A previously unrecognized, extremely rare neurodegenerative condition in young children is caused by a single mutation, scientists concluded after combing through big data.
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The good news is that the mutation is spontaneous, not inherited: No parent in any of the cases bore the same mutation as the affected child, explains team leader Prof. Orly Elpeleg of Hadassah and the Hebrew University of Jerusalem.
The bad news is that children with the condition are born seemingly normal but start losing motor, cognitive and speech functions beginning at around 3 to 6 years. By their early teens, most are completely dependent on caretakers.
The process of recognizing the disease and identifying its cause began with a 3-year-old in Jerusalem, with mysterious neurodegeneration. After her eureka moment, Elpeleg hopes the as-yet-recognized condition will be named “Jesolo syndrome,” based on the remote Italian village where she evaded her family and friends for days while putting the incoming data together. She has identified over 70 genes and syndromes to date and declines to name them after herself; that humility applies here too.
“Jesolo syndrome” turns out to be caused by a morbid malfunction of the protein manufacturing system in our cells, the ribosome. “Morbid” is short of immediately fatal, but is incompatible with normal life.
The mutation is in UBTF, a gene coding for “ribosomal template.” When mutated, as in these kids, its expression goes haywire and it starts massively overproducing ribosomal RNA, which likely gums up the cells. Essentially, brain cells become poisoned with an “overdose” of the RNA, the team explains in The American Journal of Human Genetics.
How did the professor identify the cause of such a rare condition? Long story short, facing a child with an unknown disease, Elpeleg “read” the patient’s DNA using deep-sequencing technology, and compared it with the “normal” human genome to look for genetic mistakes. (Deep sequencing is a very fast, accurate way to track down mutations in sequences.). She takes pride in using the “Human Genome Project,” once a terribly expensive analysis, to analyze the genome of each one of her undiagnosed patients.
Essentially, she “proofread” it looking for typos.
When she finds a “typo” in a gene, one that has not been recognized before and which affects an evolutionary conserved site. She checks whether this “typo” is something all the sufferers of the condition have and something healthy people do not have – and if so, bingo. It is (very probably) the cause.
Thanks to a “gene matching” program and doctors around the world who had “deposited” mysteriously sick children’s genomic information there, ultimately, seven children were found with the condition: one in a remote Russian mining village and others in Canada, France, Israel, and the United States.
Their shared problem: one tiny little change among their 3-billion-plus letters that make up human DNA.
Eureka moment by the sea
The seven children were detected thanks to scientific collaboration and a program called “gene matcher.” It turns out that five doctors, confronted with children with unexplained problems, had “deposited” the same mutation, Elpeleg says. And there she was vacationing in picturesque Jesolo by the Adriatic Sea when the data from the program starting coming in, and after three days of data comparison, she realized they were talking about a single clinical entity, and a single mutation.
How the devil does a geneticist notice one mutation (one letter replaced with another, such as A for T) out of 32 million letters which make the exons (the coding parts of the genes), called for short “the exome”? Well. People are believed to have about 20,000 genes (be not proud, carrots have 32,000.) Thus, in our exome, each of us have about 20,000 variants. Feed a genomic sequence into the deep sequencing machine and it will output the variants within a couple of days.
Since the mutated gene, UBTF, is known to regulate the amount of ribosomal RNA, Elpeleg hypothesized that the children’s problem lay in excessive amounts of their ribosomal RNA. This was tested and confirmed by Dr. George-Lucian Moldovan at Pennsylvania State University. The patients’ cells contained five times the normal level of ribosomal RNA.
Searching for similar genetic defects, they found a 9-year-old boy who had been treated at Hadassah and now lives in Russia.
"The boy had been healthy until the age of 5, and then displayed neurological deterioration just like the girl I had diagnosed. Dr. Simon Edvardson, a pediatric neurologist at Hadassah, flew to Russia, examined the boy, took genetic samples from him and from his parents and confirmed that his illness was identical to that of the Israeli girl. We then knew we had identified a new disease that was not recognized in the medical literature,” said Elpeleg.
“It is the first time that an excess of ribosomal RNA has been linked to a genetic disease in humans,” Elpeleg added.
Barely recognized, the disease is incurable, but identifying its cause could help develop a treatment mechanism, for instance by inhibiting the mutant gene.