Clinical and genetic analysis of multiple mitochondrial dysfunctions syndrome type 6 caused by biallelic PMPCB variants in children

Abstract

Multiple mitochondrial dysfunction syndrome 6 (MMDS6), caused by pathogenic variants in the PMPCB gene, is a rare autosomal recessive disorder. To date, only three studies describing a total of seven patients with MMDS6 have been published. In this report, we describe two siblings with MMDS6 who presented with significant motor and intellectual regression. Age of onset of the siblings was significantly later than that of previously reported cases. Whole-exome sequencing (WES) identified two novel compound heterozygous variants in PMPCB (c.1079C > G and c.1351C > T). These two variations originated from their father and their mother respectively. Although the two siblings have the same compound heterozygous mutation, their clinical symptoms show significant differences. Analysis via WB experiment indicated that these variants reduce PMPCB gene. PMPCB and Frataxin (FXN) protein expression. Furthermore, Analysis of protein stability prediction showed that the c.1079C > G variant decreases PMPCB protein stability. Based on these observation, we speculate that Both variants are candidate pathogenic variants pending functional validation. These findings expand the variant spectrum of PMPCB-related MMDS6 and revealed the potential pathogenic mechanism of PMPCB gene variants. We preliminary speculate that PMPCB might be a critical upstream regulator of FXN maturation.