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8.3
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Biomolecules
Special Issues
Molecular and Cellular Basis for Rare Genetic Diseases
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Molecular and Cellular Basis for Rare Genetic Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 8928

Special Issue Editors

Dr. María-Paz Marzolo

E-Mail Website
Guest Editor
Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O´Higgins 340, Santiago, Chile
Interests: membrane trafficking; LDL-R family; cell polarity; endocytosis; sorting nexins; sorting signals
Dr. Francisco Bustos

E-Mail Website
Guest Editor
Sanford Research and Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57104, USA
Interests: rare diseases; developmental disorders; development; stem cells; protein posttranslational modification; ubiquitin system; phosphorylation

Special Issue Information

Dear Colleagues,

Early-onset cognitive impairment, also known as intellectual disability, has a prevalence of close to 2% and constitutes a healthcare problem worldwide. Among early-onset intellectual disabilities, around 10% are associated with X-linked genes. Chromosomal rearrangements explain 30% (i.e., deletions, duplications, inversions, structural variants), and an undetermined proportion of these have no known causes. Of the less-known forms of cognitive impairment are the autosomal-recessive forms. In many cases, affected genes directly impact central nervous system (CNS) development and function; although these gene products are present in several tissues, some are also affected.

Rare genetic diseases have a very low prevalence. However, most of them affect children's CNS. From this point of view, they represent an opportunity to understand at the organism, cellular and molecular level the functioning and regulation of vital mechanisms and pathways underlying the development and function of the nervous system. In order to generate information about these diseases, the development of different approaches and experimental models is relevant. Considering this knowledge, therapeutic options can be envisioned for the affected children.

The Special Issue, “Molecular and Cellular Basis for Rare Genetic Diseases”, will accept submissions based on cell and molecular biology, systems biology, genetically modified mice, and other animal models, including flies and worms. We welcome the submission of both review articles and original research papers contributing significantly to our understanding of the biological processes involved in these diseases. 

Dr. María-Paz Marzolo
Dr. Francisco Bustos
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. Biomolecules 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 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

  • neurodevelopment
  • intellectual disability
  • neurodegeneration
  • rare genetic diseases
  • systems biology
  • membrane trafficking
  • epigenetics
  • metabolism

Published Papers (4 papers)

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Research

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18 pages, 3128 KiB  
Article
Heterogeneity in Lowe Syndrome: Mutations Affecting the Phosphatase Domain of OCRL1 Differ in Impact on Enzymatic Activity and Severity of Cellular Phenotypes
by Jennifer J. Lee, Swetha Ramadesikan, Adrianna F. Black, Charles Christoffer, Andres F. Pacheco Pacheco, Sneha Subramanian, Claudia B. Hanna, Gillian Barth, Cynthia V. Stauffacher, Daisuke Kihara and Ruben Claudio Aguilar
Biomolecules 2023, 13(4), 615; https://doi.org/10.3390/biom13040615 - 29 Mar 2023
Cited by 2 | Viewed by 1816
Abstract
Lowe Syndrome (LS) is a condition due to mutations in the OCRL1 gene, characterized by congenital cataracts, intellectual disability, and kidney malfunction. Unfortunately, patients succumb to renal failure after adolescence. This study is centered in investigating the biochemical and phenotypic impact of patient’s [...] Read more.
Lowe Syndrome (LS) is a condition due to mutations in the OCRL1 gene, characterized by congenital cataracts, intellectual disability, and kidney malfunction. Unfortunately, patients succumb to renal failure after adolescence. This study is centered in investigating the biochemical and phenotypic impact of patient’s OCRL1 variants (OCRL1VAR). Specifically, we tested the hypothesis that some OCRL1VAR are stabilized in a non-functional conformation by focusing on missense mutations affecting the phosphatase domain, but not changing residues involved in binding/catalysis. The pathogenic and conformational characteristics of the selected variants were evaluated in silico and our results revealed some OCRL1VAR to be benign, while others are pathogenic. Then we proceeded to monitor the enzymatic activity and function in kidney cells of the different OCRL1VAR. Based on their enzymatic activity and presence/absence of phenotypes, the variants segregated into two categories that also correlated with the severity of the condition they induce. Overall, these two groups mapped to opposite sides of the phosphatase domain. In summary, our findings highlight that not every mutation affecting the catalytic domain impairs OCRL1′s enzymatic activity. Importantly, data support the inactive-conformation hypothesis. Finally, our results contribute to establishing the molecular and structural basis for the observed heterogeneity in severity/symptomatology displayed by patients. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis for Rare Genetic Diseases)
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15 pages, 16693 KiB  
Article
Development of Lanzyme as the Potential Enzyme Replacement Therapy Drug for Fabry Disease
by Mulan Deng, Hongyu Zhou, Zhicheng Liang, Zhaoyang Li, Yanping Wang, Wanyi Guo, April Yuanyi Zhao, Fanghong Li, Yunping Mu and Allan Zijian Zhao
Biomolecules 2023, 13(1), 53; https://doi.org/10.3390/biom13010053 - 27 Dec 2022
Cited by 1 | Viewed by 1579
Abstract
Fabry disease (FD) is a progressive multisystemic disease characterized by lysosomal enzyme deficiency. Enzyme replacement therapy (ERT) is one of the most significant advancements and breakthroughs in treating FD. However, limited resources and the high cost of ERT might prevent patients from receiving [...] Read more.
Fabry disease (FD) is a progressive multisystemic disease characterized by lysosomal enzyme deficiency. Enzyme replacement therapy (ERT) is one of the most significant advancements and breakthroughs in treating FD. However, limited resources and the high cost of ERT might prevent patients from receiving prompt and effective therapy, thereby resulting in severe complications. Future progress in ERT can uncover promising treatment options. In this study, we developed and validated a recombinant enzyme (Lanzyme) based on a CHO-S cell system to provide a new potential option for FD therapy. Our results indicated that Lanzyme was heavily glycosylated, and its highest activity was similar to a commercial enzyme (Fabrazyme®). Our pharmacokinetic assessment revealed that the half-life of Lanzyme was up to 11 min, which is nearly twice that of the commercial enzyme. In vivo experiments revealed that Lanzyme treatment sharply decreased the accumulation levels of Gb3 and lyso-Gb3 in various tissues of FD model mice, with superior or comparable therapeutic effects to Fabrazyme®. Based on these data, Lanzyme may represent a new and promising treatment approach for FD. Building this enzyme production system for ERT can offer additional choice, potentially with enhanced efficacy, for the benefit of patients with FD. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis for Rare Genetic Diseases)
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Review

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24 pages, 3089 KiB  
Review
Regulation of Endosomal Trafficking by Rab7 and Its Effectors in Neurons: Clues from Charcot–Marie–Tooth 2B Disease
by Ryan J. Mulligan and Bettina Winckler
Biomolecules 2023, 13(9), 1399; https://doi.org/10.3390/biom13091399 - 16 Sep 2023
Cited by 1 | Viewed by 1527
Abstract
Intracellular endosomal trafficking controls the balance between protein degradation and synthesis, i.e., proteostasis, but also many of the cellular signaling pathways that emanate from activated growth factor receptors after endocytosis. Endosomal trafficking, sorting, and motility are coordinated by the activity of small GTPases, [...] Read more.
Intracellular endosomal trafficking controls the balance between protein degradation and synthesis, i.e., proteostasis, but also many of the cellular signaling pathways that emanate from activated growth factor receptors after endocytosis. Endosomal trafficking, sorting, and motility are coordinated by the activity of small GTPases, including Rab proteins, whose function as molecular switches direct activity at endosomal membranes through effector proteins. Rab7 is particularly important in the coordination of the degradative functions of the pathway. Rab7 effectors control endosomal maturation and the properties of late endosomal and lysosomal compartments, such as coordination of recycling, motility, and fusion with downstream compartments. The spatiotemporal regulation of endosomal receptor trafficking is particularly challenging in neurons because of their enormous size, their distinct intracellular domains with unique requirements (dendrites vs. axons), and their long lifespans as postmitotic, differentiated cells. In Charcot–Marie–Tooth 2B disease (CMT2B), familial missense mutations in Rab7 cause alterations in GTPase cycling and trafficking, leading to an ulcero-mutilating peripheral neuropathy. The prevailing hypothesis to account for CMT2B pathologies is that CMT2B-associated Rab7 alleles alter endocytic trafficking of the neurotrophin NGF and its receptor TrkA and, thereby, disrupt normal trophic signaling in the peripheral nervous system, but other Rab7-dependent pathways are also impacted. Here, using TrkA as a prototypical endocytic cargo, we review physiologic Rab7 effector interactions and control in neurons. Since neurons are among the largest cells in the body, we place particular emphasis on the temporal and spatial regulation of endosomal sorting and trafficking in neuronal processes. We further discuss the current findings in CMT2B mutant Rab7 models, the impact of mutations on effector interactions or balance, and how this dysregulation may confer disease. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis for Rare Genetic Diseases)
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23 pages, 992 KiB  
Review
Nuclear PTEN’s Functions in Suppressing Tumorigenesis: Implications for Rare Cancers
by Casey G. Langdon
Biomolecules 2023, 13(2), 259; https://doi.org/10.3390/biom13020259 - 30 Jan 2023
Cited by 4 | Viewed by 2927
Abstract
Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect [...] Read more.
Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect pediatric and adult populations. Originally discovered and characterized as a negative regulator of the cytoplasmic, pro-oncogenic phosphoinositide-3-kinase (PI3K) pathway, PTEN is also localized to the nucleus where it can exert tumor-suppressive functions in a PI3K pathway-independent manner. Cancers can usurp the tumor-suppressive functions of PTEN to promote oncogenesis by disrupting homeostatic subcellular PTEN localization. The objective of this review is to describe the changes seen in PTEN subcellular localization during tumorigenesis, how PTEN enters the nucleus, and the spectrum of impacts and consequences arising from disrupted PTEN nuclear localization on tumor promotion. This review will highlight the immediate need in understanding not only the cytoplasmic but also the nuclear functions of PTEN to gain more complete insights into how important PTEN is in preventing human cancers. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis for Rare Genetic Diseases)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: To be determined
Authors: Clara D. M. van Karnebeek; et al.
Affiliation: University of Amsterdam, 1012 WX Amsterdam, The Netherlands

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