Yanna Lee

Yale researchers recently discovered the possible functional cause of Hypomyelination and Congenital Cataract, a rare neurodegenerative disease similar to multiple sclerosis.

The team of researchers, whose original goal was to examine an enzyme responsible for the synthesis for a specific plasma membrane lipid, known as PtdIns(4)P, found that the enzyme was controlled by the gene FAM 126A. FAM 126A is the cause of HCC, but the gene’s function had previously been shrouded in mystery. With the discovery of FAM 126A’s function, another piece of the cause of HCC is known, and steps can be taken to find a possible cure for HCC, according to Mirko Messa, research scientist at the Yale School of Medicine and study co-author.

“What our study provides is an explanation for the mechanism of what might be going wrong in these mutations [in the genes of HCC patients],” study co-author and Cornell University professor Jeremy Baskin said.

According to the U.S. National Library of Medicine, HCC is one of a group of genetic disorders known as leukoencephalopathies. This class of diseases results from abnormalities in the brain’s white matter. Myelin, a fatty substance that covers nerve fibers and promotes the transfer of electronic signals through neurons, is made up of white matter. HCC is named after the two main symptoms that patients with this disease experience: the reduced ability to form myelin sheaths — hypomyelination — and the clouding over of the lens in the eyes — cataracts.

But the researchers did not originally intend to examine the pathology of neurodegenerative diseases. Baskin said the original goal of the experiment was to examine an enzyme that controlled the synthesis of the plasma membrane lipid PtdIns(4)P. But “through serendipity” the researchers were able to discover a link between the enzyme that controls lipid synthesis and FAM 126A, a gene that was known to cause HCC but had an unknown function, Baskin said.

“It really brought us out of our area of expertise,” Baskin says. “It taught us something new and we illuminated something new about this disease.”

In the study, Messa, who helped track the function of FAM 126A, created a virus with a cloned piece of DNA that included FAM 126A and a fluorescent tracker known as GFP. He then infected cells that do not express FAM 126A. These cells then became a “knockout” for the gene, a cell or animal model that does not express a specific gene, Messa said. He then tracked their function within a cell culture using the fluorescence from the tracker as well as recorded cell activity.

His examination revealed that all functions of the FAM 126A gene were restored in the fibroblast cells — which produce collagen and other fibers — after FAM 126A was reinjected into the cell via viral infection. The fibroblasts, prior to injection, had lowered protein levels, Messa noted, but these protein levels were restored when FAM 126A was added back into the cells.

“When you have all the right components, the final function is able to be performed properly,” Messa said.

According to Baskin, his research has three main impacts. First, by studying the cells of a diverse set of patients from America, Italy and Germany, the mechanisms for the cellular components of diseases, such as lipid synthesis,  are better understood. Second, the study provides a “necessary first step” in finding a cure for HCC. Finally, congenital genetic diseases, such as HCC, have key similarities to noncongenital diseases, such as multiple sclerosis, due to the shared defect that occurs in the myelin sheath. By studying the mechanisms in HCC, the mechanisms in more common diseases like MS can also be better understood.

Baskin expressed satisfaction with the unexpected results of his research.

“It’s almost like when you’re walking a dog, the dog is going where the dog wants to go and it’s not necessarily where you want to go,” Baskin said. “The analogy being the dog is science, the dog walker being me or you. And it’ll lead you to interesting places.”

There is currently no cure for HCC.

CLAIRE VICTORIA ONG