Exome Sequencing Reveals a Rare Autosomal Dominant Variant in MSTO1 Gene as a Novel Leber's Hereditary Optic Neuropathy (LHON) Modifier in a Thai Family with High Penetrance of G11778A Mutation
Issued Date
2024-01-01
Resource Type
ISSN
08574421
eISSN
2586940X
Scopus ID
2-s2.0-85191362965
Journal Title
Journal of Health Research
Volume
38
Issue
3
Start Page
240
End Page
250
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Health Research Vol.38 No.3 (2024) , 240-250
Suggested Citation
Nakhonsri V., Kaewsutthi S., Suktitipat B., Suthammarak W., Chuenkongkaew W.L., Wasitthankasem R., Tongsima S., Lertrit P. Exome Sequencing Reveals a Rare Autosomal Dominant Variant in MSTO1 Gene as a Novel Leber's Hereditary Optic Neuropathy (LHON) Modifier in a Thai Family with High Penetrance of G11778A Mutation. Journal of Health Research Vol.38 No.3 (2024) , 240-250. 250. doi:10.56808/2586-940X.1079 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/98218
Title
Exome Sequencing Reveals a Rare Autosomal Dominant Variant in MSTO1 Gene as a Novel Leber's Hereditary Optic Neuropathy (LHON) Modifier in a Thai Family with High Penetrance of G11778A Mutation
Author's Affiliation
Corresponding Author(s)
Other Contributor(s)
Abstract
Background: Leber's hereditary optic neuropathy (LHON) is a prevalent mitochondrial disease that is predominantly caused by mitochondrial (mtDNA) mutations. However, not all siblings with identical LHON mutations develop visual impairment, suggesting the influence of nuclear genetic variants. This study explores the role of these variants in LHON expression among siblings and relatives with the same maternal LHON mutations. Methods: A family with a homoplasmic G11778A mutation displaying significant LHON penetrance (50 % in female carriers) was examined. Exome sequencing was performed on four members (two affected, two unaffected). Detected variations were predicted using a Variant Effect Predictor (VEP) with a dbNSFP (database for nonsynonymous single nucleotide polymorphisms' functional predictions) plugin. Candidate variants were chosen based on their scores and LHON-related gene variations. Sanger sequencing was used for validation of 15 family members. Results: Exome analysis identified nine potential variations across eight genes. However, only the MSTO1 c.692 693delCC mutation showed a significant linkage to LHON expression in both additive (adj. p-value = 0.04) and dominant models (adj. p-value = 0.0112). This rare variant, located at the cleavage and polyadenylation site of the MSTO1 gene, could disrupt transcriptional termination, and thus alter MSTO1 gene expression. Conclusions: Given the role of the MSTO1 gene in controlling mitochondrial morphology, the MSTO1 c.692 693delCC mutation might instigate mitochondrial dysfunction. Thus, the MSTO1 gene is potentially a novel nuclear modifier for LHON. These findings pave the way for further research into the underlying mechanisms of LHON.