Genetic diseases of the Kennedy pathways for membrane synthesis

Abstract

The two branches of the Kennedy pathways (CDP-choline and CDP-ethanolamine) are the predominant pathways responsible for the synthesis of the most abundant phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively, in mammalian membranes. Recently, hereditary diseases associated with single gene mutations in the Kennedy pathways have been identified. Interestingly, genetic diseases within the same pathway vary greatly, ranging from muscular dystrophy to spastic paraplegia to a childhood blinding disorder to bone deformations. Indeed, different point mutations in the same gene (PCYT1; CCTα) result in at least three distinct diseases. In this review, we will summarize and review the genetic diseases associated with mutations in genes of the Kennedy pathway for phospholipid synthesis. These single-gene disorders provide insight, indeed direct genotype-phenotype relationships, into the biological functions of specific enzymes of the Kennedy pathway. We discuss potential mechanisms of how mutations within the same pathway can cause disparate disease.

Keywords: genetic disease; inherited; lipid; membrane; metabolism; phosphatidylcholine; phosphatidylethanolamine; phospholipid.

Figure 1.

PC and PE biosynthesis via two branches of the Kennedy pathway. The CDP-choline branch for PC synthesis (green) and CDP-ethanolamine branch for PE synthesis (purple). The standardized human names for each protein (Roman type) and gene (italic type) are indicated. Mutations in four genes (red type) have been demonstrated to cause inherited genetic diseases in humans. PC, phosphatidylcholine; PE, phosphatidylethanolamine; DAG, diacylglycerol.

Figure 2.

Summary of the currently reported mutations in human CHKB. Top, schematic drawing of the CHKB gene. Dark blue rectangles, exon noncoding regions; light blue rectangles, exon coding regions. Bottom, amino acid sequence of the CHKB (CHKβ) protein. The boxes highlight amino acids forming the ATP-binding loop (blue) and dimer interface (yellow). The conserved phosphotransferase Brenner's motif (green) and choline kinase motif (orange) are also indicated. Mutations in the CHKB gene cause a progressive megaconial congenital muscular dystrophy.

Figure 3.

Summary of the currently reported mutations in human PCYT1A. A, top, schematic drawing of the PCYT1A gene. Dark blue rectangles, exon noncoding regions; light blue rectangles, exon coding regions. Bottom, amino acid sequence of the CCTα protein. The boxes highlight domain structure of CCTα. The N-cap (light red) is common to all CCTs and contains the nuclear localization signal. Red, catalytic domain. Green, membrane-binding domain (M domain), which contains the autoinhibitory helix (AI). Orange, phosphorylation region that is the site of up to 16 phosphoserines (Phospho-Domain). The sites of all disease-linked mutations are depicted. The various PCYT1A phenotypes corresponding to the mutations are highlighted: spondylometaphyseal dysplasia with cone-rod dystrophy (dark blue), congenital lipodystrophy and severe fatty liver disease (red), and Leber congenital amaurosis (green). B, three-dimensional model of human CCTα with known inherited disease-causing mutations noted. A dimeric homology model of residues 40–367 of CCTα was built in the Molecular Operating Environment software suite (version 2019.0102) using the following Protein Data Bank structures: 4MVC, 4MVD, 3FDE, 5H53, and 4WJ4. A short molecular dynamics simulation of 1 ns was used to relax the system. C, homology model of the catalytic domain of CCTα with amino acid mutation site locations identified. D, homology model of the membrane-binding and C-terminal phosphodomain of CCTα with inherited disease amino acid mutation locations highlighted.

Figure 4.

Summary of the currently reported mutations in human PCYT2. Top, schematic drawing of the PCYT2 gene. Exons are shown in light blue. Bottom, amino acid sequence of the ECT protein. The cytidylyltransferase domains I and II are highlighted. Mutations in PCYT2 for PE synthesis cause inherited spastic paraplegias.

Figure 5.

Summary of the currently reported mutations in human EPT1. Top, schematic drawing of the EPT1 gene. Exons are shown in light blue. Bottom, amino acid sequence of the EPT1 protein. The C domain (catalytic motif of the CDP-aminoalcohol phosphotransferase domain) and predicted transmembrane domains (TM) are highlighted. Mutations in EPT1 for PE synthesis cause inherited spastic paraplegias.