July 27, 2020
by Ines Martins, PhD
A new mutation in the FUS gene, which results in a shorter version of the FUS protein that cannot enter form the cell nucleus to work as it should, may cause an aggressive form of juvenile amyotrophic lateral sclerosis (ALS), the case of an adolescent girl shows.
The case report, “A de novo c.1509dupA:p.R503fs mutation of FUS: report of a girl with sporadic juvenile amyotrophic lateral sclerosis,” was published in the journal Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. Most ALS cases occur in adults at advanced ages, but the disease can manifest before the age of 25 (juvenile ALS). Mutations in the FUS gene appear to cause the majority of these early-onset ALS cases.
This gene provides the instructions for making the RNA-binding fused in sarcoma (FUS) protein, which is involved in transporting RNA molecules — blueprints of genes that are read by the protein-making machinery to create proteins — from the cell’s nucleus to its cytoplasm. It is also involved in different steps of protein production.
The protein is mostly found in the nucleus but becomes misplaced in the cytoplasm in the motor neurons of ALS patients.
Notably, while FUS mutations in adults are located in multiple regions of the gene and affect the protein in different ways, mutations in juvenile patients appear to disrupt the signal needed for FUS to reach the nucleus. This also results in more aggressive forms of the disease. More than 50 FUS mutations are known to date, but there are still unknown FUS genetic alterations involved in ALS.
Researchers at the First Affiliated Hospital of Zhengzhou University, China, detailed the case of a 17-year-old girl who developed juvenile ALS due to a previously unknown mutation in this gene.
A college student, she came to the hospital complaining of progressive leg weakness and muscle wasting, with mild muscle stiffness (spasticity). Her family members were all healthy, and a neurological examination came back normal. Additional exams confirmed the atrophy in her legs and left bicep.
Since these are typical presentations of ALS, the girl underwent genetic testing to confirm a diagnosis. Results showed a previously unidentified mutation, called c.1509dupA:p.R503fs, in one of the FUS gene copies, leading to the diagnosis of sporadic juvenile ALS. While the course of juvenile ALS is highly variable, this patient’s condition progressed very rapidly: 15 months after disease onset, the young woman died of respiratory failure.
Researchers conducted a computer analysis to understand how the mutation affected protein function. The mutation not only caused the protein-making machinery to stop earlier than normal — resulting in a smaller protein — it also disrupted the signal that enables FUS to enter the nucleus, resulting in it wrongly localizing and aggregating in the cytoplasm.
Based on the findings, the mutation was classified as “likely pathogenic,” or likely disease-causing.
“In summary, this represents a de novo pathogenic FUS mutation associated with sporadic [juvenile ALS],” the researchers concluded.