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Exome Sequencing IDs Compound Mutation Behind Rare Ataxia Syndrome

NEW YORK (GenomeWeb) – Mutations in the SCYL1 gene can contribute to a rare inherited hepatocerebellar ataxia-neuropathy condition characterized by movement and gait problems, recurrent bouts of liver failure, tremors, delayed motor skill development, and other symptoms, a new study suggests.

As they reported online today in the American Journal of Human Genetics, researchers from the Medical University of Vienna and elsewhere did exome sequencing on members of two families affected by the condition, uncovering compound heterozygous mutations in the SCYL1 gene in all three individuals with the disease.

Through follow-up experiments, the team found that the SCYL1's gene product was missing in human fibroblast cells from individuals carrying the compound mutations. In those and other cells with SCYL1 knockdown, the Golgi apparatus was unusually large, providing clues to the basis of the ataxia condition.

"Collectively, our data provide compelling evidence that disruptive mutations in SCYL1 cause a syndrome characterized by early-onset episodes of acute liver failure, cerebellar ataxia, and peripheral motor and sensory neuropathy in humans," senior author Reginald Bittner, a neuromuscular researcher at the Medical University of Vienna, and his colleagues wrote.

"Our findings add SCYL1 to a list of several other genes implicated in disorders involving the cerebellum, whose gene products are implicated in the Golgi network," they added.

The finding fits with a mouse study that Bittner and colleagues published in EMBO Reports in 2007, which pointed to a role for the mouse version of SCYL1 in a progressive motor neuron loss condition that led to gait ataxia, atrophy of a region of the cerebellum, and other symptoms resembling some human ataxias.

The researchers ultimately identified three individuals with this hereditary cerebellar ataxia: an affected brother and affected sister from a family with unrelated, European parents and a teenage girl from a non-consanguineous Cuban family.

In each case, the individuals started developing symptoms, including fever-related, recurrent liver failure, in infancy. These episodes waned partway through childhood, the team explained, but the children were left with chronic liver disease and experienced other brain, nervous system, and muscle-related symptoms such as tremors, lower leg weakness, and unusual gait features.

To search for culprits in the condition, the researchers captured protein-coding portions of the genome in members of the European family using an Agilent SureSelect kit. The exomes — which represented one of the affected children, an unaffected sibling, and both parents — were subsequently sequenced to average depths of around 119-fold coverage using the Illumina HiSeq 2000.

Though they didn't detect alterations in genes implicated in ataxia syndromes in the past, the researchers found that both affected siblings carried compound mutations in SCYL1 that were missing or affected just one copy of the gene in their unaffected sibling and parents.

Neither gene glitch turned up when the team searched the 1000 Genomes, Exome Sequencing Project, and Exome Aggregation Consortium databases.

But the team found a third individual with compound SCYL1 mutations — from the Cuban family — by searching through thousands of exomes and some 1,200 genome sequences included in a database of families with neurological and other disorders called Genesis.

In their subsequent experiments on fibroblast cells from the three affected individuals the researchers found that the compound mutations led to levels of SCYL1 that were too low to be picked up by western blot or immunofluorescence in the patients' cells.

In those fibroblasts and in another human cell lines subjected to small interfering RNA-based SCYL1 knockdown, the team saw much larger-than-usual Golgi, pointing to intracellular trafficking problems related to the role the SCYL1 gene product is believed to play in transfer RNA export.