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Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies 3.0
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Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies 3.0

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 (31 March 2024) | Viewed by 8902

Special Issue Editor

Dr. Ivano Condò

E-Mail Website
Guest Editor
Department of Biomedicine and Prevention, School of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: frataxin; Friedreich’s ataxia; mitochondria; programmed cell death; molecular medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Most rare diseases we know arise from single gene mutations. In fact, the number of rare monogenic diseases is growing continuously, and to date, near 4000 single-gene inherited disorders have been characterized. Pathogenic mutations typically affect the coding regions, thus resulting in classical amino acid substitutions responsible for loss- or gain-of-function in protein products. However, several disease-causing defects originate from regulatory and non-coding DNA regions, ultimately affecting gene expression via transcriptional and/or post-transcriptional mechanisms.

Understanding the molecular pathophysiology of a rare monogenic disease has a double value. The identification of alterations that occur in specific genes, proteins, and pathways allows the translation of scientific advances into novel therapeutic approaches for these traits. Moreover, the investigation of rare monogenic diseases has the power to reveal fundamental biological mechanisms that would otherwise remain unknown.

This Special Issue will focus on the key molecular mechanisms that are affected within a rare monogenic disorder, such as those involving gene expression, molecular pathways, redox homeostasis, organelle stress, and cell death. Studies addressing new experimental therapies to target specific mechanisms in a monogenic disease, including drug discovery, drug repositioning, gene therapy, and protein- and nucleic acid-based therapeutics are relevant to this Special Issue. Original research articles and systematic reviews are welcome.

Dr. Ivano Condò
Guest Editor

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

  • monogenic disease
  • gene expression
  • molecular pathways
  • organelle dysfunctions
  • molecular medicine
  • drug discovery
  • molecular therapy

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Related Special Issues

Published Papers (5 papers)

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22 pages, 4358 KiB  
Article
Functional Characterization of a Spectrum of Genetic Variants in a Family with Succinic Semialdehyde Dehydrogenase Deficiency
by Miroslava Didiasova, Samuele Cesaro, Simon Feldhoff, Ilaria Bettin, Nana Tiegel, Vera Füssgen, Mariarita Bertoldi and Ritva Tikkanen
Int. J. Mol. Sci. 2024, 25(10), 5237; https://doi.org/10.3390/ijms25105237 - 11 May 2024
Viewed by 1220
Abstract
Succinic semialdehyde dehydrogenase (SSADH) is a mitochondrial enzyme involved in the catabolism of the neurotransmitter γ-amino butyric acid. Pathogenic variants in the gene encoding this enzyme cause SSADH deficiency, a developmental disease that manifests as hypotonia, autism, and epilepsy. SSADH deficiency patients usually [...] Read more.
Succinic semialdehyde dehydrogenase (SSADH) is a mitochondrial enzyme involved in the catabolism of the neurotransmitter γ-amino butyric acid. Pathogenic variants in the gene encoding this enzyme cause SSADH deficiency, a developmental disease that manifests as hypotonia, autism, and epilepsy. SSADH deficiency patients usually have family-specific gene variants. Here, we describe a family exhibiting four different SSADH variants: Val90Ala, Cys93Phe, and His180Tyr/Asn255Asp (a double variant). We provide a structural and functional characterization of these variants and show that Cys93Phe and Asn255Asp are pathogenic variants that affect the stability of the SSADH protein. Due to the impairment of the cofactor NAD+ binding, these variants show a highly reduced enzyme activity. However, Val90Ala and His180Tyr exhibit normal activity and expression. The His180Tyr/Asn255Asp variant exhibits a highly reduced activity as a recombinant species, is inactive, and shows a very low expression in eukaryotic cells. A treatment with substances that support protein folding by either increasing chaperone protein expression or by chemical means did not increase the expression of the pathogenic variants of the SSADH deficiency patient. However, stabilization of the folding of pathogenic SSADH variants by other substances may provide a treatment option for this disease. Full article
(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies 3.0)
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21 pages, 2574 KiB  
Article
AAV-Mediated CAG-Targeting Selectively Reduces Polyglutamine-Expanded Protein and Attenuates Disease Phenotypes in a Spinocerebellar Ataxia Mouse Model
by Anna Niewiadomska-Cimicka, Lorraine Fievet, Magdalena Surdyka, Ewelina Jesion, Céline Keime, Elisabeth Singer, Aurélie Eisenmann, Zaneta Kalinowska-Poska, Hoa Huu Phuc Nguyen, Agnieszka Fiszer, Maciej Figiel and Yvon Trottier
Int. J. Mol. Sci. 2024, 25(8), 4354; https://doi.org/10.3390/ijms25084354 - 15 Apr 2024
Cited by 3 | Viewed by 1648
Abstract
Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs). PolyQ-expanded SCA proteins are toxic for cerebellar neurons, with Purkinje cells (PCs) being the most vulnerable. RNA interference (RNAi) reagents targeting transcripts with expanded CAG reduce [...] Read more.
Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs). PolyQ-expanded SCA proteins are toxic for cerebellar neurons, with Purkinje cells (PCs) being the most vulnerable. RNA interference (RNAi) reagents targeting transcripts with expanded CAG reduce the level of various mutant SCA proteins in an allele-selective manner in vitro and represent promising universal tools for treating multiple CAG/polyQ SCAs. However, it remains unclear whether the therapeutic targeting of CAG expansion can be achieved in vivo and if it can ameliorate cerebellar functions. Here, using a mouse model of SCA7 expressing a mutant Atxn7 allele with 140 CAGs, we examined the efficacy of short hairpin RNAs (shRNAs) targeting CAG repeats expressed from PHP.eB adeno-associated virus vectors (AAVs), which were introduced into the brain via intravascular injection. We demonstrated that shRNAs carrying various mismatches with the CAG target sequence reduced the level of polyQ-expanded ATXN7 in the cerebellum, albeit with varying degrees of allele selectivity and safety profile. An shRNA named A4 potently reduced the level of polyQ-expanded ATXN7, with no effect on normal ATXN7 levels and no adverse side effects. Furthermore, A4 shRNA treatment improved a range of motor and behavioral parameters 23 weeks after AAV injection and attenuated the disease burden of PCs by preventing the downregulation of several PC-type-specific genes. Our results show the feasibility of the selective targeting of CAG expansion in the cerebellum using a blood–brain barrier-permeable vector to attenuate the disease phenotype in an SCA mouse model. Our study represents a significant advancement in developing CAG-targeting strategies as a potential therapy for SCA7 and possibly other CAG/polyQ SCAs. Full article
(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies 3.0)
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16 pages, 2516 KiB  
Article
AAV-SPL 2.0, a Modified Adeno-Associated Virus Gene Therapy Agent for the Treatment of Sphingosine Phosphate Lyase Insufficiency Syndrome
by Ranjha Khan, Babak Oskouian, Joanna Y. Lee, Jeffrey B. Hodgin, Yingbao Yang, Gizachew Tassew and Julie D. Saba
Int. J. Mol. Sci. 2023, 24(21), 15560; https://doi.org/10.3390/ijms242115560 - 25 Oct 2023
Cited by 3 | Viewed by 2036
Abstract
Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is an inborn error of metabolism caused by inactivating mutations in SGPL1, the gene encoding sphingosine-1-phosphate lyase (SPL), an essential enzyme needed to degrade sphingolipids. SPLIS features include glomerulosclerosis, adrenal insufficiency, neurological defects, ichthyosis, and immune deficiency. [...] Read more.
Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is an inborn error of metabolism caused by inactivating mutations in SGPL1, the gene encoding sphingosine-1-phosphate lyase (SPL), an essential enzyme needed to degrade sphingolipids. SPLIS features include glomerulosclerosis, adrenal insufficiency, neurological defects, ichthyosis, and immune deficiency. Currently, there is no cure for SPLIS, and severely affected patients often die in the first years of life. We reported that adeno-associated virus (AAV) 9-mediated SGPL1 gene therapy (AAV-SPL) given to newborn Sgpl1 knockout mice that model SPLIS and die in the first few weeks of life prolonged their survival to 4.5 months and prevented or delayed the onset of SPLIS phenotypes. In this study, we tested the efficacy of a modified AAV-SPL, which we call AAV-SPL 2.0, in which the original cytomegalovirus (CMV) promoter driving the transgene is replaced with the synthetic “CAG” promoter used in several clinically approved gene therapy agents. AAV-SPL 2.0 infection of human embryonic kidney (HEK) cells led to 30% higher SPL expression and enzyme activity compared to AAV-SPL. Newborn Sgpl1 knockout mice receiving AAV-SPL 2.0 survived ≥ 5 months and showed normal neurodevelopment, 85% of normal weight gain over the first four months, and delayed onset of proteinuria. Over time, treated mice developed nephrosis and glomerulosclerosis, which likely resulted in their demise. Our overall findings show that AAV-SPL 2.0 performs equal to or better than AAV-SPL. However, improved kidney targeting may be necessary to achieve maximally optimized gene therapy as a potentially lifesaving SPLIS treatment. Full article
(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies 3.0)
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15 pages, 1506 KiB  
Article
Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells
by Riccardo Luffarelli, Luca Panarello, Andrea Quatrana, Francesca Tiano, Silvia Fortuni, Alessandra Rufini, Florence Malisan, Roberto Testi and Ivano Condò
Int. J. Mol. Sci. 2023, 24(16), 12687; https://doi.org/10.3390/ijms241612687 - 11 Aug 2023
Cited by 2 | Viewed by 1860
Abstract
Friedreich’s ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of FXN gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is characterized by a plethora [...] Read more.
Friedreich’s ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of FXN gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is characterized by a plethora of metabolic disruptions related to iron metabolism, mitochondrial homeostasis and oxidative stress. Importantly, an impairment of the antioxidant defences exacerbates the oxidative damage. This appears closely associated with the disablement of key antioxidant proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the mitochondrial superoxide dismutase (MnSOD). The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA. Full article
(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies 3.0)
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Other

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10 pages, 1013 KiB  
Case Report
A Novel Heterozygous Mutation c.1627G>T (p.Gly543Cys) in the SLC34A1 Gene in a Male Patient with Recurrent Nephrolithiasis and Early Onset Osteopenia: A Case Report
by Francesca Giusti, Francesca Marini, Hatim Al-alwani, Elena Marasco, Paolo Garagnani, Aliya A. Khan and Maria Luisa Brandi
Int. J. Mol. Sci. 2023, 24(24), 17289; https://doi.org/10.3390/ijms242417289 - 9 Dec 2023
Cited by 1 | Viewed by 1393
Abstract
Serum phosphate concentration is regulated by renal phosphate reabsorption and mediated by sodium–phosphate cotransporters. Germline mutations in genes encoding these cotransporters have been associated with clinical phenotypes, variably characterized by hyperphosphaturia, hypophosphatemia, recurrent kidney stones, skeletal demineralization, and early onset osteoporosis. We reported [...] Read more.
Serum phosphate concentration is regulated by renal phosphate reabsorption and mediated by sodium–phosphate cotransporters. Germline mutations in genes encoding these cotransporters have been associated with clinical phenotypes, variably characterized by hyperphosphaturia, hypophosphatemia, recurrent kidney stones, skeletal demineralization, and early onset osteoporosis. We reported a 33-year-old male patient presenting a history of recurrent nephrolithiasis and early onset osteopenia in the lumbar spine and femur. He was tested, through next generation sequencing (NGS), by using a customized multigenic panel containing 33 genes, whose mutations are known to be responsible for the development of congenital parathyroid diseases. Two further genes, SLC34A1 and SLC34A3, encoding two sodium–phosphate cotransporters, were additionally tested. A novel germline heterozygous mutation was identified in the SLC34A1 gene, c.1627G>T (p.Gly543Cys), currently not reported in databases of human gene mutations and scientific literature. SLC34A1 germline heterozygous mutations have been associated with the autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1). Consistently, alongside the clinical features of NPHLOP1, our patient experienced recurrent nephrolithiasis and lumbar and femoral osteopenia at a young age. Genetic screening for the p.Gly453Cys variant and the clinical characterization of his first-degree relatives associated the presence of the variant in one younger brother, presenting renal colic and microlithiasis, suggesting p.Gly453Cys is possibly associated with renal altered function in the NPHLOP1 phenotype. Full article
(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies 3.0)
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