Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome

Abstract

Exome sequencing of an individual with congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis, all typical symptoms of Sengers syndrome, discovered two nonsense mutations in the gene encoding mitochondrial acylglycerol kinase (AGK). Mutation screening of AGK in further individuals with congenital cataracts and cardiomyopathy identified numerous loss-of-function mutations in an additional eight families, confirming the causal nature of AGK deficiency in Sengers syndrome. The loss of AGK led to a decrease of the adenine nucleotide translocator in the inner mitochondrial membrane in muscle, consistent with a role of AGK in driving the assembly of the translocator as a result of its effects on phospholipid metabolism in mitochondria.

Figure 1

Distribution of the AGK Mutations and Their Consequences on AGK Structure of AGK (A) and localization of identified mutations. AGK (B) was not detectable with immunoblot analysis (primary AGK antibody [1:1,000; rabbit polyclonal; GTX107413, Genetex]) in myoblasts form affected individual 54027 and in fibroblasts of individuals 60453 and 60455. (C1) Myoblast control. (C2 and C3) Fibroblast controls.

Figure 2

Deficiency in ATP Synthesis and ANT in Sengers Syndrome The increased ratio of [1-¹⁴C]pyruvate + malate + CCCP over [1-¹⁴C]pyruvate + malate + ADP oxidation (A) in affected individual 54027 (filled square) versus controls (triangles) indicates a deficiency in ATP synthesis. A decreased amount of ANT (B) was detected with immunoblot analysis in skeletal muscle and in differentiated myoblasts (C) of affected individual 54027. Primary antibodies and their conditions are as follows: ANT antibody (1:1,000; mouse monoclonal; MSA02, Mitosciences) and SDHA (1:30,000; mouse monoclonal; MS204, Mitosciences).

Figure 3

Potential Role of AGK in the Mitochondrial Lipid Metabolism Abbreviations are as follows: AGK, acylglycerol kinase; CDS, CDP-diacylglycerol synthase; PGS, phosphatidylglycerophosphate synthase; PTPMT, phosphatidylglycerol-phosphate phosphatase; CRLS, cardiolipin synthase; ANT, adenine nucleotide translocator; DAK, diacylglycerol kinase; GPAT, glycerol-3-phosphate acyltransferase; LPAAT, 1-acylglycerol-3-phosphate O-acyltransferase; G3P, glycerol 3-phosphate; LPA, lyso-phosphatidic acid; PA, phosphatidic acid; DAG, diacylglycerol; TAG, triacylglycerol; PL, phospholipid; CDP-DAG, cytidine diphosphate diacylglycerol; PGP, phosphatidylglycerol-phosphate; PG, phosphatidylglyceroll; CL, cardiolipin; ER, endoplasmic reticulum; OMM, outer mitochondrial membrane; and IMM, inner mitochondrial membrane.