consistent genetic background, making it much easier to link traits to a single genetic change. Armed with a list of candidate genes from mice, clinicians could home in on specific genes in human patients.

Image: A team led by UC Davis researchers has used a public database of genetic knockout mice to identify dozens of genetic mutations linked to eye and skin disorders, including forms of albinism and phakomatoses. The newly discovered genes could help clinicians identify related human genes in patients with no known cause for their disorder. This image shows an eye from an albino mouse lacking pigment (left) and a normal mouse. Image courtesy of Ala Moshiri, UC Davis.