Researchers isolate gene mutations in patients with inherited amyotrophic lateral sclerosis

Researchers at the University of Massachusetts Medical School (UMMS) have discovered a new gene whose mutations cause familial amyotrophic lateral sclerosis (ALS), a fatal neurological disorder.

Discovery of the FUS/TLS gene mutation, which is estimated to account for 5 percent of inherited ALS cases, is described in the February 27, 2009 issue of Science .

"This discovery discloses new types of molecular defects that kill motor neurons and at the same time implicates defective pathways previously identified in other genetic forms of ALS," said Dr. Robert H. Brown, Jr., MD, DPhil, the senior investigator of the study and chair of neurology at UMMS. "Understanding the mechanisms that trigger motor neuron death leads to new cellular and animal models of ALS and ultimately accelerates the search for a treatment for this devastating disease."

ALS is a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system. As motor neurons die, the brain's ability to send signals to the body's muscles is compromised. This leads to loss of voluntary muscle movement, paralysis and eventually death from respiratory failure. The cause of most cases of ALS is not known. Approximately 10 percent of cases are inherited. In 1993, a team of researchers led by Dr. Brown discovered the first gene linked to familial ALS, a protein anti-oxidant known as superoxide dismutase, or SOD1.

The current Science study details the discovery of the FUS/TLS gene mutation among four members of a family from a small Cape Verde island. The familial relationship between the patients' grandparents suggested that the disorder was a result of a recessive gene inherited from both parents. Deep sequencing of several candidate genes on chromosome 16, which has been linked to ALS in previous studies, revealed a single mutation in the FUS/TLS gene on both copies of chromosome 16 in the affected family members. Three asymptomatic family members from the Cape Verde family also had two mutated copies of FUS/TLS but had not reached the age of onset of ALS. Several unaffected family members had only a single copy of the FUS/TLS mutation. No mutations in the FUS/TLS gene were found in a control group of 1,446 North American individuals.

Sequencing of the FUS/TLS gene in two other families, previously thought to have an ALS-associated gene on chromosome 16, disclosed additional mutations. Analysis of 81 other unrelated familial ALS occurrences revealed 13 different FUS/TLS gene mutations among 17 families. No mutations were found in the 293 sporadic, non-familial ALS cases sampled or the 1,446 control cases.

While it is not certain how the mutation of the FUS/TLS gene causes ALS, the cellular functions it controls within the motor neurons are remarkably similar to those found in other gene mutations known to cause ALS. The FUS/TLS protein plays a number of roles in the neuron cell, one of which is to bind and transport RNA, regulating the processes whereby RNA leads to protein synthesis. In healthy neuron cells, FUS/TLS protein is located predominately in the cell nucleus. Samples from patients with the FUS/TLS mutation show a concentration of the FUS/TLS protein in the cytoplasm of the cell. This same build-up of proteins in the neurons' cytoplasm is found in ALS patients with a mutation of the TDP43 gene – which also binds to RNA – suggesting a potential common pathogenic mechanism in ALS cases caused by defects in either FUS/TLS or TDP43.

"The implication is that disturbance of RNA transport and function could play a role in the biology of this disease; this is particularly exciting for us at UMMS because we have outstanding scientists here in the field of RNA biology," said Brown.

Lucie Bruijn, PhD, senior vice president of research and development for the ALS Association, said "These findings will open up a completely new avenue of investigation with the potential of developing more promising therapies for ALS."