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1. Structural basis for AcrVA4 inhibition of specific CRISPR-Cas12a.

Author

Knott, GJ, Cress, BF, Liu, J-J, Thornton, BW, Lew, RJ, Al-Shayeb, B, Rosenberg, DJ, Hammel, M, Adler, BA, Lobba, MJ, Xu, M, Arkin, AP, Fellmann, C, and Doudna, JA

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biotechnology, Genetics, 1.1 Normal biological development and functioning, Acidaminococcus, Bacteriophages, CRISPR-Cas Systems, Clostridiales, Enzyme Inhibitors, Evolution, Molecular, Host-Parasite Interactions, Viral Proteins, CRISPR-Cas, E. coli, anti-CRISPR, bacteriophage, biochemistry, chemical biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

CRISPR-Cas systems provide bacteria and archaea with programmable immunity against mobile genetic elements. Evolutionary pressure by CRISPR-Cas has driven bacteriophage to evolve small protein inhibitors, anti-CRISPRs (Acrs), that block Cas enzyme function by wide-ranging mechanisms. We show here that the inhibitor AcrVA4 uses a previously undescribed strategy to recognize the L. bacterium Cas12a (LbCas12a) pre-crRNA processing nuclease, forming a Cas12a dimer, and allosterically inhibiting DNA binding. The Ac. species Cas12a (AsCas12a) enzyme, widely used for genome editing applications, contains an ancestral helical bundle that blocks AcrVA4 binding and allows it to escape anti-CRISPR recognition. Using biochemical, microbiological, and human cell editing experiments, we show that Cas12a orthologs can be rendered either sensitive or resistant to AcrVA4 through rational structural engineering informed by evolution. Together, these findings explain a new mode of CRISPR-Cas inhibition and illustrate how structural variability in Cas effectors can drive opportunistic co-evolution of inhibitors by bacteriophage.

Published
2019

2. The structural basis for the functional comparability of factor VIII and the long‐acting variant recombinant factor VIII Fc fusion protein

Author

Leksa, NC, Chiu, P‐L, Bou‐Assaf, GM, Quan, C, Liu, Z, Goodman, AB, Chambers, MG, Tsutakawa, SE, Hammel, M, Peters, RT, Walz, T, and Kulman, JD

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Biotechnology, Crystallography, X-Ray, Factor VIII, HEK293 Cells, Half-Life, Hemophilia A, Hemorrhage, Humans, Immunoglobulin Fc Fragments, Kinetics, Mass Spectrometry, Microscopy, Electron, Peptide Fragments, Protein Domains, Recombinant Fusion Proteins, Scattering, Small Angle, Surface Plasmon Resonance, X-Ray Diffraction, B-domain-deleted factor VIII, bleeding, factor VIII, hemophilia A, rFVIIIFc protein, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

Essentials Recombinant factor VIII (rFVIII) Fc fusion protein has a 1.5-fold longer half-life than rFVIII. Five orthogonal methods were used to characterize the structure of rFVIIIFc compared to rFVIII. The C-terminal Fc fusion does not perturb the structure of FVIII in rFVIIIFc. The FVIII and Fc components of rFVIIIFc are flexibly tethered and functionally independent.SummaryBackground Fusion of the human IgG1 Fc domain to the C-terminal C2 domain of B-domain-deleted (BDD) factor VIII (FVIII) results in the recombinant FVIII Fc (rFVIIIFc) fusion protein, which has a 1.5-fold longer half-life in humans. Objective To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components, and evaluating their structural independence within rFVIIIFc. Methods rFVIIIFc and its isolated FVIII and Fc components were compared by the use of hydrogen-deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by the use of X-ray crystallography, small-angle X-ray scattering (SAXS), and electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). Results HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Conclusions The FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents, and show a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII.

Published
2017

4. HU multimerization shift controls nucleoid compaction.

Author

Larabell, Carolyn, Hammel, M, Amlanjyoti, D, Reyes, FE, Chen, J-H, Parpana, R, Tang, HYH, Tainer, JA, and Adhya, S

Abstract

Molecular mechanisms controlling functional bacterial chromosome (nucleoid) compaction and organization are surprisingly enigmatic but partly depend on conserved, histone-like proteins HUαα and HUαβ and their interactions that span the nanoscale and mesosc

Published
2016

6. Marine transmissible cancer navigates urbanized waters, threatening spillover

Author

Hammel, M., Touchard, F., Burioli, E. A. V., Paradis, L., Cerqueira, F, Chailler, E., Bernard, I., Cochet, H, Simon, A., Thomas, F, Destoumieux-garzón, Delphine, Charrière, G. M., Bierne, N., Hammel, M., Touchard, F., Burioli, E. A. V., Paradis, L., Cerqueira, F, Chailler, E., Bernard, I., Cochet, H, Simon, A., Thomas, F, Destoumieux-garzón, Delphine, Charrière, G. M., and Bierne, N.

Abstract

Transmissible cancer, a unique form of microparasites that spreads through direct transmission of living cancer cells, is increasingly reported in marine bivalves. In this study, we sought to understand the ecology of the propagation ofMytilus trossulusBivalve Transmissible Neoplasia 2 (MtrBTN2), a transmissible cancer affecting fourMytilusmussel species worldwide. We investigated the prevalence of MtrBTN2 in the mosaic hybrid zone ofM. edulisandM. galloprovincialisalong the French Atlantic coast, sampling contrasting natural and anthropogenic habitats. We observed a similar prevalence in both species, likely due to the proximity of the two species in this region. Our results showed that ports had higher prevalence of MtrBTN2, with a hotspot observed at a shuttle landing dock. No cancer was found in natural beds except for two sites around the hotspot, suggesting spillover. Ports may provide favourable conditions for the transmission of MtrBTN2, such as high mussel density, confined sheltered shores, or buffered temperatures. Ships may also spread the disease through biofouling, with maritime traffic being the best predictor of MtrBTN2 prevalence. Our results suggest ports may serve as epidemiological hubs, with maritime routes providing artificial gateways for MtrBTN2 propagation. This highlights the importance of preventing biofouling on docks and ships’ hulls to limit the spread of marine pathogens.

Published
2024
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8. Marine transmissible cancer navigates urbanized waters, threatening spillover

Author

Hammel, M., primary, Touchard, F., additional, Burioli, E. A. V., additional, Paradis, L., additional, Cerqueira, F., additional, Chailler, E., additional, Bernard, I., additional, Cochet, H., additional, Simon, A., additional, Thomas, F., additional, Destoumieux-Garzón, D., additional, Charrière, G. M., additional, and Bierne, N., additional

Published
2024
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10. Transcriptomics of mussel transmissible cancer MtrBTN2 reveals accumulation of multiple cancerous traits and oncogenic pathways shared among bilaterians

Author

Burioli, E.a.v., Hammel, M., Vignal, Emmanuel, Vidal-dupiol, Jeremie, Mitta, Guillaume, Thomas, Fabien, Bierne, N., Destoumieux-garzón, Delphine, Charrière, Guillaume, Burioli, E.a.v., Hammel, M., Vignal, Emmanuel, Vidal-dupiol, Jeremie, Mitta, Guillaume, Thomas, Fabien, Bierne, N., Destoumieux-garzón, Delphine, and Charrière, Guillaume

Abstract

Transmissible cancer cell lines are rare biological entities giving rise to diseases at the crossroads of cancer and parasitic diseases. These malignant cells have acquired the amazing capacity to spread from host to host. They have been described only in dogs, Tasmanian devils and marine bivalves. The Mytilus trossulus Bivalve Transmissible Neoplasia 2 (MtrBTN2) lineage has even acquired the capacity to spread inter-specifically between marine mussels of the Mytilus edulis complex worldwide. To identify the oncogenic processes underpinning the biology of these atypical cancers we performed transcriptomics of MtrBTN2 cells. Differential gene expression, enrichment, protein-protein interaction network, and targeted analyses were used. Overall, our results suggests that the long-term evolution of MtrBTN2 has led to the accumulation of multiple cancerous traits. We also highlight that vertebrate and lophotrochozoan cancers share a large panel of common drivers, which supports the hypothesis of an ancient origin of oncogenic processes in bilaterians. TeaserMussel transmissible cancers teach us that cancerous process has a remote origin and that their long-term evolution has made them super-cancers.

Published
2023
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11. Marine transmissible cancer navigates urbanised waters, threatening to spillover

Author

Hammel, M., Touchard, F., Burioli, E. A. V., Paradis, L., Cerqueira, F, Chailler, E., Bernard, I., Cochet, H, Simon, A., Thomas, F, Destoumieux-garzón, Delphine, Charrière, G. M., Bierne, N., Hammel, M., Touchard, F., Burioli, E. A. V., Paradis, L., Cerqueira, F, Chailler, E., Bernard, I., Cochet, H, Simon, A., Thomas, F, Destoumieux-garzón, Delphine, Charrière, G. M., and Bierne, N.

Abstract

Transmissible cancer, a unique form of microparasites that spreads through direct transmission of living cancer cells, is increasingly reported in marine bivalves. In this study, we sought to understand the ecology of the propagation ofMytilus trossulusBivalve Transmissible Neoplasia 2 (MtrBTN2), a transmissible cancer affecting fourMytilusmussel species worldwide. We investigated the prevalence of MtrBTN2 in the mosaic hybrid zone ofM. edulisandM. galloprovincialisalong the French Atlantic coast, sampling contrasting natural and anthropogenic habitats. We observed a similar prevalence in both species, likely due to the proximity of the two species in this region. Our results showed that ports had higher prevalence of MtrBTN2, with a hotspot observed at a shuttle landing dock. No cancer was found in natural beds except for two sites around the hotspot, suggesting spillover. Ports may provide favourable conditions for the transmission of MtrBTN2, such as high mussel density, confined sheltered shores, or buffered temperatures. Ships may also spread the disease through biofouling, with maritime traffic being the best predictor of MtrBTN2 prevalence. Our results suggest ports may serve as epidemiological hubs, with maritime routes providing artificial gateways for MtrBTN2 propagation. This highlights the importance of preventing biofouling on docks and ships’ hulls to limit the spread of marine pathogens.

Published
2023
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12. Transcriptomics of mussel transmissible cancer MtrBTN2 suggests accumulation of multiple cancer traits and oncogenic pathways shared among bilaterians

Author

Burioli, E. A. V., Hammel, M., Vignal, Emmanuel, Vidal-dupiol, Jeremie, Mitta, Guillaume, Thomas, Frederic, Bierne, N., Destoumieux-garzón, Delphine, Charrière, G. M., Burioli, E. A. V., Hammel, M., Vignal, Emmanuel, Vidal-dupiol, Jeremie, Mitta, Guillaume, Thomas, Frederic, Bierne, N., Destoumieux-garzón, Delphine, and Charrière, G. M.

Abstract

Transmissible cancer cell lines are rare biological entities giving rise to diseases at the crossroads of cancer and parasitic diseases. These malignant cells have acquired the amazing capacity to spread from host to host. They have been described only in dogs, Tasmanian devils and marine bivalves. The Mytilus trossulus bivalve transmissible neoplasia 2 (MtrBTN2) lineage has even acquired the capacity to spread inter-specifically between marine mussels of the Mytilus edulis complex worldwide. To identify the oncogenic processes underpinning the biology of these atypical cancers we performed transcriptomics of MtrBTN2 cells. Differential expression, enrichment, protein–protein interaction network, and targeted analyses were used. Overall, our results suggest the accumulation of multiple cancerous traits that may be linked to the long-term evolution of MtrBTN2. We also highlight that vertebrate and lophotrochozoan cancers could share a large panel of common drivers, which supports the hypothesis of an ancient origin of oncogenic processes in bilaterians.

Published
2023
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16. Predictive high-throughput screening of PEGylated lipids in oligonucleotide-loaded lipid nanoparticles for neuronal gene silencing

Author

Sarode, A, Sarode, A, Fan, Y, Byrnes, AE, Hammel, M, Hura, GL, Fu, Y, Kou, P, Hu, C, Hinz, FI, Roberts, J, Koenig, SG, Nagapudi, K, Hoogenraad, CC, Chen, T, Leung, D, Yen, CW, Sarode, A, Sarode, A, Fan, Y, Byrnes, AE, Hammel, M, Hura, GL, Fu, Y, Kou, P, Hu, C, Hinz, FI, Roberts, J, Koenig, SG, Nagapudi, K, Hoogenraad, CC, Chen, T, Leung, D, and Yen, CW

Abstract

Lipid nanoparticles (LNPs) are gaining traction in the field of nucleic acid delivery following the success of two mRNA vaccines against COVID-19. As one of the constituent lipids on LNP surfaces, PEGylated lipids (PEG-lipids) play an important role in defining LNP physicochemical properties and biological interactions. Previous studies indicate that LNP performance is modulated by tuning PEG-lipid parameters including PEG size and architecture, carbon tail type and length, as well as the PEG-lipid molar ratio in LNPs. Owing to these numerous degrees of freedom, a high-throughput approach is necessary to fully understand LNP behavioral trends over a broad range of PEG-lipid variables. To this end, we report a low-volume, automated, high-throughput screening (HTS) workflow for the preparation, characterization, and in vitro assessment of LNPs loaded with a therapeutic antisense oligonucleotide (ASO). A library of 54 ASO-LNP formulations with distinct PEG-lipid compositions was prepared using a liquid handling robot and assessed for their physiochemical properties as well as gene silencing efficacy in murine cortical neurons. Our results show that the molar ratio of anionic PEG-lipid in LNPs regulates particle size and PEG-lipid carbon tail length controls ASO-LNP gene silencing activity. ASO-LNPs formulated using PEG-lipids with optimal carbon tail lengths achieved up to 5-fold lower mRNA expression in neurons as compared to naked ASO. Representative ASO-LNP formulations were further characterized using dose-response curves and small-angle X-ray scattering to understand structure-activity relationships. Identified hits were also tested for efficacy in primary murine microglia and were scaled-up using a microfluidic formulation technique, demonstrating a smooth translation of ASO-LNP properties and in vitro efficacy. The reported HTS workflow can be used to screen additional multivariate parameters of LNPs with significant time and material savings, therefore guiding

Published
2022

24. Modeling Structure and Dynamics of Protein Complexes with SAXS Profiles

Author

Schneidman-Duhovny, D and Hammel, M

Subjects
Small Angle, Protein Conformation, 1.1 Normal biological development and functioning, fungi, Conformational heterogeneity, Molecular, Molecular Dynamics Simulation, Interleukin-33, Interleukin-1 Receptor-Like 1 Protein, DNA-Binding Proteins, Scattering, DNA Ligase ATP, X-Ray Diffraction, Models, Underpinning research, Conformational ensembles, Multi-state models, Small-angle X-ray scattering, Humans, Generic health relevance, Biochemistry and Cell Biology, Other Chemical Sciences, Software, Protein-protein docking, Developmental Biology
Abstract

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Small-angle X-ray scattering (SAXS) is an increasingly common and useful technique for structural characterization of molecules in solution. A SAXS experiment determines the scattering intensity of a molecule as a function of spatial frequency, termed SAXS profile. SAXS profiles can be utilized in a variety of molecular modeling applications, such as comparing solution and crystal structures, structural characterization of flexible proteins, assembly of multi-protein complexes, and modeling of missing regions in the high-resolution structure. Here, we describe protocols for modeling atomic structures based on SAXS profiles. The first protocol is for comparing solution and crystal structures including modeling of missing regions and determination of the oligomeric state. The second protocol performs multi-state modeling by finding a set of conformations and their weights that fit the SAXS profile starting from a single-input structure. The third protocol is for protein-protein docking based on the SAXS profile of the complex. We describe the underlying software, followed by demonstrating their application on interleukin 33 (IL33) with its primary receptor ST2 and DNA ligase IV-XRCC4 complex.

Published
2018

25. Hydrogen bonds are a primary driving force for de novo protein folding

Author

Lee, S, Wang, C, Liu, H, Xiong, J, Jiji, R, Hong, X, Yan, X, Chen, Z, Hammel, M, Wang, Y, Dai, S, Wang, J, Jiang, C, and Zhang, G

Subjects
cis/trans-proline, Protein Denaturation, Protein Folding, Emerging Infectious Diseases, Proline, Protein Conformation, Cytidine Deaminase, hydrogen bonds, Humans, Bioengineering, Hydrogen Bonding
Abstract

© Lee et al. 2017. The protein-folding mechanism remains a major puzzle in life science. Purified soluble activation-induced cytidine deaminase (AID) is one of the most difficult proteins to obtain. Starting from inclusion bodies containing a C-terminally truncated version of AID (residues 1-153; AID153), an optimized in vitro folding procedure was derived to obtain large amounts of AID153, which led to crystals with good quality and to final structural determination. Interestingly, it was found that the final refolding yield of the protein is proline residue-dependent. The difference in the distribution of cis and trans configurations of proline residues in the protein after complete denaturation is a major determining factor of the final yield. A point mutation of one of four proline residues to an asparagine led to a near-doubling of the yield of refolded protein after complete denaturation. It was concluded that the driving force behind protein folding could not overcome the cis-to-trans proline isomerization, or vice versa, during the protein-folding process. Furthermore, it was found that successful refolding of proteins optimally occurs at high pH values, which may mimic protein folding in vivo. It was found that high pH values could induce the polarization of peptide bonds, which may trigger the formation of protein secondary structures through hydrogen bonds. It is proposed that a hydrophobic environment coupled with negative charges is essential for protein folding. Combined with our earlier discoveries on protein-unfolding mechanisms, it is proposed that hydrogen bonds are a primary driving force for de novo protein folding.The yield of protein refolding is reciprocal to the number of proline residues in the target protein. Hydrogen bonds are the primary driving force for de novo protein folding.

Published
2017
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27. Structural and functional characterization of the PNKP-XRCC4-LigIV DNA repair complex

Author

Daniel Aceytuno, R, Piett, CG, Havali-Shahriari, Z, Edwards, RA, Rey, M, Ye, R, Javed, F, Fang, S, Mani, R, Weinfeld, M, Hammel, M, Tainer, JA, Schriemer, DC, Lees-Miller, SP, and Mark Glover, JN

Abstract

© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. Non-homologous end joining (NHEJ) repairs DNA double strand breaks in non-cycling eukaryotic cells. NHEJ relies on polynucleotide kinase/phosphatase (PNKP), which generates 5'-phosphate/3'-hydroxyl DNA termini that are critical for ligation by the NHEJ DNA ligase, LigIV. PNKP and LigIV require the NHEJ scaffolding protein, XRCC4. The PNKP FHA domain binds to the CK2-phosphorylated XRCC4 C-terminal tail, while LigIV uses its tandem BRCT repeats to bind the XRCC4 coiled-coil. Yet, the assembled PNKP-XRCC4-LigIV complex remains uncharacterized. Here, we report purification and characterization of a recombinant PNKP-XRCC4-LigIV complex. We show that the stable binding of PNKP in this complex requires XRCC4 phosphorylation and that only one PNKP protomer binds per XRCC4 dimer. Small angle X-ray scattering (SAXS) reveals a flexiblemultistate complex that suggests that both the PNKP FHA and catalytic domains contact the XRCC4 coiled-coil and LigIV BRCT repeats. Hydrogen-deuterium exchange indicates protection of a surface on the PNKP phosphatase domain that may contact XRCC4-LigIV. Amutation on this surface (E326K) causes the hereditary neuro-developmental disorder, MCSZ. This mutation impairs PNKP recruitment to damaged DNA in human cells and provides a possible disease mechanism. Together, this work unveils multipoint contacts between PNKP and XRCC4-LigIV that regulate PNKP recruitment and activity within NHEJ.

Published
2017
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28. Structural Basis for Interactions Between Contactin Family Members and Protein-tyrosine Phosphatase Receptor Type G in Neural Tissues

Author

Nikolaienko, RM, Hammel, M, Dubreuil, V, Zalmai, R, Hall, DR, Mehzabeen, N, Karuppan, SJ, Harroch, S, Stella, SL, and Bouyain, S

Subjects
crystal structure, retina, Biochemistry & Molecular Biology, immunoglobulin|L-like domain, protein phosphatase, Molecular, Receptor-Like Protein Tyrosine Phosphatases, Nerve Tissue Proteins, cell adhesion, Biological Sciences, Biological, Medical and Health Sciences, contactin, Class 5, Mice, cell surface, Models, Contactins, Multiprotein Complexes, Chemical Sciences, Animals, Humans, Nerve Tissue, Signal Transduction
Abstract

© 2016, American Society for Biochemistry and Molecular Biology Inc. All rights reserved. Protein-tyrosine phosphatase receptor type G (RPTPγ/PTPRG) interacts in vitro with contactin-3-6 (CNTN3-6), a group of glycophosphatidylinositol-anchored cell adhesion molecules involved in the wiring of the nervous system. In addition to PTPRG, CNTNs associate with multiple transmembrane proteins and signal inside the cell via cis-binding partners to alleviate the absence of an intracellular region. Here, we use comprehensive biochemical and structural analyses to demonstrate that PTPRG·CNTN3-6 complexes share similar binding affinities and a conserved arrangement. Furthermore, as a first step to identifying PTPRG·CNTN complexes in vivo, we found that PTPRG and CNTN3 associate in the outer segments of mouse rod photoreceptor cells. In particular, PTPRG and CNTN3 form cis-complexes at the surface of photoreceptors yet interact in trans when expressed on the surfaces of apposing cells. Further structural analyses suggest that all CNTN ectodomains adopt a bent conformation and might lie parallel to the cell surface to accommodate these cis and trans binding modes. Taken together, these studies identify a PTPRG·CNTN complex in vivo and provide novel insights into PTPRG- and CNTN-mediated signaling.

Published
2016
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29. Clinical dysregulation of DNA repair by the polynucleotide kinase/phosphatase-XRCC4-DNA ligase IV in neurological disease

Author

Aceytuno, D., primary, Piett, C.G., additional, Havali-Shahriari, Z., additional, Edwards, R.A., additional, Rey, M., additional, Mani, R.S., additional, Fang, S., additional, Hammel, M., additional, Weinfeld, M., additional, Tainer, J.A., additional, Schriemer, D., additional, Lees-Miller, S.P., additional, and Glover, J.N.M., additional

Published
2017
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31. HUab-20bp

Author

Hammel, M., primary, Reyes, F.E., additional, Parpana, R., additional, Tainer, J.A., additional, Adhya, S., additional, and Amlanjyoti, D., additional

Published
2016
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32. HUaa-19bp

Author

Hammel, M., primary, Reyes, F.E., additional, Parpana, R., additional, Tainer, J.A., additional, Adhya, S., additional, and Amlanjyoti, D., additional

Published
2016
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33. Generierung einer Abca3-defizienten Mauslinie zur Charakterisierung von ABCA3

Author

Hammel, M.

Abstract

ABCA3, ein Mitglied der ABC-Transporter Proteinfamilie, ist vorwiegend in der Membran der Lamellarkörperchen von Pneumozyten Typ II lokalisiert. Mutationen im ABCA3-Gen verursachen respiratorisches Versagen des Neugeborenen durch Surfactant Mangel. Ein Mausmodell des ABCA3-Mangels wurde generiert. Die Lunge homozygoter Tiere zeigte schwerste Atelektasen und das Fehlen von Lamellarkörperchen. Der klinische Phänotyp entspricht der menschlichen Erkrankung des postpartalen Lungenversagens bei ABCA3-Mangel. In Lungengewebe ließ sich bei homozygoten, aber auch bei heterozygoten Tieren eine Verminderung von Surfactant-Phospholipiden nachweisen. Die Heterozygotie hat scheinbar keinen Einfluss auf die Lungenfunktion. Auch in der Mamma wird ABCA3 exprimiert. In der Milch zeigte sich bei heterozygoten Tieren im Vergleich mit Wildtyp-Tieren eine Verminderung der Konzentrationen von Phosphatidyl-Glycerin und Phosphatidyl-Cholin.

Published
2008

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