Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness

Abstract

Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking.

Mitochondrial Disease in Childhood: Nuclear Encoded

“…Tafazzin is a transacylase that catalyzes remodeling of immature cardiolipin to its mature composition, and the mutation in TAZ causes dysfunction of this protein [79]. 3-methylglutaconic aciduria with sensorineural deafness, encephalopathy, and Leigh-like syndrome is a recessive disorder characterized by dystonia and deafness with Leigh-like symptoms and 3-methylglutaconic aciduria caused by mutations in SERAC1, resulting in an altered cardiolipin [80]. Sengers syndrome consists of congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis, and is due to mutations in mitochondrial acylglycerol kinase (AGK), which has effects on phospholipid metabolism in mitochondria [81].…”

Inferring causality and functional significance of human coding DNA variants

“…In many cases, missense mutations result in changes of protein expression and localization. Some recent studies relied on immunostaining to assess effects of individual human alleles (50,51). Testing other aspects of protein function requires development of specific functional assays.…”

Progressive deafness–dystonia due to SERAC1 mutations: A study of 67 cases

“…Variants were found either by Sanger sequencing, exome sequencing as previously described,2, 9, 10, 11, 12, 13, 14, 15 or genome sequencing 16. All variants found in individuals, and carrier status of parents, were confirmed by Sanger sequencing (details available upon request).…”

“…In 2012, biallelic variants in SERAC1 (serine active site containing 1) were shown to cause this autosomal‐recessive deafness–dystonia disorder 2. Soon afterward, with the description of liver involvement as an additional clinical feature, hepatopathy was incorporated into the acronym (MEGDHEL; Mendelian Inheritance in Man [MIM] #614739) 3…”