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Cell Metabolism: Lessons for Common Disease from Rare Metabolic Defects

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Special Issue Information
Keywords
Published Papers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Metabolism".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 11390

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Special Issue Editors

Dr. Philippa Mills

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Guest Editor

Inborn Errors of Metabolism Section, Genetics & Genomic Medicine Unit, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK
Interests: inherited metabolic diseases; genetics & genomic

Prof. Dr. Paul Gissen

E-Mail Website
Guest Editor

Institute for Health Research, Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK
Interests: battens disease; niemann pick disease; paediatric metabolic medicine; rare paediatric diseases

Special Issue Information

Dear Colleagues,

Inherited metabolic disorders (IMDs) are a large heterogeneous group of rare diseases with a combined incidence of approximately 1 in 1000 births. IMDs occur due to protein defects that, in turn, lead to a dysfunction in a metabolic pathway or process necessary for provision of energy or cell homeostasis. The dramatic technological advances in genomics in the 21st century have allowed the identification of numerous single-gene defects causing IMDs, which now include more than 1450 disorders. With the precise genetic knowledge of these rare metabolic defects, better understanding of the molecular mechanisms responsible for common human disorders such as epilepsy, neurodegeneration, cancer, diabetes, stroke and aging has ensued.

We invite all scientists working in the field of IMDs to participate in this Special Issue. Original research articles, reviews or shorter perspective articles on aspects of the molecular and cellular mechanisms of IMD biology and therapy that provide better understanding of common disease are welcome. Articles with insights from a cell and molecular biological perspective are especially welcome. Relevant topics include, but are not limited to: mitochondrial dysfunction and neurodegeneration, lysosomal dysfunction and neurodegeneration, inherited forms of cholestasis and liver cancer, hyperhomocysteinaemia and stroke, trace metal homeostasis and neurodegeneration, Krebs cycle enzyme abnormalities and cancer, lipodystrophy and diabetes, disorders of calcium homeostasis and osteoporosis.

Dr. Philippa Mills
Prof. Dr. Paul Gissen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

inherited metabolic disorders
rare metabolic defects

Published Papers (4 papers)

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Research

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21 pages, 4055 KiB

Open AccessArticle

A Novel Small NPC1 Promoter Enhances AAV-Mediated Gene Therapy in Mouse Models of Niemann–Pick Type C1 Disease

by Michael Paul Hughes, Hemanth Ramesh Nelvagal, Oliver Coombe-Tennant, Dave Smith, Claire Smith, Giulia Massaro, Laura Poupon-Bejuit, Frances Mary Platt and Ahad Abdul Rahim

Cells 2023, 12(12), 1619; https://doi.org/10.3390/cells12121619 - 13 Jun 2023

Cited by 3 | Viewed by 3183

Abstract

Niemann–Pick disease type C1 (NP-C) is a prematurely lethal genetic lysosomal storage disorder with neurological and visceral pathology resulting from mutations in the NPC1 gene encoding the lysosomal transmembrane protein NPC1. There is currently no cure for NP-C, and the only disease modifying treatment, miglustat, slows disease progression but does not significantly attenuate neurological symptoms. AAV-mediated gene therapy is an attractive option for NP-C, but due to the large size of the human NPC1 gene, there may be packaging and truncation issues during vector manufacturing. One option is to reduce the size of DNA regulatory elements that are essential for gene expression, such as the promoter sequence. Here, we describe a novel small truncated endogenous NPC1 promoter that leads to high gene expression both in vitro and in vivo and compare its efficacy to other commonly used promoters. Following neonatal intracerebroventricular (ICV) injection into the CNS, this novel promoter provided optimal therapeutic efficacy compared to all other promoters including increased survival, improved behavioural phenotypes, and attenuated neuropathology in mouse models of NP-C. Taken together, we propose that this novel promoter can be extremely efficient in designing an optimised AAV9 vector for gene therapy for NP-C. Full article

(This article belongs to the Special Issue Cell Metabolism: Lessons for Common Disease from Rare Metabolic Defects)

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15 pages, 2468 KiB

Open AccessArticle

Loss-of-Function Variants in DRD1 in Infantile Parkinsonism-Dystonia

by Kimberley M. Reid, Dora Steel, Sanjana Nair, Sanjay Bhate, Lorenzo Biassoni, Sniya Sudhakar, Michelle Heys, Elizabeth Burke, Erik-Jan Kamsteeg, Genomics England Research Consortium, Biju Hameed, Michael Zech, Niccolo E. Mencacci, Katy Barwick, Maya Topf and Manju A. Kurian

Cells 2023, 12(7), 1046; https://doi.org/10.3390/cells12071046 - 30 Mar 2023

Cited by 1 | Viewed by 2194

Abstract

The human dopaminergic system is vital for a broad range of neurological processes, including the control of voluntary movement. Here we report a proband presenting with clinical features of dopamine deficiency: severe infantile parkinsonism-dystonia, characterised by frequent oculogyric crises, dysautonomia and global neurodevelopmental impairment. CSF neurotransmitter analysis was unexpectedly normal. Triome whole-genome sequencing revealed a homozygous variant (c.110C>A, (p.T37K)) in DRD1, encoding the most abundant dopamine receptor (D₁) in the central nervous system, most highly expressed in the striatum. This variant was absent from gnomAD, with a CADD score of 27.5. Using an in vitro heterologous expression system, we determined that DRD1-T37K results in loss of protein function. Structure-function modelling studies predicted reduced substrate binding, which was confirmed in vitro. Exposure of mutant protein to the selective D₁ agonist Chloro APB resulted in significantly reduced cyclic AMP levels. Numerous D₁ agonists failed to rescue the cellular defect, reflected clinically in the patient, who had no benefit from dopaminergic therapy. Our study identifies DRD1 as a new disease-associated gene, suggesting a crucial role for the D₁ receptor in motor control. Full article

(This article belongs to the Special Issue Cell Metabolism: Lessons for Common Disease from Rare Metabolic Defects)

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Review

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26 pages, 3487 KiB

Open AccessReview

Overlapping Machinery in Lysosome-Related Organelle Trafficking: A Lesson from Rare Multisystem Disorders

by Blerida Banushi and Fiona Simpson

Cells 2022, 11(22), 3702; https://doi.org/10.3390/cells11223702 - 21 Nov 2022

Viewed by 3498

Abstract

Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs. Full article

(This article belongs to the Special Issue Cell Metabolism: Lessons for Common Disease from Rare Metabolic Defects)

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13 pages, 312 KiB

Open AccessReview

Rare Inherited Cholestatic Disorders and Molecular Links to Hepatocarcinogenesis

by Rebecca Jeyaraj and Deirdre Kelly

Cells 2022, 11(16), 2570; https://doi.org/10.3390/cells11162570 - 18 Aug 2022

Cited by 2 | Viewed by 1828

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer affecting adults and the second most common primary liver cancer affecting children. Recent years have seen a significant increase in our understanding of the molecular changes associated with HCC. However, HCC is a complex disease, and its molecular pathogenesis, which likely varies by aetiology, remains to be fully elucidated. Interestingly, some inherited cholestatic disorders that manifest in childhood are associated with early HCC development. This review will thus explore how three genes that are associated with liver disease in childhood (ABCB11, TJP2 and VPS33B) might play a role in the initiation and progression of HCC. Specifically, chronic bile-induced damage (caused by ABCB11 changes), disruption of intercellular junction formation (caused by TJP2 changes) and loss of normal apical–basal cell polarity (caused by VPS33B changes) will be discussed as possible mechanisms for HCC development. Full article

(This article belongs to the Special Issue Cell Metabolism: Lessons for Common Disease from Rare Metabolic Defects)

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