Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis

Punetha, Jaya; Mackay-Loder, Loren; Harel, Tamar; Coban‐Akdemir, Zeynep; Jhangiani, Shalini N.; Gibbs, Richard A.; Lee, Ian; Terespolsky, Deborah; Lupski, James R.; Posey, Jennifer E.

doi:10.1016/j.ymgme.2018.08.005

Cited by 14 publications

(28 citation statements)

References 29 publications

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“…A specific case, not within the scope of the current study, is the effect on the observed supramolecular assembly by the several P2 mutations linked to CMT (25)(26)(27)(28)(29). In our earlier study, we showed that three of these mutations were linked to both lowered protein stability and altered membrane binding properties (30).…”

Section: Functional Residues Revealed By Point Mutationsmentioning

confidence: 74%

“…Further analyses on the mutant mice revealed that P2 has a role in remyelination of an injured PNS (23) and melanoma cell invasion (24). Five Charcot-Marie-Tooth 1 (CMT1) disease point mutations in human P2 have been discovered (25)(26)(27)(28)(29). Three CMT1associated P2 protein variants have been characterized at the molecular level, showing altered fatty acid and lipid membrane binding properties.…”

mentioning

confidence: 99%

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Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice

Ruskamo

Krokengen

Kowal

et al. 2020

Journal of Biological Chemistry

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Myelin protein P2 is a peripheral membrane protein of the fatty acid–binding protein family that functions in the formation and maintenance of the peripheral nerve myelin sheath. Several P2 gene mutations cause human Charcot-Marie-Tooth neuropathy, but the mature myelin sheath assembly mechanism is unclear. Here, cryo-EM of myelin-like proteolipid multilayers revealed an ordered three-dimensional (3D) lattice of P2 molecules between stacked lipid bilayers, visualizing supramolecular assembly at the myelin major dense line. The data disclosed that a single P2 layer is inserted between two bilayers in a tight intermembrane space of ∼3 nm, implying direct interactions between P2 and two membrane surfaces. X-ray diffraction from P2-stacked bicelle multilayers revealed lateral protein organization, and surface mutagenesis of P2 coupled with structure-function experiments revealed a role for both the portal region of P2 and its opposite face in membrane interactions. Atomistic molecular dynamics simulations of P2 on model membrane surfaces suggested that Arg-88 is critical for P2-membrane interactions, in addition to the helical lid domain. Negatively charged lipid headgroups stably anchored P2 on the myelin-like bilayer surface. Membrane binding may be accompanied by opening of the P2 β-barrel structure and ligand exchange with the apposing bilayer. Our results provide an unprecedented view into an ordered, multilayered biomolecular membrane system induced by the presence of a peripheral membrane protein from human myelin. This is an important step toward deciphering the 3D assembly of a mature myelin sheath at the molecular level.

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Section: Functional Residues Revealed By Point Mutationsmentioning

confidence: 74%

mentioning

confidence: 99%

Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice

Ruskamo

Krokengen

Kowal

et al. 2020

Journal of Biological Chemistry

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“…Notably, knock-out of one or both proteins does not affect myelin structure, and its only consequence is a minor retardation in motor nerve conduction (Zenker et al, 2014). However, several point mutations of FABP8 have been associated to the inherited neuropathy known as Charcot-Marie-Tooth disease (Motley et al, 2016; Punetha et al, 2018).…”

Section: Receptors For Fatty Acids Signalingmentioning

confidence: 99%

Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors

Falomir-Lockhart

Cavazzutti

Giménez

et al. 2019

Front. Cell. Neurosci.

128

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Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by β-oxidation or used in phospholipids’ synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary messengers, as well as modulators of enzymatic activities and substrates for cytokines synthesis. More recently, it has been documented a direct activity of free FAs as ligands of membrane, cytosolic, and nuclear receptors, and cumulative evidence has emerged, demonstrating its participation in a wide range of physiological and pathological conditions. It has been long known that the central nervous system is enriched with poly-unsaturated FAs, such as arachidonic (C20:4ω-6) or docosohexaenoic (C22:6ω-3) acids. These lipids participate in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory response. Furthermore, a whole family of low molecular weight compounds derived from FAs has also gained special attention as the natural ligands for cannabinoid receptors or key cytokines involved in inflammation, largely expanding the role of FAs as precursors of signaling molecules. Nutritional deficiencies, and alterations in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems, as well as with neurodegenerative diseases. The molecular mechanism behind these effects still remains elusive. But in the last two decades, different families of proteins have been characterized as receptors mediating FAs signaling. This review focuses on different receptors sensing and transducing free FAs signals in neural cells: (1) membrane receptors of the family of G Protein Coupled Receptors known as Free Fatty Acid Receptors (FFARs); (2) cytosolic transport Fatty Acid-Binding Proteins (FABPs); and (3) transcription factors Peroxisome Proliferator-Activated Receptors (PPARs). We discuss how these proteins modulate and mediate direct regulatory functions of free FAs in neural cells. Finally, we briefly discuss the advantages of evaluating them as potential targets for drug design in order to manipulate lipid signaling. A thorough characterization of lipid receptors of the nervous system could provide a framework for a better understanding of their roles in neurophysiology and, potentially, help for the development of novel drugs against aging and neurodegenerative processes.

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“…Further analyses on the mutant mice revealed that P2 has a role in remyelination of an injured PNS 23 and melanoma cell invasion 24 . Five Charcot-Marie-Tooth 1 (CMT1) disease point mutations in human P2 have been discovered 25–29 . Three CMT1-associated P2 protein variants have been characterized at the molecular level, showing altered fatty acid and lipid membrane binding properties.…”

Section: Introductionmentioning

confidence: 99%

Determinants for forming a supramolecular myelin-like proteolipid lattice

Ruskamo

Krokengen

Kowal

et al. 2020

Preprint

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Myelin protein P2 is a peripheral membrane protein of the fatty acid binding protein family. It functions in the formation and maintenance of the peripheral nerve myelin sheath, and several P2 mutations causing human Charot-Marie-Tooth neuropathy have been reported. Here, electron cryomicroscopy of myelin-like proteolipid multilayers revealed a three-dimensionally ordered lattice of P2 molecules between stacked lipid bilayers, visualizing its possible assembly at the myelin major dense line. A single layer of P2 is inserted between two bilayers in a tight intermembrane space of ∼3 nm, implying direct interactions between P2 and two membrane surfaces. Further details on lateral protein organization were revealed through X-ray diffraction from bicelles stacked by P2. Surface mutagenesis of P2 coupled to structural and functional experiments revealed a role for both the portal region and the opposite face of P2 in membrane interactions. Atomistic molecular dynamics simulations of P2 on myelin-like and model membrane surfaces suggested that Arg88 is an important residue for P2-membrane interactions, in addition to the helical lid domain on the opposite face of the molecule. Negatively charged myelin lipid headgroups anchor P2 stably on the bilayer surface. Membrane binding may be accompanied by opening of the P2 β barrel structure and ligand exchange with the apposing lipid bilayer. Our results provide an unprecedented view into an ordered, multilayered biomolecular membrane system induced by the presence of a peripheral membrane protein from human myelin. This is an important step towards deciphering the 3-dimensional assembly of a mature myelin sheath at the molecular level.

show abstract

Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis

Cited by 14 publications

References 29 publications

Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice

Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice

Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors

Determinants for forming a supramolecular myelin-like proteolipid lattice

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