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Diagnosis and Therapies for Genetic Diseases
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Diagnosis and Therapies for Genetic Diseases

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (10 January 2024) | Viewed by 8391

Special Issue Editors

Dr. Maria Monticelli

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Guest Editor
1. Department Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania “Luigi Vanvitelli”, Via Vivaldi 43, 81100 Caserta, Italy
2. Institute of Biomolecular Chemistry ICB, CNR, Via Campi Flegrei 34, 80078 Pozzuoli, Italy
3. Department Biology, University of Napoli «Federico II», Complesso Universitario Monte Sant’Angelo, Via Cinthia, 80126 Napoli, Italy
Interests: biochemistry; proteins; protein folding; drug discovery; rare diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Bruno Hay Mele

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Guest Editor
Department Biology, University of Napoli Federico II, Complesso Universitario Monte Sant’Angelo, Via Cinthia, 80126 Napoli, Italy
Interests: protein folding; structural biology; biological networks; complex systems; rare diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Giuseppina Andreotti

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Guest Editor
Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Naples, Italy
Interests: pharmacological chaperones; glycosyl hydrolases; metabolomic; NMR; protein expression; protein purification; enzymatic assay; peptide/protein structure; thermal shift assay; Fabry disease; PMM2-CDG
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We invite you to contribute to this Special Issue on “Diagnosis and Therapies for Genetic Diseases”. Genetic disorders share common aspects, particularly related to the difficulties experienced in the diagnosis, treatment, and management. This link is even more true when considering the subset of rare genetic diseases. Within this Special Issue, we would like to expand our knowledge in the field, focusing on the different prominent aspects. On the one hand, the identification of known or new disease-associated variants, and the improvement in the related technologies, are essential to guarantee the possibility of diagnosis. On the other hand, de novo drug discovery and drug repositioning represent the hot topic of finding treatments for uncured diseases and ameliorating many therapies with significant limitations.

Dr. Maria Monticelli
Dr. Bruno Hay Mele
Dr. Giuseppina Andreotti
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. Genes is an international peer-reviewed open access monthly 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 2600 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

  • genetic diseases
  • variant identification
  • drug discovery

Published Papers (4 papers)

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Research

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27 pages, 3063 KiB  
Article
Sex Differences in Anderson–Fabry Cardiomyopathy: Clinical, Genetic, and Imaging Analysis in Women
by Denise Cristiana Faro, Valentina Losi, Margherita Stefania Rodolico, Elvira Mariateresa Torrisi, Paolo Colomba, Giovanni Duro and Ines Paola Monte
Genes 2023, 14(9), 1804; https://doi.org/10.3390/genes14091804 - 15 Sep 2023
Cited by 2 | Viewed by 1388
Abstract
Anderson–Fabry Disease (AFD) is a rare, systemic lysosomal storage disease triggered by mutations in the GLA gene, leading to α-galactosidase A (α-Gal A) deficiency. The disease’s X-linked inheritance leads to more severe, early-onset presentations in males, while females exhibit variable, often insidious, manifestations, [...] Read more.
Anderson–Fabry Disease (AFD) is a rare, systemic lysosomal storage disease triggered by mutations in the GLA gene, leading to α-galactosidase A (α-Gal A) deficiency. The disease’s X-linked inheritance leads to more severe, early-onset presentations in males, while females exhibit variable, often insidious, manifestations, notably impacting cardiac health. This study aims to examine gender-based AFD cardiac manifestations in correlation with the variant type: classical (CL), late-onset (LO), or variants of uncertain significance (VUS). We analyzed data from 72 AFD patients (53 females, 19 males) referred to the “G. Rodolico” University Hospital, employing enzyme activity measurements, genetic analysis, periodic lyso-Gb3 monitoring, comprehensive medical histories, and advanced cardiac imaging techniques. Statistical analysis was performed using SPSS version 26. Our AFD cohort, with an average age of 45 ± 16.1 years, comprised 12 individuals with hypertrophy (AFD-LVH) and 60 without (AFD-N). Women, representing about 75% of the subjects, were generally older than men (47.2 ± 16.2 vs. 38.8 ± 14.6, p = 0.046). In the female group, 17% had CL variants, 43.3% LO, and 39.6% had VUS, compared to 21.1%, 36.8%, and 31.6% in the male group, respectively. Females exhibited significantly higher α-Gal A values (median 7.9 vs. 1.8 nmol/mL/h, p < 0.001) and lower lyso-Gb3 levels (1.5 [IQR 1.1–1.7] vs. 1.9 [1.5–17.3] nmol/L, p = 0.02). Regarding the NYHA class distribution, 70% of women were in class I and 28% in class II, compared to 84% and 16% of men, respectively. Among women, 7.5% exhibited ventricular arrhythmias (10.5% in men), and 9.4% had atrial fibrillation (10.5% in men). Cardiac MRIs revealed fibrosis in 57% of examined women, compared to 87% of men. Even among patients without LVH, significant differences persisted in α-Gal A and lyso-Gb3 levels (p = 0.003 and 0.04), as well as LVMi (61.5 vs. 77.5 g/sqm, p = 0.008) and GLS values (−20% vs. −17%, p = 0.01). The analysis underscored older age, decreased lyso-Gb3 deposition, reduced hypertrophy, and lesser GLS compromise in females, suggesting later disease onset. Severe cardiac patterns were associated with classic variants, while more nuanced manifestations were noted in those with VUS. Early GLS impairment in males, irrespective of hypertrophy, emphasized the role of subclinical damage in AFD. Full article
(This article belongs to the Special Issue Diagnosis and Therapies for Genetic Diseases)
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16 pages, 2600 KiB  
Article
New Insights into Dyskerin-CypA Interaction: Implications for X-Linked Dyskeratosis Congenita and Beyond
by Valentina Belli, Daniela Maiello, Concetta Di Lorenzo, Maria Furia, Rosario Vicidomini and Mimmo Turano
Genes 2023, 14(9), 1766; https://doi.org/10.3390/genes14091766 - 06 Sep 2023
Cited by 1 | Viewed by 860
Abstract
The highly conserved family of cyclophilins comprises multifunctional chaperones that interact with proteins and RNAs, facilitating the dynamic assembly of multimolecular complexes involved in various cellular processes. Cyclophilin A (CypA), the predominant member of this family, exhibits peptidyl–prolyl cis–trans isomerase activity. This enzymatic [...] Read more.
The highly conserved family of cyclophilins comprises multifunctional chaperones that interact with proteins and RNAs, facilitating the dynamic assembly of multimolecular complexes involved in various cellular processes. Cyclophilin A (CypA), the predominant member of this family, exhibits peptidyl–prolyl cis–trans isomerase activity. This enzymatic function aids with the folding and activation of protein structures and often serves as a molecular regulatory switch for large multimolecular complexes, ensuring appropriate inter- and intra-molecular interactions. Here, we investigated the involvement of CypA in the nucleus, where it plays a crucial role in supporting the assembly and trafficking of heterogeneous ribonucleoproteins (RNPs). We reveal that CypA is enriched in the nucleolus, where it colocalizes with the pseudouridine synthase dyskerin, the catalytic component of the multifunctional H/ACA RNPs involved in the modification of cellular RNAs and telomere stability. We show that dyskerin, whose mutations cause the X-linked dyskeratosis (X-DC) and the Hoyeraal–Hreidarsson congenital ribosomopathies, can directly interact with CypA. These findings, together with the remark that substitution of four dyskerin prolines are known to cause X-DC pathogenic mutations, lead us to indicate this protein as a CypA client. The data presented here suggest that this chaperone can modulate dyskerin activity influencing all its partecipated RNPs. Full article
(This article belongs to the Special Issue Diagnosis and Therapies for Genetic Diseases)
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Review

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17 pages, 1639 KiB  
Review
Drug Repurposing and Lysosomal Storage Disorders: A Trick to Treat
by Bruno Hay Mele, Federica Rossetti, Maria Vittoria Cubellis, Maria Monticelli and Giuseppina Andreotti
Genes 2024, 15(3), 290; https://doi.org/10.3390/genes15030290 - 25 Feb 2024
Viewed by 1086
Abstract
Rare diseases, or orphan diseases, are defined as diseases affecting a small number of people compared to the general population. Among these, we find lysosomal storage disorders (LSDs), a cluster of rare metabolic diseases characterized by enzyme mutations causing abnormal glycolipid storage. Drug [...] Read more.
Rare diseases, or orphan diseases, are defined as diseases affecting a small number of people compared to the general population. Among these, we find lysosomal storage disorders (LSDs), a cluster of rare metabolic diseases characterized by enzyme mutations causing abnormal glycolipid storage. Drug repositioning involves repurposing existing approved drugs for new therapeutic applications, offering advantages in cost, time savings, and a lower risk of failure. We present a comprehensive analysis of existing drugs, their repurposing potential, and their clinical implications in the context of LSDs, highlighting the necessity of mutation-specific approaches. Our review systematically explores the landscape of drug repositioning as a means to enhance LSDs therapies. The findings advocate for the strategic repositioning of drugs, accentuating its role in expediting the discovery of effective treatments. We conclude that drug repurposing represents a viable pathway for accelerating therapeutic discovery for LSDs, emphasizing the need for the careful evaluation of drug efficacy and toxicity in disease-specific contexts. Full article
(This article belongs to the Special Issue Diagnosis and Therapies for Genetic Diseases)
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14 pages, 1683 KiB  
Review
Hereditary Thrombotic Thrombocytopenic Purpura
by Sanober Nusrat, Kisha Beg, Osman Khan, Arpan Sinha and James George
Genes 2023, 14(10), 1956; https://doi.org/10.3390/genes14101956 - 18 Oct 2023
Cited by 1 | Viewed by 4372
Abstract
Hereditary thrombotic thrombocytopenic purpura (hTTP), also known as Upshaw–Schulman syndrome, is a rare genetic disorder caused by mutations in the ADAMTS13 gene that leads to decreased or absent production of the plasma von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13. The result is circulating ultra-large [...] Read more.
Hereditary thrombotic thrombocytopenic purpura (hTTP), also known as Upshaw–Schulman syndrome, is a rare genetic disorder caused by mutations in the ADAMTS13 gene that leads to decreased or absent production of the plasma von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13. The result is circulating ultra-large multimers of VWF that can cause microthrombi, intravascular occlusion and organ damage, especially at times of turbulent circulation. Patients with hTTP may have many overt or clinically silent manifestations, and a high index of suspicion is required for diagnosis. For the treatment of hTTP, the goal is simply replacement of ADAMTS13. The primary treatment is prophylaxis with plasma infusions or plasma-derived factor VIII products, providing sufficient ADAMTS13 to prevent acute episodes. When acute episodes occur, prophylaxis is intensified. Recombinant ADAMTS13, which is near to approval, will immediately be the most effective and also the most convenient treatment. In this review, we discuss the possible clinical manifestations of this rare disease and the relevant differential diagnoses in different age groups. An extensive discussion on prophylaxis and treatment strategies is also presented. Unique real patient cases have been added to highlight critical aspects of hTTP manifestations, diagnosis and treatment. Full article
(This article belongs to the Special Issue Diagnosis and Therapies for Genetic Diseases)
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