Abstract
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common subtype of inherited peripheral neuropathies. It is an autosomal dominant disease caused by a 1.5-Mb tandem duplication on chromosome 17, which includes the primary disease gene PMP22. CMT1A affects both motor and sensory functions. Typical phenotype includes distal muscle weakness and atrophy, sensory loss, weak ankle dorsiflexion, depressed tendon reflexes, and foot deformity. Interestingly, CMT1A patients show high clinical variability in their disease onset, severity, and progression. The cause of the phenotypic variability is largely unknown. Phenotypic manifestation of diseases can be modulated by genetic factors other than the primary disease gene, known as genetic modifiers. Thus far, the involvement of genetic modifiers in CMT1A is still not well studied. The aim of my thesis project is to identify potential genetic modifiers in CMT1A. The project utilizes genotyping data from a cohort of 971 CMT1A patients collected over a timeframe of seven years. First, I used genome-wide association study (GWAS) to identify SNPs associated with muscle strength impairment in CMT1A. Analyses were performed in a subset of 330 extreme-phenotype individuals with European ancestry, based on the assumption that samples at phenotypic extremes are more likely to harbor causative variants. From GWAS analysis, I identified a significant association signal in the SIPA1L2 gene. Functional studies suggest that SIPA1L2 is involved in actin network remodeling, which plays a crucial role in Schwann cells. Expression of SIPA1L2 is regulated by transcription factor SOX10 as part of the myelination-related gene network. Genomic findings and functional evidence together support SIPA1L2 as a genetic modifier for muscle strength impairment in CMT1A. In addition to the previous work, I also conducted a series of genome-wide scanning to identify potential genetic associations in other subphenotypes in CMT1A. TUBB, which encodes a beta tubulin protein, was identified as a potential genetic modifier for hand dysfunction in CMT1A. A 600-kb genomic region on chromosome 5, including genes LMNB1, MARCH3, C5orf63 and MEGF10, was identified as a candidate modifier locus in sensorineural hearing loss. These preliminary association results have only suggestive significance from genome-wide study, but they show great promise for future modifier studies. Lastly, I tested the association of a recently reported CMT1A modifier, MIR149, in our study cohort. This association was previously identified in a group of Asian patients. In our cohort, I confirmed the association of MIR149 polymorphism with onset age in the Asian samples. This association, however, was not replicated in the European samples, suggesting that the effect of MIR149 may be ancestry specific. In conclusion, results from this study revealed novel genetic mechanisms of CMT1A. Genetic modifiers may serve as potential targets for safer and more effective therapeutic interventions.