Novel LIAS variants in a patient with epilepsy and profound developmental disabilities
Issued Date
2023-03-01
Resource Type
ISSN
10967192
eISSN
10967206
Scopus ID
2-s2.0-85146602223
Pubmed ID
36680912
Journal Title
Molecular Genetics and Metabolism
Volume
138
Issue
3
Rights Holder(s)
SCOPUS
Bibliographic Citation
Molecular Genetics and Metabolism Vol.138 No.3 (2023)
Suggested Citation
Wongkittichote P., Chhay C., Zerafati-Jahromi G., Weisenberg J.L., Mian A., Jensen L.T., Grange D.K. Novel LIAS variants in a patient with epilepsy and profound developmental disabilities. Molecular Genetics and Metabolism Vol.138 No.3 (2023). doi:10.1016/j.ymgme.2023.107373 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/82382
Title
Novel LIAS variants in a patient with epilepsy and profound developmental disabilities
Other Contributor(s)
Abstract
Multiple mitochondrial enzymes employ lipoic acid as a coenzyme. Pathogenic variants in LIAS, encoding lipoic acid synthase (LIAS), are associated with autosomal recessive LIAS-related disorder (OMIM# 614462). This disorder is characterized by infantile-onset hypotonia, profound psychomotor delay, epileptic encephalopathy, nonketotic hyperglycinemia, and lactic acidosis. We present the case of a 20-year-old female who experienced developmental deficits at the age of 6 months and began to have seizures at 3 years of age. Exome sequencing revealed compound heterozygous novel variants in LIAS, designated c.277delC (p.Leu93Ter) and c.542A > T (p.Asp181Val). The p.Leu93Ter variant is predicted to cause loss of function due to the severe truncation of the encoded protein. To examine the p.Asp181Val variant, functional analysis was performed using Baker's yeast (Saccharomyces cerevisiae) lacking LIP5, the homologue of human LIAS. Wild-type LIAS promoted oxidative growth of the lip5∆ yeast strain. In contrast, lip5∆ yeast expressing p.Asp181Val exhibited poor growth, similar to known pathogenic variants, p.Asp215Glu and p.Met310Thr. Our work has expanded the phenotypic and genotypic spectrum of LIAS-related disorder and established the use of the yeast model as a system for functional study of novel missense variants in LIAS.