summary: Researchers have identified a novel mutation in the ARPP21 gene that is associated with ALS, found in 10 ALS patients from seven unrelated families in the Spanish region of La Rioja.
This discovery could improve the diagnosis of ALS and pave the way for personalized treatment. The discovery highlights the importance of genetic research in understanding and treating neurodegenerative diseases.
Key Facts:
- New mutations: ARPP21 gene mutations have been linked to ALS in 10 patients.
- Improved diagnostics: The potential for more accurate ALS diagnosis and personalized treatment.
- Global impact: This discovery could lead to new ALS research around the world.
sauce: Sant Pau Institute
Researchers from the Neuromuscular Diseases Group and the Dementia Neurobiology Group at the Sant Pau Institute (IR Sant Pau), led by neurologist Dr. Ricardo Rojas García, and the Memory Unit at the Sant Pau Hospital, have identified a new mutation in the ARPP21 gene that may be responsible for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease.
Specifically, the shared mutation (c.1586C>T; p.Pro529Leu) in the ARPP21 gene, which codes for an RNA-binding protein, was found in a total of 10 ALS patients from seven unrelated families in the southeastern region of La Rioja.
The study was initiated following the discovery of an unusually high number of ALS cases in La Rioja, particularly in the southeastern part of the community: the number of confirmed cases in the region, especially the number of familial cases, and the calculated minimum incidence rates, far exceeded the number of cases expected during the study period, based on normal incidence data (usually 2-3 cases per 100,000 people per year).
“We noticed that many patients were coming from very nearby towns in the region, and that attracted a lot of attention,” explains Dr. Ricardo Rojas García, a researcher in IR’s Neuromuscular Diseases Group and one of the study’s lead authors.
Between 5% and 10% of ALS patients have a family history, and in 30% of these cases, an underlying genetic cause could not be identified despite thorough research to date of known genes linked to ALS. The aim of the Sant Pau researchers, prompted by a significant increase in the incidence of ALS in this small geographical area of Spain, was to identify new genes associated with ALS in cases where genetic testing had been negative.
Scientists performed whole genome sequencing on a group of 12 ALS patients from this unique region, five of whom had a family history. The study was expanded to include affected family members and additional cases from the wider surrounding region. The mutations 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 southeastern part of La Rioja has an area of 1219.42 km². The average population from 2009 to 2022 was 43,433, of which 31,324 were aged 18 or over. The population density was 35.62 inhabitants/km². The region has a high emigration rate, so similar cases may exist in other parts of the province.
With an average incidence rate of ALS of 1.4–2.47 cases per 100,000 people per year, the expected annual incidence in this region is 0.44–0.77 cases, with an estimated 5–10 cases occurring during the study period (2009–2022). For familial ALS cases, assuming a frequency of 5–10%, the expected number of cases in this region is 0.02–0.08 cases per year, or 1 new case every 12.5–50 years.
Nevertheless, between 2009 and 2022, 15 patients from the study area who fulfilled the diagnostic criteria for ALS were seen in Sant Pau. Seven of the 15 (46.6%) had a family history of ALS and were considered possible familial cases. Known disease-causing mutations were excluded by exome sequencing or a custom gene panel.
“This mutation will not only help us to diagnose ALS more accurately, but it will also open the door to researching new personalized treatments and the function of this protein in the disease,” added Dr Oriol Dols-Icardo, researcher in the Dementia Neurobiology Group and Memory Unit at IR Sant Pau and first signatory of the study.
Dr. Dorus Icardo believes that these discoveries could open new avenues in the diagnosis and treatment of ALS. The identification of ARPP21 as the causative gene highlights the importance of continuing research in specific regions to discover new genetic factors.
Global impact
Although the discovery was made in one particular region of Spain, the researchers believe it could have global implications.
“This paves the way for other research teams around the world to investigate databases and patients to determine whether this mutation is present elsewhere,” the researchers explain.
The discovery of a new gene associated with ALS will not only allow better diagnosis and genetic counseling for affected families, but also open new avenues of research into the function of this particular protein and its relationship to disease.
This advancement 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 even more effective treatments in the future.
More on this genetics and ALS research news
author: Carla Islas
sauce: Sant Pau Institute
contact: Carla Islas – Sant Pau Institute
image: Image courtesy of Neuroscience News
Original Research: Open access.
“Identification of pathogenic mutations in ARPP21 in patients with amyotrophic lateral sclerosisRicard Rojas-García et al. Journal of Neurology Neurosurgery and Psychiatry
Abstract
Identification of pathogenic mutations in ARPP21 in patients with amyotrophic lateral sclerosis
Background and Objectives
Between 5% and 10% of cases of amyotrophic lateral sclerosis (ALS) have a family history, of which 30% have no identifiable underlying genetic cause even after a comprehensive study of known ALS-related genes. Based on a significant increase in the incidence of ALS in a small geographical area of Spain, the aim of this study was to identify new ALS-related genes in ALS cases with negative genetic testing.
Method
We found that a small region of Spain showed an increased incidence of sporadic and especially familial ALS cases compared with available demographic and epidemiological data. We performed whole-genome sequencing on a group of 12 ALS patients (5 of which were familial) from this particular region. We then extended the study to include affected family members and cases from the surrounding area.
result
We investigated the mechanism of action of cyclic AMP-regulated phosphoprotein 21 (ARPP21) Mutations in genes that code for RNA-binding proteins were identified in 10 ALS patients from seven unrelated families, but no mutations were found in other ALS-causing genes.
Conclusion
In previous studies, ARPP21 In ALS, our results strongly support ARPP21 It was discovered as a new causative gene for ALS.
