Point Mutation Knockin Mouse Models

For academic research: Study protein function (gain or loss of function) Analyze the role of non-coding regions and regulatory elements Investigate disease-causing mutations

For bio-pharmaceutical research & development: Study drug-resistant mutants Alter drug-antibody affinities Pharmacological off-target and efficacy studies Mimic human genetic diseases

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Best way to reproduce human disease when due to mutations High physiological relevancy of the scientific data obtained from the model (regulatory elements conserved, under control of endogenous promoter, expression of all splice variants, etc.) = cleaner way than classical KO where the whole gene is deleted Phenotype due only to the mutation: alteration of a single function without disturbing other domains of a protein

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Mutation of the gene of interest may affect development, resulting in an impaired phenotype or embryonic death →  Limitation can be bypassed by applying conditions such as time-specific gene inactivation 1. Modification or disruption of splicing regulation 2. Genetic redundancy →  Can be assessed via constitutive Knockout of the gene of interest

Model with heterozygous point mutations, exactly homologous to human retinitis pigmentosa (RP).

Sothilingam V, et al. Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype. Hum Mol Genet. 2015.

Mutations in the PDE6A gene can cause rod photoreceptor degeneration and the blinding disease retinitis pigmentosa.

Model: Novel mouse model for the Pde6a^R562W point mutation in combination with an existing line carrying the V685M point mutation to generate compound heterozygous Pde6a^V685M/R562W animals, exactly homologous to a case of human RP.

Aim: Predict time-courses for Pde6a-related retinal degeneration and thereby facilitate the definition of a window of opportunity for clinical interventions.

Results: The study provides a rational basis for predictions on human RP phenotypes and disease progression in compound heterozygous situations, and suggests the targeting of non-apoptotic processes as a feasible treatment approach.

 

Figure 1. Loss of PDE6A expression causes cGMP accumulation.

Excessive accumulation of cGMP and subsequent rod photoreceptor death, followed by a mutation-independent, secondary death of cone photoreceptors.

	A, B) In the PN11 wildtype (wt) retina (A), immunostaining for PDE6A shows strong protein expression in photoreceptor OS. In contrast, at the same age, in the compound heterozygous V685M/R562W retina (C), the protein is essentially absent.
	C, D) At PN11, wt retina is essentially negative for cGMP immunoreactivity (C). PDE6A mutants, however, display individual rod photoreceptor cells that have accumulated large amounts of cGMP (D).
E) The quantification of cGMP-positive cells in the ONL and the PDE6A pixel intensity in the OS (arbitrary units; AU) shows an inverse correlation. Images are representative for immunostaining performed on retinal sections from at least three independent animals for each genotype.

 

Figure 2. Photoreceptor cell death and survival.

A-C) The TUNEL assay in the wt retina occasionally labeled cells dying due to developmental processes. D-F) In Pde6a mutants, photoreceptor cell death was dramatically increased. The images show the situation at P12, P15 and P21, time-points corresponding to the peak of cell death..   G, H) The line graph at the bottom left (G) illustrates the progression of photoreceptor cell death as evidenced by the TUNEL assay in different Pde6a mutants. The green line corresponds to the V685M*R562W mutant. The peak times as well as the peak amplitudes correspond to the speed of retinal degeneration, which is illustrated by the loss of photoreceptors (H). Images are representative for TUNEL assays performed on retinal sections from at least three independent animals; quantifications in G, H include data from 3-7 animals per genotype and time-point.

 

Figure 3. Photoreceptor degeneration in Pde6a mutants correlates with calpain, not caspase, activity.

Calpain activity is often associated with non-apoptotic forms of cell death, and in all Pde6a mutants it is strongly correlated in time with the progression of photoreceptor cell death.

A) Quantification of caspase-3-positive cells, which shows only extremely low numbers of cells at the respective peaks of degeneration, with no significant (n.s.) differences to wt. B) The progression of calpain activity was analyzed over time and showed a strong correlation to the extent of cell death and the progression of retinal degeneration.

2022

Arianne Papa, Sergey I Zakharov, Alexander N Katchman, Jared S Kushner, Bi-Xing Chen, Lin Yang, Guoxia Liu, Alejandro Sanchez Jimenez, Robyn J Eisert, Gary A Bradshaw, Wen Dun, Shah R Ali, Aaron Rodriques, Karen Zhou, Veli Topkara, Mu Yang, John P Morrow, Emily J Tsai, Arthur Karlin, Elaine Wan, Marian Kalocsay, Geoffrey S Pitt, Henry M Colecraft, Manu Ben-Johny, Steven O Marx.
Rad regulation of CaV1.2 channels controls cardiac fight-or-flight response.
Nat Cardiovasc Res. 2022 Nov

Nicholas L Weilinger, Leigh E Wicki-Stordeur, Christopher J Groten, Jeffrey M LeDue, Kristopher T Kahle, Brian A MacVicar.
KCC2 drives chloride microdomain formation in dendritic blebbing.
Cell Rep. 2022 Oct 25

Margarita Brilkova, Martina Nigri, Harshitha Santhosh Kumar, James Moore, Matilde Mantovani, Claudia Keller, Amandine Grimm, Anne Eckert, Dimitri Shcherbakov, Rashid Akbergenov, Petra Seebeck, Stefanie D Krämer, David P Wolfer, Thomas C Gent, Erik C Böttger.
Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice.
Cell Rep. 2022 Sep 27

Dimitri Shcherbakov, Martina Nigri, Rashid Akbergenov, Margarita Brilkova, Matilde Mantovani, Patricia Isnard Petit, Amandine Grimm, Agnieszka A Karol, Youjin Teo, Adrián Cortés Sanchón, Yadhu Kumar, Anne Eckert, Kader Thiam, Petra Seebeck, David P Wolfer, Erik C Böttger.
Premature aging in mice with error-prone protein synthesis
Sci Adv. 2022 Mar 4

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2021

Yasemin Özgür-Günes, Catherine Le Stunff, Malha Chedik, Marie-Pierre Belot, Pierre-Hadrien Becker, Véronique Blouin, Pierre Bougnères.
Correction of a knock-in mouse model of acrodysostosis with gene therapy using a rAAV9-CAG-human PRKAR1A vector.
Gene Ther. 2021 Oct 1

Christoph S Clemen, Andreas Schmidt, Lilli Winter, Fabio Canneva, Ilka Wittig, Lore Becker, Roland Coras, Carolin Berwanger, German Mouse Clinic Consortium; Andreas Hofmann, Britta Eggers, Katrin Marcus, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Marcus Krüger, Stephan von Hörsten, Ludwig Eichinger, Rolf Schröder.
N471D WASH complex subunit strumpellin knock-in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue.
Neuropathol Appl Neurobiol. 2021 Jul 27

Anastasia Noël, Bénédicte Foveau, Andréa C LeBlanc.
Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits.
Cell Death Dis. 2021 Mar 1

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2020

Amos Fumagalli, Joyce Heuninck, Anne Pizzoccaro, Enora Moutin, Joyce Koenen, Martial Séveno, Thierry Durroux, Marie-Pierre Junier, Géraldine Schlecht-Louf, Francoise Bachelerie, Dagmar Schütz, Ralf Stumm, Martine J Smit, Nathalie C Guérineau, Séverine Chaumont-Dubel, Philippe Marin.
The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication.
Nat Commun. 2020 Sep 25

Julia Schuld, Zacharias Orfanos, Frédéric Chevessier, Britta Eggers, Lorena Heil, Julian Uszkoreit, Andreas Unger, Gregor Kirfel, Peter F M van der Ven, Katrin Marcus, Wolfgang A Linke, Christoph S Clemen, Rolf Schröder, Dieter O Fürst.
Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation.
Acta Neuropathol Commun. 2020 Sep 4

Lu Long, Xudong Yang, Mark Southwood, Stephen Moore, Alexi Crosby, Paul D Upton, Benjamin J Dunmore, Nicholas W Morrell.
Targeting translational read-through of premature termination mutations in BMPR2 with PTC124 for pulmonary arterial hypertension.
Pulm Circ. 2020 Jul 20

Amanda Haage, Kelsey Wagner, Wenjun Deng, Bhavya Venkatesh, Caitlin Mitchell, Katharine Goodwin, Aaron Bogutz, Louis Lefebvre, Catherine D Van Raamsdonk, Guy Tanentzapf.
Precise coordination of cell-ECM adhesion is essential for efficient melanoblast migration during development.
Development. 2020 Jul 17

L Francisco Lorenzo-Martín, Sonia Rodríguez-Fdez, Salvatore Fabbiano, Antonio Abad, María C García-Macías, Mercedes Dosil, Myriam Cuadrado, Javier Robles-Valero, Xosé R Bustelo.
Vav2 Pharmaco-Mimetic Mice Reveal the Therapeutic Value and Caveats of the Catalytic Inactivation of a Rho Exchange Factor.
Oncogene. 2020 Jun 11.

Mathieu Milh, Pierre Roubertoux, Najoua Biba, Julie Chavany, Adeline Spiga Ghata, Camille Fulachier, Stephan Christopher Collins, Christel Wagner, Jean-Christophe Roux, Binnaz Yalcin, Marie-Solenne Félix, Florence Molinari, Pierre-Pascal Lenck-Santini, Laurent Villard.
A knock-in mouse model for KCNQ2-related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment.
Epilepsia. 2020 May.

Benjamin J Dunmore, XuDong Yang, Alexi Crosby, Stephen Moore, Lu Long, Christopher Huang, Mark Southwood, Eric D Austin, Amer Rana, Paul D Upton, Nicholas W Morrell.
4PBA Restores Signalling of a Cysteine-substituted Mutant BMPR2 Receptor Found in Patients With PAH.
Am J Respir Cell Mol Biol. 2020 Apr 7.

Nobuaki Fukuma, Eiki Takimoto, Kazutaka Ueda, Pangyen Liu, Miyu Tajima, Yu Otsu, Taro Kariya, Mutsuo Harada, Haruhiro Toko, Kaori Koga, Robert M Blanton Jr, Richard H Karas, Issei Komuro.
Estrogen Receptor-α Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy.
JACC Basic Transl Sci. 2020 Mar 4.

Sophie J Bradley, Colin Molloy, Paulina Valuskova, Louis Dwomoh, Miriam Scarpa, Mario Rossi, Lisa Finlayson, Kjell A Svensson, Eyassu Chernet, Vanessa N Barth, Karolina Gherbi, David A Sykes, Caroline A Wilson, Rajendra Mistry, Patrick M Sexton, Arthur Christopoulos, Adrian J Mogg, Elizabeth M Rosethorne, Shuzo Sakata, R A John Challiss, Lisa M Broad, Andrew B Tobin.
Biased M1-muscarinic-receptor-mutant Mice Inform the Design of Next-Generation Drugs.
Nat Chem Biol. 2020 Mar.

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2019

Shcherbakov D, Teo Y, Boukari H, Cortes-Sanchon A, Mantovani M, Osinnii I, Moore J, Juskeviciene R, Brilkova M, Duscha S, Kumar HS, Laczko E, Rehrauer H, Westhof E, Akbergenov R, Böttger EC.
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Sci Signal. 2019 Oct 15.

Oberbeck N, Pham VC, Webster JD, Reja R, Huang CS, Zhang Y, Roose-Girma M, Warming S, Li Q, Birnberg A, Wong W, Sandoval W, Kőműves LG, Yu K, Dugger DL, Maltzman A, Newton K, Dixit VM.
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Nature. 2019 Oct.

DiCarlo GE, Aguilar JI, Matthies HJ, Harrison FE, Bundschuh KE, West A, Hashemi P, Herborg F, Rickhag M, Chen H, Gether U, Wallace MT, Galli A.
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Molybdenum cofactor deficiency type B knock-in mouse models carrying patient-identical mutations and their rescue by singular AAV injections.
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2018

Haage A, Goodwin K, Whitewood A, Camp D, Bogutz A, Turner CT, Granville DJ, Lefebvre L, Plotnikov S, Goult BT, Tanentzapf G.
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The heterozygous R155C VCP mutation: Toxic in humans! Harmless in mice?
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2017

Andrew RJ, Fernandez CG, Stanley M, Jiang H, Nguyen P, Rice RC, Buggia-Prévot V, De Rossi P, Vetrivel KS, Lamb R, Argemi A, Allaert ES, Rathbun EM, Krause SV, Wagner SL6, Parent AT, Holtzman DM, Thinakaran G.
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Proc Natl Acad Sci U S A. 2017 Nov 7.

Hu LR, Ackermann MA, Hecker PA, Prosser BL, King B, O'Connell KA, Grogan A, Meyer LC, Berndsen CE, Wright NT, Jonathan Lederer W, Kontrogianni-Konstantopoulos A.
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2016

Kauskot A, Poirault-Chassac S, Adam F, Muczynski V, Aymé G, Casari C, Bordet JC, Soukaseum C, Rothschild C, Proulle V, Pietrzyk-Nivau A, Berrou E, Christophe OD, Rosa JP, Lenting PJ, Bryckaert M, Denis CV, Baruch D.
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JCI Insight. 2016 Oct 6.

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J Bone Miner Res. 2016 Sep 2.

Jiao K, Sahaboglu A, Zrenner E, Ueffing M, Ekström PA, Paquet-Durand F.
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Cell Death Discov. 2016 Jul 4.

Adam F, Casari C, Prévost N, Kauskot A, Loubière C, Legendre P, Repérant C, Baruch D, Rosa JP, Bryckaert M, de Groot PG, Christophe OD, Lenting PJ, Denis CV.
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Sci Rep. 2016 May 23.

Qu Y, Misaghi S, Newton K, Maltzman A, Izrael-Tomasevic A, Arnott D, Dixit VM.
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Yavari A, Stocker CJ, Ghaffari S, Wargent ET, Steeples V, Czibik G, Pinter K, Bellahcene M, Woods A, Martínez de Morentin, Cansell C, Lam BY, Chuster A, Petkevicius K, Nguyen-Tu MS, Martinez-Sanchez A, Pullen TJ, Oliver PL, Stockenhuber A, Nguyen C, Lazdam M, O'Dowd JF, Harikumar P, Tóth M, Beall C, Kyriakou T, Parnis J, Sarma D, Katritsis G, Wortmann DD, Harper AR, Brown LA, Willows R, Gandra S, Poncio V, de Oliveira Figueiredo MJ, Qi NR, Peirson SN, McCrimmon RJ, Gereben B, Tretter L, Fekete C, Redwood C, Yeo GS, Heisler LK, Rutter GA, Smith MA, Withers DJ, Carling D, Sternick EB, Arch JR, Cawthorne MA, Watkins H, Ashrafian H.
Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.
Cell Metab. 2016 Apr 26.

Ness JK, Skiles AA, Yap EH, Fajardo EJ, Fiser A, Tapinos N.
Nuc-ErbB3 regulates H3K27me3 levels and HMT activity to establish epigenetic repression during peripheral myelination.
Glia. 2016 Mar 28.

Viuff D, Antunes F, Evans L, Cameron J, Dyrnesli H, Thue Ravn B, Stougaard M, Thiam K, Andersen B, Kjærulff S, Howard KA.
Generation of a double transgenic humanized neonatal Fc receptor (FcRn)/albumin mouse to study the pharmacokinetics of albumin-linked drugs.
J Control Release. 2016 Feb 10.

Butcher AJ, Bradley SJ, Prihandoko R, Brooke SM, Mogg A, Bourgognon JM, Macedo-Hatch T, Edwards JM, Bottrill AR, Challiss RA, Broad LM, Felder CC, Tobin AB.
An antibody biosensor establishes the activation of the M1 muscarinic acetylcholine receptor during learning and memory.
J Biol Chem. 2016 Jan 29.

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2015

Chevessier F, Schuld J, Orfanos Z, Plank AC, Wolf L, Maerkens A, Unger A, Schlötzer-Schrehardt U, Kley RA, Von Hörsten S, Marcus K, Linke WA, Vorgerd M, van der Ven PF, Fürst DO, Schröder R.
Myofibrillar instability exacerbated by acute exercise in filaminopathy.
Hum Mol Genet. 2015 Dec 20.

Yzaguirre AD, Padmanabhan A, de Groh ED, Engleka KA, Li J, Speck NA, Epstein JA.
Loss of neurofibromin Ras-GAP activity enhances the formation of cardiac blood islands in murine embryos.
Elife. 2015 Oct 13.

Sothilingam V, Garcia Garrido M, Jiao K, Buena-Atienza E, Sahaboglu A, Trifunović D, Balendran S, Koepfli T, Mühlfriedel R, Schön C, Biel M, Heckmann A, Beck SC, Michalakis S, Wissinger B, Seeliger MW, Paquet-Durand F.
Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype.
Hum Mol Genet. 2015 Oct 1.

Mellgren AE, Bruland O, Vedeler A, Saraste J, Schönheit J, Bredrup C, Knappskog PM, Rødahl E.
Development of congenital stromal corneal dystrophy is dependent on export and extracellular deposition of truncated decorin.
Invest Ophthalmol Vis Sci. 2015 May 31.

Smallie T, Ross EA, Ammit AJ, Cunliffe HE, Tang T, Rosner DR, Ridley ML, Buckley CD, Saklatvala J, Dean JL, Clark AR.
Dual-Specificity Phosphatase 1 and Tristetraprolin Cooperate To Regulate Macrophage Responses to Lipopolysaccharide.
J Immunol. 2015 May 27.

Ross EA, Smallie T, Ding Q, O'Neil JD, Cunliffe HE, Tang T, Rosner DR, Klevernic I, Morrice NA, Monaco C, Cunningham AF, Buckley CD, Saklatvala J, Dean JL, Clark AR.
Dominant Suppression of Inflammation via Targeted Mutation of the mRNA Destabilizing Protein Tristetraprolin.
J Immunol. 2015 May 22.

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2007-2014

Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C, Guo H, Lich JD, Finger J, Kasparcova V, Votta B, Ouellette M, King BW, Wisnoski D, Lakdawala AS, DeMartino MP, Casillas LN, Haile PA, Sehon CA, Marquis RW, Upton J, Daley-Bauer LP, Roback L, Ramia N, Dovey CM, Carette JE, Chan FK, Bertin J, Gough PJ, Mocarski ES, Kaiser WJ.
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Mol Cell. 2014 Nov 20.

Clemen CS, Stöckigt F, Strucksberg KH, Chevessier F, Winter L, Schütz J, Bauer R, Thorweihe JM, Wenzel D, Schlötzer-Schrehardt U, Rasche V, Krsmanovic P, Katus HA, Rottbauer W, Just S, Müller OJ, Friedrich O, Meyer R, Herrmann H, Schrickel JW, Schröder R
The toxic effect of R350P mutant desmin in striated muscle of man and mouse.
Acta Neuropathol. 2014 Nov 14.

Fantin A, Herzog B, Mahmoud M, Yamaji M, Plein A, Denti L, Ruhrberg C, Zachary I.
Neuropilin 1 (NRP1) hypomorphism combined with defective VEGF-A binding reveals novel roles for NRP1 in developmental and pathological angiogenesis.
Development. 2014 Jan 8.

Puszyk W, Down T, Grimwade D, Chomienne C, Oakey RJ, Solomon E, Guidez F.
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EMBO J. 2013 May 31.

Chen CM, Bentham J, Cosgrove C, Braganca J, Cuenda A, Bamforth SD, Schneider JE, Watkins H, Keavney B, Davies B, Bhattacharya S.
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PLoS One. 2012 Oct 17.

Kollmann K, Damme M, Markmann S, Morelle W, Schweizer M, Hermans-Borgmeyer I, Röchert AK, Pohl S, Lübke T, Michalski JC, Käkelä R, Walkley SU, Braulke T.
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Brain. 2012 Sep.

Nogales-Gadea G, Pinós T, Lucia A, Arenas J, Camara Y, Brull A, de Luna N, Martín MA, Garcia-Arumí E, Martí R, Andreu AL.
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Shu X, Luhmann UF, Aleman TS, Barker SE, Lennon A, Tulloch B, Chen M, Xu H, Jacobson SG, Ali R, Wright AF.
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PLoS One. 2011 Nov 16.

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A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget's disease-like disorder in mice.
Hum Mol Genet. 2011 Jul 15.

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