Navigation Links
UMMS researchers isolate gene mutations in patients with inherited amyotrophic lateral sclerosis
Date:7/15/2012

WORCESTER, Mass. A new genetic mutation that causes familial amyotrophic lateral sclerosis (ALS), a fatal neurological disorder also known as Lou Gehrig's Disease, has been identified by a team of scientists led by researchers at the University of Massachusetts Medical School (UMMS). Mutations to the profilin (PFN1) gene, which is essential to the growth and development of nerve cell axons, is estimated to account for one to two percent of inherited ALS cases. The finding, described today in the online edition of Nature, points to defects in a neuron's cytoskeleton structure as a potential common feature among diverse ALS genes.

"This discovery identifies what may possibly be a common biological mechanism involved across familial ALS cases regardless of genetics," said John Landers, PhD, associate professor of neurology and senior author of the study. "We know of at least three other ALS genes, in addition to PFN1, that adversely impact axon growth. If indeed, this is part of the disease's mechanism, then it might also be a potential target for therapeutics."

Robert Brown, MD, DPhil, a co-author on the study and chair of neurology at UMass Medical School, said "Dr. Landers has done great work in defining this new pathway for motor neuron death. We are delighted to have identified the defects in families from the U.S., Israel and France that we have been investigating for several years. Our finding is particularly exciting because it may provide new insights into ALS treatment targets."

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 respiratory failure. The cause of most cases of ALS is not known. Approximately 10 percent of cases are inherited. Though investigators at UMass Medical School and elsewhere have identified several genes shown to cause inherited or familial ALS, almost 50 percent of these cases have an unknown genetic cause.

The current Nature study details the discovery of the PFN1 gene mutation among two large ALS families. Both families were negative for known ALS-causing mutations and displayed familial relationships that suggested a dominant inheritance mode for the disease. For each family, two affected members with maximum genetic distance were selected for deep DNA sequencing. To identify an ALS-causing mutation, genetic variations between the family members were identified and screened against known databases of human genetic variation, such as the 1000 Genomes Project. This narrowed down the resulting number of candidate, ALS-causing mutations to two within the first family and three within the second. Interestingly, both families contained different mutations within the same gene PFN1, the likely causative mutation. With additional screening, the team documented that in a total of 274 families sequenced, seven contained a mutation to the PFN1 gene, establishing it as a likely cause for ALS.

While it is not certain how the PFN1 mutation causes ALS, the cellular functions it controls within the motor neurons are responsible for regulation of a number of activities, including the growth and development of the axon, the slender projection through which neurons transmit electrical impulses to neighboring cells, such as muscle. When introduced into motor neuron cells, normal PFN1 protein was found diffused throughout the cytoplasm. Conversely, the mutant PFN1 observed in ALS patients was found to collect in dense aggregates, keeping it from functioning properly. Motor neurons producing mutated PFN1 showed markedly shorter axon outgrowth.

"The discovery that mutant PFN1 interferes with axon outgrowth was very exciting to us," said Claudia Fallini, PhD, a postdoctoral researcher at Emory University School of Medicine who collaborated with the UMass Medical School authors to investigate PFN1's functions in cultured motor neurons. "It suggests that alterations in actin dynamics may be an important mechanism at the basis of motor neuron degeneration."

"In healthy neurons, PFN1 acts almost like a railroad tie for fibrous filaments called actin, which make up the axon" said Landers. "PFN1 helps bind these filaments to each other, promoting outgrowth of the axon. Without properly functioning PFN1 these filaments can't come together. Here we show that mutant PFN1 may contribute to ALS pathogeneses by accumulating in these aggregates and altering the actin dynamics in a way that inhibits axon outgrowth."


'/>"/>

Contact: Jim Fessenden
james.fessenden@umassmed.edu
508-856-2000
University of Massachusetts Medical School
Source:Eurekalert

Related biology news :

1. Cleveland Clinic researchers receive $5 million grant to discover novel pathways to heart disease
2. Researchers take hibiscus efforts to commercialization
3. UI researchers develop technique to help pollution forecasters see past clouds
4. UC Santa Barbara researchers play key role in UN Environmental Assessment
5. Researchers discover molecule in immune system that could help treat dangerous skin cancer
6. Researchers moving towards ending threat of West Nile virus
7. NOAA researchers see dramatic decline of endangered white abalone
8. BESC researchers tap into genetic reservoir of heat-loving bacteria
9. Researchers and communities at risk join forces in volcano study
10. Penn researchers improve living tissues with 3-D printed vascular networks made from sugar
11. BUSM researchers identify role of FOXO1 gene in Parkinsons disease
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:3/30/2017)... March 30, 2017  On April 6-7, 2017, Sequencing.com ... Genome hackathon at Microsoft,s headquarters in ... will focus on developing health and wellness apps that ... Hack the Genome is the first hackathon for ... world,s largest companies in the genomics, tech and health ...
(Date:3/29/2017)... 29, 2017  higi, the health IT company that ... North America , today announced a Series B ... of EveryMove. The new investment and acquisition accelerates higi,s ... to transform population health activities through the collection and ... higi collects and secures data today on behalf ...
(Date:3/24/2017)... The Controller General of Immigration from Maldives Mr. Mohamed Anwar ... the prestigious international IAIR Award for the most innovative high security ePassport ... ... Maldives Immigration Controller General, Mr. ... on the right) have received the IAIR award for the "Most innovative ...
Breaking Biology News(10 mins):
(Date:4/21/2017)... ... April 21, 2017 , ... The University ... first round funding to three startups through the UConn Innovation Fund. The $1.5 ... business startups affiliated with UConn. , The UConn Innovation Fund provides investments of ...
(Date:4/21/2017)... ... April 21, 2017 , ... The AMA is happy to announce that $48,000 ... the nation. The scholarships are created through funds donated by model aviation organizations and ... set by the AMA Scholarship Committee, which is made up of model aviation pilots ...
(Date:4/21/2017)... (PRWEB) , ... April 21, 2017 , ... ... accelerator dedicated to nourishing a range of emerging technology-based businesses, recently earned a ... Metropolitan Court location. , Founded in 2004, FITCI is Frederick’s first incubator. ...
(Date:4/20/2017)... ... April 20, 2017 , ... ... strategic partnership to offer a full spectrum of digital security goods and services. ... biometric products and the ground-breaking proactive cybersecurity services and products through Assured Enterprises. ...
Breaking Biology Technology: