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Molecular Research on Inherited Metabolic Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 14024

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Special Issue Editors

Prof. Dr. Margherita Ruoppolo

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Guest Editor

Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
Interests: inherited metabolic disorders; metabolomics; newborn screening; proteomics; protein-protein interaction
Special Issues, Collections and Topics in MDPI journals

Dr. Ida Chiara Guerrera

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Guest Editor

Proteomics Platform 3P5-Necker, Université Paris Descartes - Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, 75014 Paris, France
Interests: rare genetic disease; proteomics; glycoproteomics; multi-omics; system biology; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rapid advances have been made in the prediction, detection, understanding, and monitoring of inherited disorders in humans using proteomic and metabolomic technologies. These disorders are genetic conditions that result in metabolism problems. Most people with inherited disorders have a defective gene that results in an enzyme deficiency and/or gain of function. There are hundreds of different genetic metabolic disorders, and their symptoms, treatments, and prognoses vary widely. Examples of these disorders include aminoacidopathies, defects of the oxidation of fatty acids, organic acidemias, lysosomal storage disease, and disorders of glycosylation.

The rarity of these conditions places a considerable burden on the individuals affected, and contributes to significant challenges in the medical care of these patients. It is clear that treatments applied as early as possible could greatly improve outcomes for patients.

Molecular research and in particular proteomics and metabolomics offers great promise in this field. On one hand, they leat to the discovery of new, biologically and clinically relevant biomarkers for inherited metabolic disorders, for both diagnosis and prognosis. On the other hand, they contribute new knowledge in terms of the molecular mechanisms of inherited metabolic disorders. Furthermore the combined proteo-mebtabolomic approaches are developing rapidely, and are particularly relevant in unserstanding metabolic diseases.

The special issue will be devoted to molecular research in Inherited Disorders. It will contain up-to-date review articles, plus original research, concerning any aspect of molecular mechanism, diagnosis and treatment of Inherited Disorders to provide a state-of-the-art overview of this fast moving area.

Prof. Margherita Ruoppolo
Dr. Ida Chiara Guerrera
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

Differential proteomics
Fluxomics
Glycoproteomics
Human disease model
Inherited disorders
Mass spectrometry
Multi-omics
Protein–protein interactions
NMR
Targeted metabolomics
Untargeted metabolomics

Published Papers (5 papers)

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22 pages, 12007 KiB

Open AccessArticle

Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome

by Emanuela Marchese, Marianna Caterino, Roberta Fedele, Francesca Pirozzi, Armando Cevenini, Neha Gupta, Diego Ingrosso, Alessandra Perna, Giovambattista Capasso, Margherita Ruoppolo and Miriam Zacchia

Int. J. Mol. Sci. 2022, 23(16), 9420; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169420 - 20 Aug 2022

Cited by 4 | Viewed by 2607

Abstract

Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy resulting in multiple organ dysfunctions, including chronic kidney disease (CKD). Despite the recent progress in the ’ciliopathy’ field, there is still little information on the mechanisms underlying renal disease. To elucidate these pathomechanisms, we conducted a translational study, including (i) the characterization of the urine metabolomic pattern of BBS patients and controls in a pilot and confirmation study and (ii) the proteomic analysis of the BBS10 interactome, one of the major mutated BBS genes in patients, in a renal-epithelial-derived cell culture model. The urine metabolomic fingerprinting of BBS patients differed from controls in both pilot and confirmation studies, demonstrating an increased urinary excretion of several monocarboxylates, including lactic acid (LA), at both early and late CKD stages. Increased urine LA was detected in the absence of both increased plasmatic LA levels and generalized proximal tubular dysfunction, suggesting a possible renal-specific defective handling. The inner medulla renal epithelial (IMCD3) cell line, where Bbs10 was stably invalidated, displayed an increased proliferative rate, increased ATP production, and an up-regulation of aerobic glycolysis. A mass spectrometry-based analysis detected several putative BBS10 interactors in vitro, indicating a potential role of BBS10 in several biological processes, including renal metabolism, RNA processing, and cell proliferation. The present study suggests that the urine metabolomic pattern of BBS patients may reflect intra-renal metabolic aberrations. The analysis of BBS10 interactors unveils possible novel functions, including cell metabolism. Full article

(This article belongs to the Special Issue Molecular Research on Inherited Metabolic Disorders)

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17 pages, 3417 KiB

Open AccessArticle

Unravelling the Complex Denaturant and Thermal-Induced Unfolding Equilibria of Human Phenylalanine Hydroxylase

by María Conde-Giménez and Javier Sancho

Int. J. Mol. Sci. 2021, 22(12), 6539; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126539 - 18 Jun 2021

Cited by 2 | Viewed by 1845

Abstract

Human phenylalanine hydroxylase (PAH) is a metabolic enzyme involved in the catabolism of L-Phe in liver. Loss of conformational stability and decreased enzymatic activity in PAH variants result in the autosomal recessive disorder phenylketonuria (PKU), characterized by developmental and psychological problems if not treated early. One current therapeutic approach to treat PKU is based on pharmacological chaperones (PCs), small molecules that can displace the folding equilibrium of unstable PAH variants toward the native state, thereby rescuing the physiological function of the enzyme. Understanding the PAH folding equilibrium is essential to develop new PCs for different forms of the disease. We investigate here the urea and the thermal-induced denaturation of full-length PAH and of a truncated form lacking the regulatory and the tetramerization domains. For either protein construction, two distinct transitions are seen in chemical denaturation followed by fluorescence emission, indicating the accumulation of equilibrium unfolding intermediates where the catalytic domains are partly unfolded and dissociated from each other. According to analytical centrifugation, the chemical denaturation intermediates of either construction are not well-defined species but highly polydisperse ensembles of protein aggregates. On the other hand, each protein construction similarly shows two transitions in thermal denaturation measured by fluorescence or differential scanning calorimetry, also indicating the accumulation of equilibrium unfolding intermediates. The similar temperatures of mid denaturation of the two constructions, together with their apparent lack of response to protein concentration, indicate the catalytic domains are unfolded in the full-length PAH thermal intermediate, where they remain associated. That the catalytic domain unfolds in the first thermal transition is relevant for the choice of PCs identified in high throughput screening of chemical libraries using differential scanning fluorimetry. Full article

(This article belongs to the Special Issue Molecular Research on Inherited Metabolic Disorders)

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29 pages, 3748 KiB

Open AccessArticle

Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients

by Laura Bianchi, Maria Sframeli, Lorenza Vantaggiato, Gian Luca Vita, Annamaria Ciranni, Francesca Polito, Rosaria Oteri, Eloisa Gitto, Fabrizio Di Giuseppe, Stefania Angelucci, Antonio Versaci, Sonia Messina, Giuseppe Vita, Luca Bini and M’hammed Aguennouz

Int. J. Mol. Sci. 2021, 22(9), 4329; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094329 - 21 Apr 2021

Cited by 13 | Viewed by 3556

Abstract

Spinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene (SMN1) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense oligonucleotide nusinersen has recently improved the natural course of this disease. Here, we investigated, with a functional proteomic approach, cerebrospinal fluid (CSF) protein profiles from SMA type 1 patients who underwent nusinersen administration to clarify the biochemical response to the treatment and to monitor disease progression based on therapy. Six months after starting treatment (12 mg/5 mL × four doses of loading regimen administered at days 0, 14, 28, and 63), we observed a generalized reversion trend of the CSF protein pattern from our patient cohort to that of control donors. Notably, a marked up-regulation of apolipoprotein A1 and apolipoprotein E and a consistent variation in transthyretin proteoform occurrence were detected. Since these multifunctional proteins are critically active in biomolecular processes aberrant in SMA, i.e., synaptogenesis and neurite growth, neuronal survival and plasticity, inflammation, and oxidative stress control, their nusinersen induced modulation may support SMN improved-expression effects. Hence, these lipoproteins and transthyretin could represent valuable biomarkers to assess patient responsiveness and disease progression. Full article

(This article belongs to the Special Issue Molecular Research on Inherited Metabolic Disorders)

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19 pages, 1874 KiB

Open AccessArticle

Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia

by Ana Ching-López, Luis Javier Martinez-Gonzalez, Luisa Arrabal, Jorge Sáiz, Ángela Gavilán, Coral Barbas, Jose Antonio Lorente, Susana Roldán, Maria José Sánchez and Purificacion Gutierrez-Ríos

Int. J. Mol. Sci. 2021, 22(6), 2990; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062990 - 15 Mar 2021

Cited by 3 | Viewed by 2660

Abstract

Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient’s amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease. Full article

(This article belongs to the Special Issue Molecular Research on Inherited Metabolic Disorders)

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14 pages, 1437 KiB

Open AccessCase Report

3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature

by Francesca Nardecchia, Anna Caciotti, Teresa Giovanniello, Sabrina De Leo, Lorenzo Ferri, Serena Galosi, Silvia Santagata, Barbara Torres, Laura Bernardini, Claudia Carducci, Amelia Morrone and Vincenzo Leuzzi

Int. J. Mol. Sci. 2022, 23(8), 4422; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084422 - 16 Apr 2022

Cited by 2 | Viewed by 2624

Abstract

3-Methylglutaconic aciduria type I (MGCA1) is an inborn error of the leucine degradation pathway caused by pathogenic variants in the AUH gene, which encodes 3-methylglutaconyl-coenzyme A hydratase (MGH). To date, MGCA1 has been diagnosed in 19 subjects and has been associated with a variable clinical picture, ranging from no symptoms to severe encephalopathy with basal ganglia involvement. We report the case of a 31-month-old female child referred to our center after the detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening, which were associated with increased urinary excretion of 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and 3-methylglutaric acid. A next-generation sequencing (NGS) panel for 3-methylglutaconic aciduria failed to establish a definitive diagnosis. To further investigate the strong biochemical indication, we measured MGH activity, which was markedly decreased. Finally, single nucleotide polymorphism array analysis disclosed the presence of two microdeletions in compound heterozygosity encompassing the AUH gene, which confirmed the diagnosis. The patient was then supplemented with levocarnitine and protein intake was slowly decreased. At the last examination, the patient showed mild clumsiness and an expressive language disorder. This case exemplifies the importance of the biochemical phenotype in the differential diagnosis of metabolic diseases and the importance of collaboration between clinicians, biochemists, and geneticists for an accurate diagnosis. Full article

(This article belongs to the Special Issue Molecular Research on Inherited Metabolic Disorders)

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