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An N-ethyl-N-nitrosourea (ENU)-induced Tyr265Stop mutation of the DNA polymerase accessory subunit gamma 2 (Polg2) is associated with renal calcification in mice
Caroline M. Gorvin, Bushra N. Ahmad, Michael J. Stechman, Nellie Y. Loh, Tertius A. Hough, Paul Leo, Mhairi Marshall, Siddharth Sethi, Liz Bentley, Sian E. Piret, Anita Reed, Jeshmi Jeyabalan, Paul T. Christie, Sara Wells, Michelle M. Simon, Ann-Marie Mallon, Herbert Schulz, Norbert Huebner, Matthew A. Brown, Roger D. Cox, Steve D. Brown, and Rajesh V. Thakker
SUPPLEMENTAL TABLES
Table S1 Genes identified to be associated with nephrocalcinosis or nephrolithiasis by investigations of syndrome or disorder association studies
GeneGene Name Disease/ associationReferenceADCY10/SACAdenylate cyclase 10 (soluble)Idiopathic (absorptive) hypercalciuria, susceptibility; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (1,2)AGXTAlanine-glyoxylate aminotransferasePrimary hyperoxaluria, type 1; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (2-6)ALPLAlkaline phosphatase, liver/ kidney/ boneAssociated with kidney stones ADDIN EN.CITE ADDIN EN.CITE.DATA (1)APRTAdenine phosphoribosyltransferaseAdenine phosphoribosyltransferase deficiency ADDIN EN.CITE ADDIN EN.CITE.DATA (1)ATP6V0A4ATPase, H+ transporting, lysosomal V0 subunit a4Distal renal tubular acidosis (dRTA); association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (4,7,8)ATP6V1B1ATPase, H+ transporting, lysosomal 56/58kDa, V1 subunit B1dRTA with deafness; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (2,5,6,9,10)BSNDBarttinBartter syndrome type 4 ADDIN EN.CITE Hunter200210101017Hunter, D. J.Lange, M.Snieder, H.MacGregor, A. J.Swaminathan, R.Thakker, R. V.Spector, T. D.Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.Genetic contribution to renal function and electrolyte balance: a twin studyClinical scienceClinical scienceClin Sci (Lond)259-6510332002Sep12193151http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12193151(11)CA2Carbonic anhydrase IIOsteopetrosis with dRTA ADDIN EN.CITE Goldfarb200511111117Goldfarb, D. S.Fischer, M. E.Keich, Y.Goldberg, J.Nephrology Section, New York Harbor VAMC, New York, NY, USA. david.goldfarb@med.va.govA twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) RegistryKidney IntKidney Int1053-616732005Mar15698445http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15698445(12)CASRCalcium-sensing receptorAutosomal dominant hypocalcaemia; Bartter syndrome type 5 ADDIN EN.CITE ADDIN EN.CITE.DATA (1,6,13-15)CLCN5Chloride channel 5Dents disease type 1 ADDIN EN.CITE Oliveira201615151517Oliveira, B.Kleta, R.Bockenhauer, D.Walsh, S. B.University College London, Centre for Nephrology, London, United Kingdom.
University College London, Centre for Nephrology, London, United Kingdom r.kleta@ucl.ac.uk.Genetic, pathophysiological, and clinical aspects of nephrocalcinosisAm J Physiol Renal PhysiolAmerican journal of physiology. Renal physiologyAm J Physiol Renal PhysiolAmerican journal of physiology. Renal physiologyAm J Physiol Renal PhysiolAmerican journal of physiology. Renal physiologyF1243-F12523116AnimalsCalcium Oxalate/metabolismCalcium Phosphates/metabolismHumansKidney/metabolism/*pathologyNephrocalcinosis/*genetics/metabolism/pathology2016Dec 11522-1466 (Electronic)
1522-1466 (Linking)27605580http://www.ncbi.nlm.nih.gov/pubmed/2760558010.1152/ajprenal.00211.2016(16)CLCNKBChloride channel KbBartter syndrome type 3 ADDIN EN.CITE ADDIN EN.CITE.DATA (13,17)CLDN14Claudin 14Association with kidney stones ADDIN EN.CITE ADDIN EN.CITE.DATA (1,17,18)CLDN16Claudin 16Familial hypomagnesemia with hypercalciuria and NC (FHHNC); association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (6,18-20)CLDN19Claudin 19FHHNC with ocular abnormalities; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (6,21)CYP24A1Cytochrome P450, family 24, subfamily
A, polypeptide 1Infantile hypercalcemia; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (22,23)FAM20AFamily with sequence similarity 20,
member AEnamel-Renal syndrome, amelogenesis imperfect and NC ADDIN EN.CITE Stechman200922222217Stechman, M. J.Loh, N. Y.Thakker, R. V.Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.Genetic causes of hypercalciuric nephrolithiasisPediatr NephrolPediatr Nephrol2321-3224122009Dec18446382http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18446382(23)GRHPRGlyoxylate reductase/hydroxypyruvate
ReductasePrimary hyperoxaluria type 2 ADDIN EN.CITE ADDIN EN.CITE.DATA (6,22)HNF4AHepatocyte nuclear factor 4, alphaMaturity-onset diabetes of the young (MODY) with Fanconi syndrome and NC ADDIN EN.CITE ADDIN EN.CITE.DATA (22)HOGA14-hydroxy-2-oxoglutarate aldolase 1Primary hyperoxaluria type 3 ADDIN EN.CITE Loh201320202017Loh, N. Y.Bentley, L.Dimke, H.Verkaart, S.Tammaro, P.Gorvin, C. M.Stechman, M. J.Ahmad, B. N.Hannan, F. M.Piret, S. E.Evans, H.Bellantuono, I.Hough, T. A.Fraser, W. D.Hoenderop, J. G.Ashcroft, F. M.Brown, S. D.Bindels, R. J.Cox, R. D.Thakker, R. V.Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism-OCDEM, Churchill Hospital, Headington, Oxford, United Kingdom.Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5PLoS OnePloS onePLoS OnePloS onePLoS OnePloS onee554128120131932-6203 (Electronic)
1932-6203 (Linking)23383183http://www.ncbi.nlm.nih.gov/pubmed/23383183355960210.1371/journal.pone.0055412(21)HPRT1Hypoxanthine
phosphoribosyltransferase 1Kelley-Seegmiller syndrome, partial HPRT
deficiency, HPRT-related gout ADDIN EN.CITE Ronaghi199823232317Ronaghi, M.Uhlen, M.Nyren, P.Department of Biochemistry and Biotechnology, The Royal Institute of Technology, SE-10044 Stockholm, Sweden.A sequencing method based on real-time pyrophosphateScienceScience363, 36528153751998Jul 179705713http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9705713(24)ITPKCInositol 1,4,5-trisphosphate (IP3) 3-kinase CAssociation with NL ADDIN EN.CITE Loh201320202017Loh, N. Y.Bentley, L.Dimke, H.Verkaart, S.Tammaro, P.Gorvin, C. M.Stechman, M. J.Ahmad, B. N.Hannan, F. M.Piret, S. E.Evans, H.Bellantuono, I.Hough, T. A.Fraser, W. D.Hoenderop, J. G.Ashcroft, F. M.Brown, S. D.Bindels, R. J.Cox, R. D.Thakker, R. V.Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism-OCDEM, Churchill Hospital, Headington, Oxford, United Kingdom.Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5PLoS OnePloS onePLoS OnePloS onePLoS OnePloS onee554128120131932-6203 (Electronic)
1932-6203 (Linking)23383183http://www.ncbi.nlm.nih.gov/pubmed/23383183355960210.1371/journal.pone.0055412(21)KCNJ1Potassium inwardly-rectifying channel,
subfamily J, member 1Bartter syndrome type 2 ADDIN EN.CITE Li201095959517Li, H.Homer, N.Broad Institute, Cambridge, MA 02142, USA. hengli@broadinstitute.orgA survey of sequence alignment algorithms for next-generation sequencingBrief BioinformBriefings in bioinformaticsBrief BioinformBriefings in bioinformaticsBrief BioinformBriefings in bioinformatics473-83115*Algorithms*Base SequenceGenome, HumanHumansSequence Alignment/*methodsSequence Analysis, DNA/*methodsSoftware2010Sep1477-4054 (Electronic)
1467-5463 (Linking)20460430http://www.ncbi.nlm.nih.gov/pubmed/20460430294399310.1093/bib/bbq015(25)OCRLOculocerebrorenal syndrome of LoweLowe syndrome / Dent disease 2; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (25,26)ORAI1Orai calcium release-activated calcium modulator 1Associated with NL ADDIN EN.CITE Wang201097979717Wang, K.Li, M.Hakonarson, H.Center for Applied Genomics, Children's Hospital of Philadelphia, PA 19104, USA. kai@openbioinformatics.orgANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids ResNucleic acids researchNucleic Acids Rese1643816GenesGenetic Predisposition to Disease*Genetic VariationGenome, Human*GenomicsHigh-Throughput Screening AssaysHumansSequence Analysis, DNA*Software2010Sep1362-4962 (Electronic)
0305-1048 (Linking)20601685http://www.ncbi.nlm.nih.gov/pubmed/20601685293820110.1093/nar/gkq603(27)ROMKRenal outer medullary potassium channelBartter syndrome type 2 ADDIN EN.CITE Adzhubei201098989817Adzhubei, I. A.Schmidt, S.Peshkin, L.Ramensky, V. E.Gerasimova, A.Bork, P.Kondrashov, A. S.Sunyaev, S. R.A method and server for predicting damaging missense mutationsNat MethodsNature methodsNat Methods248-9742010/04/01*Data Interpretation, StatisticalGenetic VariationHumans*Models, Genetic*Mutation, MissenseSoftware2010Apr1548-7105 (Electronic)
1548-7091 (Linking)20354512https://www.ncbi.nlm.nih.gov/pubmed/20354512PMC285588910.1038/nmeth0410-248(28)SLC12A1Solute carrier family 12, member 1Bartter syndrome type 1; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (6,21,29-31)SLC22A12Solute carrier family 22 (organic
anion/urate transporter), member 12Renal hypouricemia type 1 ADDIN EN.CITE Loh201320202017Loh, N. Y.Bentley, L.Dimke, H.Verkaart, S.Tammaro, P.Gorvin, C. M.Stechman, M. J.Ahmad, B. N.Hannan, F. M.Piret, S. E.Evans, H.Bellantuono, I.Hough, T. A.Fraser, W. D.Hoenderop, J. G.Ashcroft, F. M.Brown, S. D.Bindels, R. J.Cox, R. D.Thakker, R. V.Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism-OCDEM, Churchill Hospital, Headington, Oxford, United Kingdom.Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5PLoS OnePloS onePLoS OnePloS onePLoS OnePloS onee554128120131932-6203 (Electronic)
1932-6203 (Linking)23383183http://www.ncbi.nlm.nih.gov/pubmed/23383183355960210.1371/journal.pone.0055412(21)SLC2A9Solute carrier family 2 (facilitated
glucose transporter), member 9Renal hypouricemia type 2 ADDIN EN.CITE Schwarz201431313117Schwarz, J. M.Cooper, D. N.Schuelke, M.Seelow, D.1] Department of Neuropediatrics, Charite - Universitatsmedizin Berlin, Berlin, Germany. [2] NeuroCure Clinical Research Center, Charite - Universitatsmedizin Berlin, Berlin, Germany.
Institute of Medical Genetics, Cardiff University, Cardiff, UK.MutationTaster2: mutation prediction for the deep-sequencing ageNat MethodsNat Methods361-21142014/04/01*Base SequenceDNA/*geneticsDNA Barcoding, Taxonomic*Mutation*Software2014Apr1548-7105 (Electronic)
1548-7091 (Linking)24681721https://www.ncbi.nlm.nih.gov/pubmed/2468172110.1038/nmeth.2890(32)SLC26A1Solute Carrier family 26 (sulfate transporter), Member 1Associated with calcium NL ADDIN EN.CITE Loh201320202017Loh, N. Y.Bentley, L.Dimke, H.Verkaart, S.Tammaro, P.Gorvin, C. M.Stechman, M. J.Ahmad, B. N.Hannan, F. M.Piret, S. E.Evans, H.Bellantuono, I.Hough, T. A.Fraser, W. D.Hoenderop, J. G.Ashcroft, F. M.Brown, S. D.Bindels, R. J.Cox, R. D.Thakker, R. V.Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism-OCDEM, Churchill Hospital, Headington, Oxford, United Kingdom.Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5PLoS OnePloS onePLoS OnePloS onePLoS OnePloS onee554128120131932-6203 (Electronic)
1932-6203 (Linking)23383183http://www.ncbi.nlm.nih.gov/pubmed/23383183355960210.1371/journal.pone.0055412(21)SLC26A6Solute Carrier family 26 (anion exchanger), Member 6Associated with calcium NL ADDIN EN.CITE ADDIN EN.CITE.DATA (33)SLC34A1Solute carrier family 34 (sodium
phosphate), member 1Hypophosphatemic nephrolithiasis/ osteoporosis-1/ Fanconi renotubular syndrome 2; Idiopathic infantile hypercalcemia; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (1,6,21,34,35)SLC34A3Solute carrier family 34 (sodium
phosphate), member 3Hypophosphatemic rickets with hypercalciuria ADDIN EN.CITE ADDIN EN.CITE.DATA (21,33)SLC3A1Solute carrier family 3 (cystine, dibasic
and neutral amino acid transporters), member 1Cystinuria type A; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (6,36-38)SLC4A1Solute carrier family 4, anion exchanger, member 1 (erythrocyte membrane protein band 3)dRTA; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (4,8,32)SLC7A9Solute carrier family 7 (glycoprotein associated
amino acid transporter light chain), member 9Cystinuria type B ADDIN EN.CITE ADDIN EN.CITE.DATA (5)SLC9A3R1Solute carrier family 9, subfamily A (cation proton antiporter 3), member 3 regulator 1Hypophosphatemic NL/osteoporosis-2; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (2,6,39,40)SSP1Secreted phosphoprotein 1, osteopontinAssociated with NL ADDIN EN.CITE ADDIN EN.CITE.DATA (41)TRPV5Transient receptor potential cation channel subfamily V, member 5Association with NL ADDIN EN.CITE ADDIN EN.CITE.DATA (1,42,43)UMODUromodulinAssociation with NL ADDIN EN.CITE Vervaet200942424217Vervaet, B. A.Verhulst, A.D'Haese, P. C.De Broe, M. E.Department of Medicine, Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium.Nephrocalcinosis: new insights into mechanisms and consequencesNephrol Dial TransplantNephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal AssociationNephrol Dial TransplantNephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal AssociationNephrol Dial TransplantNephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association2030-5247HumansKidney Tubules*Nephrocalcinosis/etiology2009Jul1460-2385 (Electronic)
0931-0509 (Linking)19297353http://www.ncbi.nlm.nih.gov/pubmed/1929735310.1093/ndt/gfp115(44)VDRVitamin D (1,25- dihydroxyvitamin D3) receptorIdiopathic hypercalciuria; association with NC/NL ADDIN EN.CITE ADDIN EN.CITE.DATA (40,45,46)XDHXanthine dehydrogenaseXanthinuria type 1 ADDIN EN.CITE Lee200910510510517Lee, Y. S.Kennedy, W. D.Yin, Y. W.Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.Structural insight into processive human mitochondrial DNA synthesis and disease-related polymerase mutationsCellCellCellCell312-241392Amino Acid SequenceCrystallography, X-Ray*DNA ReplicationDNA, Mitochondrial/*metabolismDNA-Directed DNA Polymerase/*chemistry/*geneticsHumansModels, MolecularMolecular Sequence DataNervous System Diseases/geneticsSequence Alignment2009Oct 161097-4172 (Electronic)
0092-8674 (Linking)19837034http://www.ncbi.nlm.nih.gov/pubmed/19837034301853310.1016/j.cell.2009.07.050(47)
NC, nephrocalcinosis; NL, nephrolithiasis.
Table S2 Variants found in RCALC2 mice by exome capture
GeneFull NameNucleotide ChangeProtein changeMutation TypeChrSlc39a10Solute carrier family 39 (zinc transporter), member 10c.A516Cp.Q172Hnonsynonymous SNV1Clca5Chloride channel calcium activated 5c.476-2T>CN/Asplicing3PdgfraPlatelet derived growth factor receptor, alpha polypeptidec.G1588Tp.A530Snonsynonymous SNV5Lilra6Leukocyte immunoglobulin-like receptor, subfamily A, member 6c.C1975Tp.P659Snonsynonymous SNV7Gtf3c1General transcription factor III C 1c.3493+2T>CN/Asplicing7McmbpMCM (minichromosome maintenance deficient) binding proteinc.A1775Gp.D592Gnonsynonymous SNV7Clcn3Chloride channel 3 c.C1113Ap.N371Knonsynonymous SNV8CalrCalreticulinc.C280Tp.Q94Xstopgain SNV8Myo1eMyosin IEc.A1799Gp.E600Gnonsynonymous SNV9Rrp9Ribosomal RNA processing 9c.T442Ap.S148Tnonsynonymous SNV9Nav3Neuron navigator 3c.C4558Tp.1520Fnonsynonymous SNV10Acap1ArfGAP with coiled-coil, ankyrin repeat and PH domains 1 c.C1255Ap.Q419Knonsynonymous SNV11Polg2Polymerase (DNA directed), accessory subunit gamma 2c.C795Ap.Y265Xstopgain SNV11NalcnSodium leak channel, non-selective c.G428Ap.R143Qnonsynonymous SNV14Nfe2Nuclear factor, erythroid derived 2c.A884Gp.E295Gnonsynonymous SNV15Slc29a1Solute carrier family 29 (nucleoside transporters), member 1c.C948Gp.I316Mnonsynonymous SNV17GlyatGlycine-N-acyltransferasec.A310Tp.I104Fnonsynonymous SNV199930023K05RikRIKEN cDNA 9930023K05 genec.T515Ap.I172Nnonsynonymous SNV19FlnaFilamin, alpha c.C1846Tp.P616Snonsynonymous SNVX4932429P05RikRIKEN cDNA 4932429P05c.C1596Ap.S532Rnonsynonymous SNVX
Unique single nucleotide variants (SNV) found in the DNA of two RCALC2 G2 mice, when compared to WT Balb/c and WT C3H parental strains. No variants were identified in genes previously associated with nephrocalcinosis or nephrolithiasis (Table S1). Two genes are located within the interval flanked by D11Mit132 and D11Mit214 on chromosome 11, identified by haplotype analysis to contain the Rcalc2 locus interval (Fig. 1). Investigation of G2 mice by restriction digest analysis revealed the Polg2 (Y265X) mutation to be present in 84% of mice with renal calcification (Table 1).
Table S3 Differentially expressed genes in kidneys of RCALC2 (Polg2+/Y265X) mice compared to parental Balb/c and C3H (Polg2+/+) mice
PathwayGeneGene NameFold changevs. Balb/cvs. C3HApoptosis/ UbiquitinationMum1Melanoma associated antigen 1-1.38*-1.35*PpargPeroxisome proliferator activated receptor gamma-1.83*-1.22*Ube2cUbiquitin-conjugating enzyme E2C-4.19*-1.31*Usp40Ubiquitin specific peptidase 40-1.27*-1.12$Complement pathwayC1qbComplement component 1, q subcomponent, beta polypeptide+1.33$+1.39*C1qcComplement component 1, q subcomponent, C chain+1.26*+1.25$C3Complement component 3+2.45*+1.57*InflammationApomApolipoprotein M+1.29*+1.33*AnpepAlanyl aminopeptidase-1.60*-1.39*Apoc1Apolipoprotein C-I-1.35*-1.26*Pxmp4Peroxisomal membrane protein 4-1.21$-1.22$Intracellular traffickingRabac1Rab acceptor 1 +1.29*+1.15$Snx7Sorting nexin 7+1.26*+1.13*Mitochondrial DNA functionMrpl3Mitochondrial ribosomal protein L3+1.42*+1.30*Mrpl34Mitochondrial ribosomal protein L34+1.24$+1.22*Mrpl53Mitochondrial ribosomal protein L53+1.30*+1.17Mrps26Mitochondrial ribosomal protein S26+1.26*+1.13*Gpd2Glycerol phosphate dehydrogenase 2, mitochondrial-2.33*-1.57*OtherAdcy6Adenylate cyclase 6-1.37*-1.24*Adssl1Adenylosuccinate synthetase like 1-1.81*-1.20$Arhgef10lRho guanine nucleotide exchange factor 10-like-1.99*-1.19*Protein synthesis ER/GolgiSar1aSAR1 gene homolog A +1.30*+1.21$Yif1aYip1 interacting factor homolog A +1.22*+1.15*TranscriptionCcndbp1Cyclin D-type binding-protein 1+1.39*+1.10*Cited2Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2-1.54*-1.76*Eml3Echinoderm microtubule associated protein like 3-1.34*-1.19$
Genes differentially expressed in kidneys of Polg2+/Y265X mice compared to parental Balb/c and C3H WT (Polg2+/+) mice. N = 4 - 8 mice per group. Pairwise comparisons of expression data were performed using the t-statistic, $p<0.05, *p<0.02. No changes in gene expression were identified in genes previously associated with nephrocalcinosis or nephrolithiasis (Table S1), nor were there changes in expression of other genes identified by exome capture (Table S2). cDNA microarray expression profiling, rather than RNA-seq, was used as it is a less expensive method. RNA-seq analysis is likely to have detected a higher number of genes than cDNA expression profiling as it has a larger dynamic range of e x p r e s s i o n t h a t e n a b l e s i t t o d e t e c t g e n e s a t a l o w e r a b u n d a n c e a n d t h u s R N A - s e q i s m o r e s e n s i t i v e t h a n c D N A e x p r e s s i o n p r o f i l i n g A D D I N E N . C I T E A D D I N E N . C I T E . D A T A ( 4 8 - 5 0 ) . T a b l e S 4 C t v a l u e s f r o m q R T - P C R a n a l y s i s p r e s e n t e d i n F i g u r e s 2 , 3 a n d 4
Figure 2Figure 3Figure 4Polg2Ube2cc1qcc3ApomPxmp4Mrpl3Gpd2Ndufa1Ndufa4AcadmCycsCasp3Casp9Ucp2Timd4Polg2+/+1.441.825.342.333.300.592.623.853.203.802.71-0.249.2813.228.5914.402.121.635.773.743.340.021.403.193.604.200.23-0.327.8112.285.6814.241.400.707.183.754.290.052.192.193.143.863.491.527.6112.575.9414.161.261.346.122.372.890.332.083.003.284.310.32-0.409.0512.696.1113.34Polg2+/Y265X2.012.454.081.53-0.47-5.073.205.205.034.690.48-1.608.0313.223.3415.433.163.054.94-0.73-0.43-6.594.235.235.683.931.54-1.028.3713.945.2815.363.133.195.43-0.831.65-3.124.095.095.304.183.92-2.597.5412.523.7015.622.672.954.71-1.091.49-3.772.767.004.213.552.11-2.129.0513.233.5914.051.942.454.69-0.25-1.384.435.134.75
C t v a l u e s u s e d t o c a l c u l a t e c D N A f o l d - c h a n g e s f o r q R T - P C R r e s u l t s s h o w n i n F i g u r e s 2 , 3 a n d 4 . C t v a l u e s w e r e d e r i v e d b y s u b t r a c t i n g t h e C t v a l u e o f t h e h o u s e k e e p i n g g e n e f r o m t h e e x p e r i m e n t a l g e n e . T h e a v e r a g e o f t h e C t v a l u e s w a s t h e n u s e d a s a r e f e r e n c e t o c a l c u l a t e C t v a l u e s . F o l d - c h a n g e s w e r e c a l c u l a t e d u s i n g t h e f o r m u l a 2 - ( ""C t ) .
S U P P L E M E N T A L F I G U R E S
F i g . S 1 I n v e s t i g a t i o n o f f i b r o s i s a n d e c t o p i c c a l c i f i c a t i o n i n R C A L C 2 m i c e
( A ) H i s t o l o g i c a l s e c t i o n s o f t h e k i d n e y s o f R C A L C 2 m i c e a n d u n a f f e c t e d ( w i l d - t y p e , W T ) l i t t e r m a t e s s t a i n e d w i t h M a s s o n s t r i c h r o m e f o r d e t e c t i o n o f f i b r o s i s . F i b r o s i s w a s a b s e n t i n R C A L C 2 a n d W T m o u s e k i d n e y s . S c a l e = 1 0 m . ( B ) H i s t o l o g i c a l s e c t i o n s o f t h e h e a r t o f R C A L C 2 m i c e a n d W T l i t t e r m a t e s . S e c t i o n s w e r e s t a i n e d w i t h ( t o p ) v o n K o s s a t o d e t e c t c a l c i u m d e p o s i t s a n d ( b o t t o m ) h a e m a t o x y l i n a n d e o s i n ( H a n d E ) , t o a s s e s s g r o s s m o r p h o l o g y . N o d i f f e r e n c e s w e r e o b s e r v e d b e t w e e n t h e h e a r t s e c t i o n s o f t h e R C A L C 2 a n d W T l i t t e r m a t e s . S c a l e = 1 0 m .
F i g . S 2 I n v e s t i g a t i o n o f u r i n ary protein output in Polg2+/Y265X mice
Coomassie analysis of proteins in urine from Polg2+/+ and Polg2+/Y265X mice. No difference in amounts of total protein or low-molecular-weight proteins was evident from the Coomassie Blue analysis.
Fig. S3 Multiple sequence alignment of POLG2 protein sequence from twelve species
Mouse ALEHYVNCLDLVNRKLPFGLAQIGVCFHPVSNSNQTPSSVTRVGEKTEASLVWFTPTRTS 222
Human ALEHYVNCLDLVNKRLPYGLAQIGVCFHPVFDTKQIRNGVKSIGEKTEASLVWFTPPRTS 248
Rat ALEHYVHCLDLVNRKLPYGLAQIGVCFHPVLNPKEIPNSVTRVGEKTEASLVWFTPTRTS 222
Cow ALEHYVSYLDLVNKRLPFGLAQIGACFHPVSDTKQTPDGVKRIGEKTEASLVWFTSARTA 248
Dog ALEHYVSCLDLVNKRLPYGLAQIGVCFHPVSDTKQTPDGVKRIGEKTEASLVWFTSARTA 248
Chicken ALAQYVSCLEFVNKRLPCGLAEVGVCFHSIPGSEQHNEKLRRIGERTTSLLTWFSSPRTA 227
Guinea fowl ALAQYASCLEFVNKRLPCGLAEVGVCFHSIPGSEQHNEKLRRIGERTTSLLTWFSSPRTA 231
Anole lizard VLEHYVECLELVNKRLPFGAAQIGTCFHAVATNEKE--NNVRTGERMMSILVWYSSGRTA 232
Python ALEHYVECLELVNKRLPFGLAQIGICFHPND----K--NPMRTGERTMASLVWYSSARTA 290
Zebrafish ALQQYIQALELVNRTLPFGLAETGLCYNFDNQLRH---SSDCSSEVTESSLVWFCSPRTS 203
Rainbow trout ALEQYVPSLELVNRKLPFGLAETGLCFQPS----G---GPSCPDEVTQSSLVWFCSPRTS 221
Xenopus ALLEYVPSMELLNKKMPFGLAEIGKCFHSIPEERNKGTILPRIGERTVASLVWFSSPKSS 226
.* .* ::::*: :* * *: * *:: .* : *.*: :::
Mouse SQWLDFWLRHRLLWWRKFAMSPSNFSSADCQDEL----GRKGSKLYYSFPWGKEPIETLW 278
Human NQWLDFWLRHRLQWWRKFAMSPSNFSSSDCQDEE----GRKGNKLYYNFPWGKELIETLW 304
Rat SQWLDFWLRHRLLWWRKFAVSPSNFSSVDCQDGS----GRKGCRLYYSFPWGKEPLETLW 278
Cow SQWLDFWLRHRLLWWRKFAMSPSNFSSGDCQDEA----GRKGNRLYYNFPWGKEPIETLW 304
Dog GQWLDFWLRHRLLWWRKFAVSPSNFSSSDCQDEE----GRKGNQLYYNFPWGKEPIETLW 304
Chicken GQWLDYWFRQRLQWWRKFAVGPSNFSSSDFQDEE----GRRGFNLHYEFPWGTETVETLK 283
Guinea fowl GQWLDYWLRQRLQWWRKFAVGPSNFSSSDFQDEE----GRRGFNLHYDFPWGTETIETLK 287
Anole lizard GQWLDYWLRQRLQWWRKFAICPSNFSSSHHHDEE----GRRGSNLYYSFPWGKELIETLR 288
Python GQWLDYWLRQRLQWWRKFAISPSNFSSSS-HNEE----GRRGNNLYYNFPWGKETIETLR 345
Zebrafish SQWMDYWVHHRLKWWRKFALGPSDFNLCNVGDESLKEGASHGVKVLYNFPWGSETLETLW 263
Rainbow trout SQWLDYWARHRLQWWRKFALGPSDFSCSDITEEELAGRASRGVKIVYNFPWGQEALETLL 281
Xenopus GQWQDYWLRQRLQWWQKFAQSPSGFSCNDIQDGQ----GRKSSLIQYEFPWGRETIETLC 282
.** *:* ::** **:*** **.*. : . :. : *.**** * :***
Mouse NLGDQELLHTYPGNVSTIQGRDGRKNVVPCVLSVSGDVDLGTLAYLYDSFQLAENSFARK 338
Human NLGDHELLHMYPGNVSKLHGRDGRKNVVPCVLSVNGDLDRGMLAYLYDSFQLTENSFTRK 364
Rat DLGEQELLNVYPGDVSAIQGRDGRKNVVPSVLSVNGDLDLGTLAYLYDSFQFTENSFSRK 338
Cow NLGDHELLHMYPGSVAQVHGRDGRKNVVPSVLSINGDLDRGMLAYLYDSFQLTENSFTRK 364
Dog NLGDHELLHMYPGNESQLHGRDGRKNVVPYVLSINGNLDRGVLAYLYDSFQLTENSFTRK 364
Chicken NLGDTELLQMYPGDRSKLLGRDGRKSVIPHVLSVSGNLDQGALAYLFDSLQLAENPLTTK 343
Guinea fowl NLGDTELLQMYPGDRSKLLGRDGRKSVLPHVLSVSGNLDQGALAYLFDSLQLAENPLTKK 347
Anole lizard SLGDNELLKMYPGKGSQLHGRDGRKSMVPHILSVSGNLDSGVLAYLFDGFQLGENAVTRK 348
Python ILGDNELLQMYPGRVSRLHGRDGRKHVVPHILSVSGNLDSGVLAYLCDSMQVAENGLTKK 405
Zebrafish TLGDTQLLKTHQETSVKVQCRDGRKSVVPHVISVSVNVDRGMLAYLFNSLQRLKKTDSKQ 323
Rainbow trout SRGDAELLQTHKSARNKLQCLDGRKSVVPYAISVTGNLERGVLAYLYNSLQQVKKVDSKQ 341
Xenopus NMDDSALFQMHPGCTTKLQARDGRKSVVPHVVWVSGDLDRGILAYLSDALQQTEAPAVRG 342
.: *:: : : **** ::* : :. ::: * **** :.:* :
Mouse KSLQRKVLKLHPCLAPIKVALDVGKGPTVELRQVCQGLLNELLENGISVWPGYSETVHSS 398
Human KNLHRKVLKLHPCLAPIKVALDVGRGPTLELRQVCQGLFNELLENGISVWPGYLETMQSS 424
Rat KSLQRKVLKLHPCLAPIKVALDVGKGPTVELRQVCQGLLNELLENGIAVWPGYLETAQSS 398
Cow KDLHRKVLKLHPCLAPIKAALDVGRGPTVELRQVCQGLFNELLENGISVWPGYLETVQSS 424
Dog KNLHRKVLKLHPCLAPVKVALDVGRGPTVELRQVCQGLFNELLENGISVWPGYMETVQSS 424
Chicken KNSQRKVLKLHPCLTPIKVALDVGKGPTTELRQVCQGLFNELSENRIAVWPGYLETTQVS 403
Guinea fowl KNSQRKVLKLHPCLTPIKVALDVGKGPTTELRQVCQGLFNELSENRISVWPGYLETTQVS 407
Anole lizard KTQQRKVLKLHPSLTPIKVALDVARGPTTELRQVCQGLFSELLENGISVWPGYLETMPLT 408
Python KALQRKVLKLHPCLAPIRVALDVGRGPAIELRQVCQGLFKELLENGISVWPGYLETMQSS 465
Zebrafish KLHQRTVLKLHPALTPVKVALDIGRGSNSELRQVCEGLLQEFLEVGISTWPGYLDTK--S 381
Rainbow trout RLQQRKVLKLHPILSPVKVALDMGRGATVELRQVCEGLLKEFLEGGVSAWPGYLETMPTS 401
Xenopus QYHQREVLKLHPTLAPIKVAVDMGKGPTGELRLVCQGLSSELREQGVYVWPGYQETLHGS 402
: :* ****** *:*::.*:*:.:* *** **:** .*: * : .**** :* :
Mouse LEQLHSKYDEMSVLFSVLVTETTLENGLIQLRSRDTTMKEMMHISKLRDFLVKYLASASN 458
Human LEQLYSKYDEMSILFTVLVTETTLENGLIHLRSRDTTMKEMMHISKLKDFLIKYISSAKN 484
Rat LEQLYSKYDEMSILFTVLITETTLESGLIQLRSRDTTMKEMMHISRLRDFLVKYLASAGK 458
Cow LEQLYSKYDEMSILFTVLITEATLENGLIQLRSRDTTMKEMMHISKVKDFLTKYISSAKN 484
Dog LEQLYSKYDEMSILFTVLITETTLENGLIHLRNRDTTMKEMMHISKVKGFLIKYISSAKN 484
Chicken LEQLYTKYDEMGVLFMILISDSTLENGVVQLRSRDTTMKEMMHISRLKDFLTKYIASAKN 463
Guinea fowl LEQLYTKYDEMSVLFMVLISDATLENGVVQLRSRDTTMKEMMHISRLKDFLIKYIASAKN 467
Anole lizard LEQLYTKYDEMSILFTILVSEATLENGVVQLRNRNTTMKEMMHISRLKDFLTKYISAAKN 468
Python LEQLYTKYDEMGVLFTVLISDATLENGLVQLRSRDTTLKEMMHISRLKDFLIKYISAAKN 525
Zebrafish LENLNTKYDEMGVLFTVMVSESTLKSGLLLVRNRDTTIRETMHISEIKCFLLKYISASEN 441
Rainbow trout MEQLNTKYDEMGVLFTVVISDNTLESGLLQVRSRDTTIKETMHISEVKNFLARYISAAQN 461
Xenopus LEQLYTKYDKMGVLFTVLVSESTLENGLLQVRSRDTTLKETIHVSKVKDFLVRYIAAAGN 462
:*:* :***:*.:** ::::: **:.*:: :*.*:**::* :*:*.:: ** :*:::: :
Alignment of part of the POLG2 protein sequence in twelve species demonstrating that the Tyr265 (Y265) residue affected in RCALC2 mice is conserved across species. In addition, the majority (87%) of the C-terminal amino acids predicted to be lost in mice with the Polg2-Y265X mutation are conserved between mouse and human. POLG2 is only conserved in vertebrates, and not in invertebrates, in which it acts as a monomer. Symbols are exported from ClustalW ADDIN EN.CITE Sievers201830303017Sievers, F.Higgins, D. G.School of Medicine and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.Clustal Omega for making accurate alignments of many protein sequencesProtein SciProtein Sci135-1452712017/09/09Proteins/chemistry/*geneticsSequence Alignment/*methodsSequence Analysis, Protein/*methods*Softwarebenchmarkingclustal omegamultiple sequence alignmentprotein structure2018Jan1469-896X (Electronic)
0961-8368 (Linking)28884485https://www.ncbi.nlm.nih.gov/pubmed/28884485PMC573438510.1002/pro.3290(51). An asterisk (*) indicates positions which have a single, fully conserved residue, a colon (:) indicates conservation between groups of strongly similar properties, and a full-stop (.) indicates conservation between groups of weakly similar properties ADDIN EN.CITE Sievers201830303017Sievers, F.Higgins, D. G.School of Medicine and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.Clustal Omega for making accurate alignments of many protein sequencesProtein SciProtein Sci135-1452712017/09/09Proteins/chemistry/*geneticsSequence Alignment/*methodsSequence Analysis, Protein/*methods*Softwarebenchmarkingclustal omegamultiple sequence alignmentprotein structure2018Jan1469-896X (Electronic)
0961-8368 (Linking)28884485https://www.ncbi.nlm.nih.gov/pubmed/28884485PMC573438510.1002/pro.3290(51). Fig. S4 Full Western blots from Figure 2
(A) Full gels from Western blots presented in Figure 2B. Gels were probed with POLG, then stripped and reprobed with calnexin. An image of the gel ladder was then taken. (B) Full gels from Western blots presented in Figure 2C. Gels were probed with POLG2, then stripped and reprobed with calnexin. An image of the gel ladder was then taken.
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