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  1. Article ; Online: The Emerging Physiological Role of AGMO 10 Years after Its Gene Identification

    Sabrina Sailer / Markus A. Keller / Ernst R. Werner / Katrin Watschinger

    Life, Vol 11, Iss 2, p

    2021  Volume 88

    Abstract: The gene encoding alkylglycerol monooxygenase (AGMO) was assigned 10 years ago. So far, AGMO is the only known enzyme capable of catalysing the breakdown of alkylglycerols and lyso-alkylglycerophospholipids. With the knowledge of the genetic information, ...

    Abstract The gene encoding alkylglycerol monooxygenase (AGMO) was assigned 10 years ago. So far, AGMO is the only known enzyme capable of catalysing the breakdown of alkylglycerols and lyso-alkylglycerophospholipids. With the knowledge of the genetic information, it was possible to relate a potential contribution for mutations in the AGMO locus to human diseases by genome-wide association studies. A possible role for AGMO was implicated by genetic analyses in a variety of human pathologies such as type 2 diabetes, neurodevelopmental disorders, cancer, and immune defence. Deficient catabolism of stored lipids carrying an alkyl bond by an absence of AGMO was shown to impact on the overall lipid composition also outside the ether lipid pool. This review focuses on the current evidence of AGMO in human diseases and summarises experimental evidence for its role in immunity, energy homeostasis, and development in humans and several model organisms. With the progress in lipidomics platform and genetic identification of enzymes involved in ether lipid metabolism such as AGMO, it is now possible to study the consequence of gene ablation on the global lipid pool and further on certain signalling cascades in a variety of model organisms in more detail.
    Keywords AGMO ; tetrahydrobiopterin ; alkylglycerols ; plasmalogens ; neurodevelopment ; autism ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Phospholipid Acyl Chain Diversity Controls the Tissue-Specific Assembly of Mitochondrial Cardiolipins

    Gregor Oemer / Jakob Koch / Yvonne Wohlfarter / Mohammad T. Alam / Katharina Lackner / Sabrina Sailer / Lukas Neumann / Herbert H. Lindner / Katrin Watschinger / Markus Haltmeier / Ernst R. Werner / Johannes Zschocke / Markus A. Keller

    Cell Reports, Vol 30, Iss 12, Pp 4281-4291.e

    2020  Volume 4

    Abstract: Summary: Cardiolipin (CL) is a phospholipid specific for mitochondrial membranes and crucial for many core tasks of this organelle. Its acyl chain configurations are tissue specific, functionally important, and generated via post-biosynthetic remodeling. ...

    Abstract Summary: Cardiolipin (CL) is a phospholipid specific for mitochondrial membranes and crucial for many core tasks of this organelle. Its acyl chain configurations are tissue specific, functionally important, and generated via post-biosynthetic remodeling. However, this process lacks the necessary specificity to explain CL diversity, which is especially evident for highly specific CL compositions in mammalian tissues. To investigate the so far elusive regulatory origin of CL homeostasis in mice, we combine lipidomics, integrative transcriptomics, and data-driven machine learning. We demonstrate that not transcriptional regulation, but cellular phospholipid compositions are closely linked to the tissue specificity of CL patterns allowing artificial neural networks to precisely predict cross-tissue CL compositions in a consistent mechanistic specificity rationale. This is especially relevant for the interpretation of disease-related perturbations of CL homeostasis, by allowing differentiation between specific aberrations in CL metabolism and changes caused by global alterations in cellular (phospho-)lipid metabolism. : The lipid architecture of biomembranes is crucial for their cellular functions. The regulatory origins of the strong tissue specificity of cardiolipins, a vital mitochondrial phospholipid class, were so far largely unresolved. Oemer et al. find that a single mechanism explains cardiolipin diversity across tissues on basis of the phospholipid environment. Keywords: cardiolipin, phospholipids, structural diversity, mouse tissue-specificity, membrane lipids, mitochondria, LC-MS/MS, lipidomics, machine learning, artificial neural network
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: When the genome bluffs

    Sabrina Sailer / Stefan Coassin / Katharina Lackner / Caroline Fischer / Eileen McNeill / Gertraud Streiter / Christian Kremser / Manuel Maglione / Catherine M. Green / Daniela Moralli / Alexander R. Moschen / Markus A. Keller / Georg Golderer / Gabriele Werner-Felmayer / Irmgard Tegeder / Keith M. Channon / Benjamin Davies / Ernst R. Werner / Katrin Watschinger

    Cell & Bioscience, Vol 11, Iss 1, Pp 1-

    a tandem duplication event during generation of a novel Agmo knockout mouse model fools routine genotyping

    2021  Volume 10

    Abstract: Abstract Background Genome editing in mice using either classical approaches like homologous recombination or CRISPR/Cas9 has been reported to harbor off target effects (insertion/deletion, frame shifts or gene segment duplications) that lead to ... ...

    Abstract Abstract Background Genome editing in mice using either classical approaches like homologous recombination or CRISPR/Cas9 has been reported to harbor off target effects (insertion/deletion, frame shifts or gene segment duplications) that lead to mutations not only in close proximity to the target site but also outside. Only the genomes of few engineered mouse strains have been sequenced. Since the role of the ether-lipid cleaving enzyme alkylglycerol monooxygenase (AGMO) in physiology and pathophysiology remains enigmatic, we created a knockout mouse model for AGMO using EUCOMM stem cells but unforeseen genotyping issues that did not agree with Mendelian distribution and enzyme activity data prompted an in-depth genomic validation of the mouse model. Results We report a gene segment tandem duplication event that occurred during the generation of an Agmo knockout-first allele by homologous recombination. Only low homology was seen between the breakpoints. While a single copy of the recombinant 18 kb cassette was integrated correctly around exon 2 of the Agmo gene, whole genome nanopore sequencing revealed a 94 kb duplication in the Agmo locus that contains Agmo wild-type exons 1–3. The duplication fooled genotyping by routine PCR, but could be resolved using qPCR-based genotyping, targeted locus amplification sequencing and nanopore sequencing. Despite this event, this Agmo knockout mouse model lacks AGMO enzyme activity and can therefore be used to study its physiological role. Conclusions A duplication event occurred at the exact locus of the homologous recombination and was not detected by conventional quality control filters such as FISH or long-range PCR over the recombination sites. Nanopore sequencing provides a cost convenient method to detect such underrated off-target effects, suggesting its use for additional quality assessment of gene editing in mice and also other model organisms.
    Keywords Homologous recombination ; Mouse models ; Ether lipid metabolism ; Genomic structural variation ; Alkylglycerol monooxygenase ; Biotechnology ; TP248.13-248.65 ; Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
    Subject code 572
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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