Exploring the Genetic Links Between Familial Multiple Sclerosis and Single-Gene Disorders
Multiple Sclerosis (MS) is a complex inflammatory disease of the central nervous system (CNS) that affects millions of people globally. Characterized by the loss of myelin, axonal damage, and progressive neurological dysfunction, MS presents with a wide array of symptoms including visual disturbances, mobility issues, and cognitive deficits. While the etiology of MS is multifactorial, involving both genetic and environmental factors, studies have highlighted the potential role of single-gene disorders that exhibit clinical and radiological similarities to MS. This blog post delves into the findings of a study investigating the common genetic etiology between "MS-like" single-gene disorders and familial MS.
The study conducted by Anthony L. Traboulsee and colleagues aimed to identify genetic variants shared between MS and various single-gene disorders. The researchers hypothesized that mutations in genes associated with these disorders might also contribute to the pathophysiology of MS. To test this hypothesis, they selected 28 candidate genes known to cause single-gene disorders with clinical features overlapping with MS and performed exome sequencing on MS patients.
The study included samples from 2131 MS patients and 830 healthy controls from the Canadian Collaborative Project on the Genetic Susceptibility to Multiple Sclerosis (CCPGSMS). The majority of participants were of European ancestry, with a small percentage of Asian, African, and First Nations ancestry. MS patients were diagnosed according to the Poser criteria before 2001 and McDonald criteria thereafter.
Exome Sequencing and Genotyping
Exome sequencing was performed on a subset of 270 MS patients, focusing on rare coding variants in the 28 candidate genes. Variants identified were then genotyped in the larger cohort of MS patients and healthy controls to assess their frequency and segregation with disease within families.
The study identified 31 rare variants in six genes (CYP27A1, LYST, PDHA1, CLCN2, GALC, and POLG) that segregated with MS in 13 families.
Key Findings:
CYP27A1: Four different mutations were identified, including a pathogenic mutation for cerebrotendinous xanthomatosis (CTX) in a multi-incident family. The p.R405W mutation was observed in six family members, three of whom were diagnosed with MS.
LYST: The p.V1678A mutation was found in five MS patients from three families, suggesting a potential link between LYST and MS.
PDHA1: The p.K387Q mutation was observed in five MS patients from three families, indicating a possible contribution of PDHA1 to MS pathogenesis.
Other Genes: Mutations in CLCN2, GALC, and POLG were identified in single families, warranting further investigation.
The findings suggest a shared genetic etiology between MS and certain single-gene disorders, particularly those involving cholesterol metabolism and lysosomal function. The identification of the CYP27A1 p.R405W mutation in MS patients highlights the potential role of cholesterol and oxysterol metabolism in MS. Additionally, the study supports the involvement of LYST and PDHA1 in the disease, although further functional characterization is needed.
Conclusion
This study sheds light on the genetic complexity of MS and underscores the importance of investigating rare genetic variants in familial forms of the disease. Understanding the genetic overlap between MS and single-gene disorders could pave the way for new therapeutic targets and personalized treatment strategies. As the genetic landscape of MS continues to unravel, studies like this are crucial in advancing our knowledge and improving patient outcomes.
References
Traboulsee, A. L., Sadovnick, A. D., Encarnacion, M., Bernales, C. Q., Yee, I. M., Criscuoli, M. G., & Vilariño-Güell, C. (2017). Common genetic etiology between “multiple sclerosis-like” single-gene disorders and familial multiple sclerosis. Human genetics, 136, 705-714.
