Disease relevance of LRPPRC

• Leigh syndrome French Canadian (LSFC) is a variant of cytochrome oxidase deficiency found in Québec and caused by mutations in the LRPPRC (leucine-rich pentatricopeptide repeat cassette) gene [1].
• Here we illustrate how such data sets can expedite disease-gene discovery, by using them to identify the gene causing Leigh syndrome, French-Canadian type (LSFC, Online Mendelian Inheritance in Man no. 220111), a human cytochrome c oxidase deficiency that maps to chromosome 2p16-21 [2].
• Using an antibody to screen a phage expression library of HepG2 complementary DNA (cDNA), we identified and cloned a 4734 base pair cDNA which codes for a 130-kDa leucine-rich protein (lrp 130) when expressed in transfected cells [3].
• Consistent with the higher levels of expression of lrp130 antigen, Northern hybridization analysis indicated that HepG2 cells express high levels of the major 4.8 kilobase lrp130 mRNA relative to other hepatoma cells [3].

High impact information on LRPPRC

• Resequencing identified two mutations on two independent haplotypes, providing definitive genetic proof that LRPPRC indeed causes LSFC [2].
• Patients with LSFC show a phenotype similar to that of patients with LS, but the two groups differ in clinical presentation [4].
• Because of founder effects in the SLSJ region, considerable linkage disequilibrium (LD) was expected to surround the LSFC mutation [4].
• The majority of LRP130 proteins are located within mitochondria, where they are directly bound to polyadenylated RNAs in vivo [5].
• LRP130, a pentatricopeptide motif protein with a noncanonical RNA-binding domain, is bound in vivo to mitochondrial and nuclear RNAs [5].

Biological context of LRPPRC

• Sequence analysis of LRPPRC and its SEC1 domain interaction partners suggests roles in cytoskeletal organization, vesicular trafficking, nucleocytosolic shuttling, and chromosome activity [6].
• We found that 23 copies of tandem repeats that are similar to pentatricopeptide, tetratricopeptide, and huntingtin-elongation A subunit-TOR repeats characterize the LRPPRC sequence [6].
• Here we report results of a sequence homology analysis of LRPPRC and its SEC1 domain interactive partners [6].
• Together these features suggest a regulatory role of LRPPRC and its SEC1 domain-interactive partners in integration of cytoskeletal networks with vesicular trafficking, nucleocytosolic shuttling, transcription, chromosome remodeling, and cytokinesis [6].
• Here, we show that the C-terminus of C19ORF5 (C19ORF5C) interacts with mitochondria-associated DNA binding protein, LRPPRC, in liver cells [7].

Anatomical context of LRPPRC

• GFP-tagged UXT and GFP-tagged C19ORF5 appeared in both cytosol and nuclei and colocalized with LRPPRC and beta-tubulin [8].
• LRPPRC (originally called LRP130) is an intracellular, 130-kD, leucine-rich protein that copurifies with the fibroblast growth factor receptor from liver cell extracts and has been detected in diverse multiprotein complexes from the cell membrane, cytoskeleton, and nucleus [6].
• Import of [(35)S]methionine LRPPRC into rat liver mitochondria was slower for the mutant (A354V) protein [1].
• A more diffuse distribution of LRPPRC in LSFC cells compared with controls was evident when viewed by immunofluorescence microscopy, with less LRPPRC present in peripheral mitochondria [1].
• Although currently of unknown function, lrp130 may be of utility as a marker for liver cell lineages represented by the HepG2 cell line [3].

Associations of LRPPRC with chemical compounds

• To further analyze the subcellular localization of LRP130, a nuclear/ER fraction was fractionated into the nucleoplasm (NP) and nuclear envelope (NE)/ER, and the latter was further separated into outer nuclear membrane (ONM)/ER and inner nuclear membrane (INM) by treatment with Triton X-100 [9].

Other interactions of LRPPRC

• In addition, since the invMED1 sequence is primarily located in the -160/-100 bp region of mammalian MDR-related genes, our results present the invMED1/LRP130 couple as a potential central regulator of the transcription of these genes [10].
• Sequencing and BLAST database screening confirmed the location of one gene (UCHL1) and allowed the assignment of two other previously identified genes (LRP130 and cDNA IB871.)[11]
• These include the alternatively spliced isoforms D01 and D02 of the hnRNP D proteins, the E0 isoform of the hnRNP E proteins, and LRP130, a previously reported protein with unknown function that appears to have a novel type of RNA-binding domain [12].

Analytical, diagnostic and therapeutic context of LRPPRC

• Like LRPPRC, C19ORF5 also binds DNA with an affinity and specificity sufficient to be of utility in DNA affinity chromatography to purify homogeneous recombinant C19ORF5C from bacterial extracts [7].
• Northern blots showed that the LRPPRC mRNA levels seen in skeletal muscle>heart>placenta>kidney>liver>lung=brain were proportionally almost opposite in strength to the severity of the enzymic cytochrome oxidase defect [1].

References