Summary: Researchers have identified a new mutation in the ARPP21 gene linked to ALS. The mutation was found in 10 ALS patients from 7 unrelated families in La Rioja, Spain.
This discovery could improve the diagnosis of ALS and pave the way for personalized therapies. These results highlight the importance of genetic research in understanding and treating neurodegenerative diseases.
Highlights:
- New mutation: ARPP21 gene mutation linked to ALS in 10 patients.
- Improved diagnosis: Potential for more accurate ALS diagnosis and personalized therapies.
- Global consequences: These findings could lead to further research into ALS worldwide.
Source: Sant Pau Research Institute
Researchers from the Neuromuscular Diseases Group and the Neurobiology of Dementia Group of the Sant Pau Research Institute (IR Sant Pau) and the Memory Unit of the Sant Pau Hospital, led by neurologist Dr Ricard Rojas-García, have identified a new mutation in the ARPP21 gene that could be the cause of amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease.
Specifically, it is a shared mutation (c.1586C>T; p.Pro529Leu) in the ARPP21 gene that encodes an RNA-binding protein and was found in a total of 10 ALS patients from 7 unrelated families in a southeastern region of the autonomous community of La Rioja.
The investigation was launched after detecting an abnormally high number of ALS cases in La Rioja, specifically in the southeastern region of the autonomous community. The number of cases identified in the area, especially familial, and the calculated minimum incidence considerably exceeded the number of cases expected during the study period given the usual incidence data, which are usually between two and three cases per 100,000 inhabitants per year.
“We noticed that there were many patients from this area, from very close villages, which attracted a lot of attention,” explains Dr. Ricard Rojas-García, a researcher in the Neuromuscular Diseases Group of the IR and one of the main authors of the study.
Between 5 and 10% of ALS cases have a family history of the disease, and in 30% of these cases, no underlying genetic cause could be identified after a thorough study of the genes known to date to be linked to ALS. The aim of the Sant Pau researchers was to identify new genes linked to ALS in cases where genetic testing was negative, motivated by a significantly increased incidence of ALS in this small geographical region of Spain.
The scientists performed whole-genome sequencing of a group of 12 ALS patients (5 with a family history) from this unique region. The study was expanded to include members of affected families and additional cases from a larger surrounding region. The mutation identified in ARPP21 had not been found in other ALS-causing genes. This finding strongly suggests that ARPP21 is a new ALS-causing gene.
The southeast region of the community of La Rioja has an area of 1,219.42 km². Between 2009 and 2022 it had an average population of 43,433 inhabitants, of which 31,324 were over 18 years old. The population density was 35.62 inhabitants/km². It is an area with a high emigration rate, so there may be cases in the rest of the state.
Given an average incidence of ALS of 1.4–2.47 cases/100,000 persons/year, we calculated an expected number of cases of 0.44–0.77 per year in this area, which equates to 5–10 patients over the study period (2009–2022). For familial cases of ALS, assuming a frequency of 5–10%, the expected number of cases in the area would be 0.02–0.08 cases/year, or one new case every 12.5–50 years.
Despite this, between 2009 and 2022, 15 patients from the study area who met the diagnostic criteria for ALS were consulted in Sant Pau. 7 of the 15 (46.6%) had a family history of ALS and were considered possible familial cases. Known mutations responsible for the disease were excluded by exome sequencing analysis or a personalized gene panel.
“This mutation will not only help to diagnose ALS more accurately, but will also open the door to the search for new personalized therapies and the study of the function of this protein in the disease,” adds Dr. Oriol Dols-Icardo, researcher in the Neurobiology of Dementia group and the Memory Unit of IR Sant Pau and first signatory of the study.
Dr. Dols-Icardo believes that these results could open new perspectives for the diagnosis and treatment of ALS. The identification of ARPP21 as the responsible gene underlines the importance of continuing research in specific geographical areas to discover new genetic factors.
GLOBAL IMPLICATIONS
Although this discovery was made in a specific region of Spain, researchers believe it could have global implications.
“This opens the door for other research teams around the world to examine their databases and patients to see if this mutation is also present elsewhere,” they explain.
The discovery of the new gene associated with ALS will not only allow for better diagnosis and genetic counseling for affected families, but will also open new avenues of research into how this specific protein works and its relationship to the disease.
This advance highlights the importance of genetic research in understanding and treating rare diseases and underscores the need to continue exploring the genetic causes of ALS in order to develop more effective treatments in the future.
About this news on genetics and ALS research
Author: Karla Islands
Source: Sant Pau Research Institute
Contact: Karla Islas – Sant Pau Research Institute
Picture: Image credited to Neuroscience News
Original research: Free access.
“Identification of a pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis” by Ricard Rojas-García et al. Journal of Neurology, Neurosurgery and Psychiatry
Abstract
Identification of a pathogenic mutation in the ARPP21 gene in patients with amyotrophic lateral sclerosis
Background and objective
Between 5 and 10% of cases of amyotrophic lateral sclerosis (ALS) have a family history of the disease, 30% of which have no identifiable underlying genetic cause after a thorough study of known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region of Spain, the aim of this work was to identify new ALS-related genes in ALS cases with negative genetic tests.
Methods
We detected an increased incidence of sporadic and, especially, familial ALS cases in a small region of Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 ALS patients (5 of them familial) from this unique region. We expanded the study to include affected family members and other cases from a larger surrounding region.
Results
We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in cyclic AMP-regulated phosphoprotein 21 (ARPP21) gene encoding an RNA-binding protein, in a total of 10 ALS patients from 7 unrelated families. No mutations were found in other ALS-causing genes.
Conclusions
While previous studies have rejected the causal role of ARPP21 in ALS, our results strongly support ARPP21 as a new gene responsible for ALS.