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By comparing the proteomes of affected and unaffected family members, researchers have gained new insights into the rare genetic disorder Menkes disease, and found that it has molecular connections to Parkinson's disease (PD).

The team published its findings in the Jan. 31, 2018, online issue of Cell Systems.

The technique itself, which the authors termed genealogical proteomics, is "probably the big asset here," first author Stephanie Zlatic, a postdoctoral fellow at Emory University, told BioWorld MedTech. "You can use the patients' families to get at these relatively rare disease mechanisms" that are otherwise hard to study in humans.

Menkes disease, for example, which results from mutations in the copper transporter ATP7A, occurs in somewhere between one in 100,000 and one in 250,000 individuals, making it rare even among the rare diseases. (Cystic fibrosis, which is one of the most common of the rare monogenic diseases, is present in one in 3,500 individuals, making it at least 28 times more common than Menkes.)

One consequence is that very rare diseases are hard to study in humans, because treatment groups are so small that within-group variability is likely to drown out any between-group differences.

In their work, Zlatic and her co-authors applied the idea of genealogical research, which has been used to identify rare disease-causing mutations, to protein alterations.

While they are still more different from each other than isogenic mice and cell lines, parents, siblings and children all share, on average, 50 percent of their genes.

And like children can resemble a parent in their outward physical appearance, "if you were to look at the signature of the proteins of the cell, you can say 'Oh, this looks more like this [parent],'" Victor Faundez told BioWorld MedTech. "You can get closer to what is different between individuals by looking at individuals within a family."

Faundez is a professor of cell biology at Emory University, and the senior author of the paper.

In their work, the team looked at the proteomes of two individuals with Menkes disease, and compared them to those of their unaffected siblings and their parents. The same principle could be used to look at other aspects such as transcriptomes, or epigenetic changes to DNA or RNA. Faundez said the team decided to focus on protein expression because other types of changes "in the end result in changes in protein expression . . . [It] is the closest element of all the elements available" to cell behavior.

They identified slightly more than 200 proteins whose expression levels were altered in the Menkes patients, and found that one of the proteins affected was UCHL1/PARK5, which is a putative Parkinson's risk gene – an intriguing finding, Faundez said, because "we know that in PD, metals play an important environmental role."

Zlatic, Faundez and their team intend to test whether their method can be used to gain insights into disorders that involve more than one gene, such as microdeletion syndromes.

They also plan to compare the results they have obtained in fibroblasts to results in iPSC-derived neurons.

ATP7A mutations lead to copper deficiency throughout the body, but the brain is among the most strongly affected tissues.

Faundez said that fibroblasts are "a really good entry door" to studying neurological diseases, "because many of the genes that cause neurological disease are expressed everywhere."

"But the bummer is that you are losing all the riches of information that come from cell-specific gene expression."

The only way to test just how much information is lost, he said, is to directly compare different cell types.

His team plans to do such comparisons in several disorders, he said. "And then we'll see."

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