In small villages across Israel, some ethnic groups are known for arranging marriages between close relatives. Genetic studies of these families are shedding light on a formerly obscure subgroup of metabolic disorders.
More information could help screen for, diagnose—and perhaps treat—these poorly understood and rare disorders.
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The disorders stem from abnormalitiesin mitochondria, organelles that power the cell's activities. “When the mitochondriaare defective, the entire metabolism is flawed, everything is stuck—it's like blocking traffic at the biggest intersectionnext to a large city,” says Orly Elpeleg, director of the Metabolic Diseases Unit at Hadassah University in Jerusalem.
Elpeleg and others are studying mitochondrial diseases in large families with a high proportion of consanguinity—marriages between close relatives,such as first cousins. The custom is common in several Israeli communities and particularly among Muslim minorities in rural areas.
“Israel is one of the best places in the world to do genetic studies because of the high consanguinity rates,” Elpeleg says.
The families are a geneticist's dream: if one of their ancestors carried a certain mutation, the third-generation offspring might inherit this same mutation twice, through both the mother and father. Such double-whammies show up readily on linkage analysis, making disease-causing genetic defects easier to find. “We don't want people to be marrying their first cousins but if they do, it helps us find the gene,” says Eric Schon, professor of genetics and development at Columbia University.
In the early 1990s, Schon discovered a subgroup of diseases, known as mitochondrial DNA depletion syndromes, in which the organelles produce little or no DNA. Most patients with the syndrome die in their first year of life.
Mitochondrial defects are notoriously difficult to diagnose because their symptoms vary greatly. In adults, about 2% of diabetes cases can be traced back to mitochondrial defects that deprive the pancreas of the energy it needs to produce insulin. Abnormalities in the organelle can also lead to kidney dysfunction, high blood pressure, hearing impairment, dementia and stroke. In children, they can cause liver failure, mental retardation and fatal muscle weakness.
The genetic defects behind mitochondrial disorders are also largely unknown because of the great number of genes involved. Although mitochondria have only 37 genes, hundreds of genes in the cell's nucleus, most of which have yet to be revealed, are needed for their regulation and maintenance. “The fact that so many genes are involved in the functioning of the mitochondria, and that each mutated gene causes its own symptoms, probably explains the baffling diversity of mitochondrial disorders,” Elpeleg says.
The Israeli researchers and others have thus far identified five genes that trigger mitochondrial DNA depletion. In 2001, in collaboration with researchers at Haifa's Rambam Medical Center, Elpeleg's team identified two genes that interfere with mitochondrial DNA synthesis. Most recently, based on her work in one large Muslim-Bedouinfamily, Elpeleg found yet another gene that interferes with DNA synthesis through a different mechanism and causes encephalopathy, a degenerative disease of the brain.
There is no treatment yet for mitochondrial disorders, but pinpointing their genetic causes is a move in that direction, Elpeleg notes. “The mitochondria are so central to the cell that all the usual therapeutic tricks, such as bypassing or blocking this or that pathway, don't work,” she says. “But if you don't know where things went wrong, how can you even start thinking about treatment?”
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Vikhanski, L. Inbred Israeli families aid research on rare diseases. Nat Med 12, 28 (2006). https://doi.org/10.1038/nm0106-28a