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Genetic Variants in Neurological and Psychiatric Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 30 September 2024 | Viewed by 7680

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Prof. Dr. Maria A. Mariggiò

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Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy
Interests: diagnostics; molecular oncology and pathology; precision medicine
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Dr. Maria A. Bonifacio

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Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
Interests: tissue engineering; regenerative medicine; spectroscopy; biological characterization; composite materials; hydrogels; coatings; phytochemicals
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Dear Colleagues,

Genetic susceptibility to multifactorial neurological and psychiatric diseases is one of the hottest topics in molecular biology and translational medicine. Indeed, improvements in diagnostics, as well as the findings of multicenter studies, are changing the perspectives of researchers. The overlapping symptoms of common disorders are now being explained as genetic risk factors, shared by patients with several psychiatric conditions (i.e., anxiety, depression, epilepsy).

In addition, genetic variants and single-nucleotide polymorphisms have been associated with immune-mediated diseases, leading to neuroinflammatory disorders, as well as to neurological dysfunctions. Meanwhile, through genome-wide studies, the scientific community is revealing the genetic architecture underlying high-impact neurodegenerative diseases, such as Alzheimer and Parkinson diseases, making individual genetic profiling a concrete opportunity to prevent or delay disease onset. Furthermore, the opportunity to identify variants associated with enzymes responsible for drug metabolism (i.e., cytochromes, monoamine oxidases, catechol-o-methyltransferases) is opening new landscapes in personalized therapy. All these outcomes allow the provision of the most effective treatment for each patient in terms of therapeutic molecule selection and dose adjustment.

This Special Issue welcomes every paper (i.e., original research article, systematic review, case report, short communication, and meta-analysis) representing a significant contribution in this research field.

Prof. Dr. Maria A. Mariggiò
Dr. Maria A. Bonifacio
Guest Editors

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Keywords

genetic variants
polymorphisms
genetic profile
neurological diseases
psychiatric disorders
therapeutic drug monitoring (TDM)

Published Papers (7 papers)

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15 pages, 1073 KiB

Open AccessArticle

Unveiling New Genetic Variants Associated with Age at Onset in Alzheimer’s Disease and Frontotemporal Lobar Degeneration Due to C9orf72 Repeat Expansions

by Antonio Longobardi, Sonia Bellini, Roland Nicsanu, Andrea Pilotto, Andrea Geviti, Alessandro Facconi, Chiara Tolassi, Ilenia Libri, Claudia Saraceno, Silvia Fostinelli, Barbara Borroni, Alessandro Padovani, Giuliano Binetti and Roberta Ghidoni

Int. J. Mol. Sci. 2024, 25(13), 7457; https://doi.org/10.3390/ijms25137457 - 7 Jul 2024

Viewed by 639

Abstract

Alzheimer’s disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN/C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin (TF) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 (CLSTN1) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism (TF) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles (CLSTN1) as genetic modulators in AD and FTLD due to C9orf72 expansions. Full article

(This article belongs to the Special Issue Genetic Variants in Neurological and Psychiatric Diseases)

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28 pages, 7326 KiB

Open AccessArticle

Novel Insights into Changes in Gene Expression within the Hypothalamus in Two Asthma Mouse Models: A Transcriptomic Lung–Brain Axis Study

by Eslam M. Bastawy, Izel M. Eraslan, Lara Voglsanger, Cenk Suphioglu, Adam J. Walker, Olivia M. Dean, Justin L. Read, Mark Ziemann and Craig M. Smith

Int. J. Mol. Sci. 2024, 25(13), 7391; https://doi.org/10.3390/ijms25137391 - 5 Jul 2024

Viewed by 546

Abstract

Patients with asthma experience elevated rates of mental illness. However, the molecular links underlying such lung–brain crosstalk remain ambiguous. Hypothalamic dysfunction is observed in many psychiatric disorders, particularly those with an inflammatory component due to many hypothalamic regions being unprotected by the blood–brain barrier. To gain a better insight into such neuropsychiatric sequelae, this study investigated gene expression differences in the hypothalamus following lung inflammation (asthma) induction in mice, using RNA transcriptome profiling. BALB/c mice were challenged with either bacterial lipopolysaccharide (LPS, E. coli) or ovalbumin (OVA) allergens or saline control (n = 7 per group), and lung inflammation was confirmed via histological examination of postmortem lung tissue. The majority of the hypothalamus was micro-dissected, and total RNA was extracted for sequencing. Differential expression analysis identified 31 statistically significant single genes (false discovery rate FDR5%) altered in expression following LPS exposure compared to controls; however, none were significantly changed following OVA treatment, suggesting a milder hypothalamic response. When gene sets were examined, 48 were upregulated and 8 were downregulated in both asthma groups relative to controls. REACTOME enrichment analysis suggests these gene sets are involved in signal transduction metabolism, immune response and neuroplasticity. Interestingly, we identified five altered gene sets directly associated with neurotransmitter signaling. Intriguingly, many of these altered gene sets can influence mental health and or/neuroinflammation in humans. These findings help characterize the links between asthma-induced lung inflammation and the brain and may assist in identifying relevant pathways and therapeutic targets for future intervention. Full article

(This article belongs to the Special Issue Genetic Variants in Neurological and Psychiatric Diseases)

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9 pages, 2501 KiB

Open AccessArticle

Phenotypic Variability in Novel Doublecortin Gene Variants Associated with Subcortical Band Heterotopia

by Radha Procopio, Francesco Fortunato, Monica Gagliardi, Mariagrazia Talarico, Ilaria Sammarra, Maria Chiara Sarubbi, Donatella Malanga, Grazia Annesi and Antonio Gambardella

Int. J. Mol. Sci. 2024, 25(10), 5505; https://doi.org/10.3390/ijms25105505 - 18 May 2024

Viewed by 725

Abstract

Doublecortin, encoded by the DCX gene, plays a crucial role in the neuronal migration process during brain development. Pathogenic variants of the DCX gene are the major causes of the “lissencephaly (LIS) spectrum”, which comprehends a milder phenotype like Subcortical Band Heterotopia (SBH) in heterozygous female subjects. We performed targeted sequencing in three unrelated female cases with SBH. We identified three DCX-related variants: a novel missense (c.601A>G: p.Lys201Glu), a novel nonsense (c.210C>G: p.Tyr70*), and a previously identified nonsense (c.907C>T: p.Arg303*) variant. The novel c.601A>G: p.Lys201Glu variant shows a mother–daughter transmission pattern across four generations. The proband exhibits focal epilepsy and achieved seizure freedom with a combination of oxcarbazepine and levetiracetam. All other affected members have no history of epileptic seizures. Brain MRIs of the affected members shows predominant fronto-central SBH with mixed pachygyria on the overlying cortex. The two nonsense variants were identified in two unrelated probands with SBH, severe drug-resistant epilepsy and intellectual disability. These novel DCX variants further expand the genotypic–phenotypic correlations of lissencephaly spectrum disorders. Our documented phenotypic descriptions of three unrelated families provide valuable insights and stimulate further discussions on DCX-SBH cases. Full article

(This article belongs to the Special Issue Genetic Variants in Neurological and Psychiatric Diseases)

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13 pages, 1134 KiB

Open AccessArticle

ABCB1 C1236T, G2677TA and C3435T Genetic Polymorphisms and Antidepressant Response Phenotypes: Results from a Portuguese Major Depressive Disorder Cohort

by Marlene Santos, Luis Lima, Serafim Carvalho, Andreia Brandão, Fátima Barroso, Agostinho Cruz and Rui Medeiros

Int. J. Mol. Sci. 2024, 25(10), 5112; https://doi.org/10.3390/ijms25105112 - 8 May 2024

Viewed by 826

Abstract

P-glycoprotein (P-GP) is a transporter molecule expressed on the apical surface of capillary endothelial cells of the Blood–Brain Barrier (BBB), whose activity heavily influences drug distribution, including antidepressants. This transporter is encoded by ABCB1 gene, and genetic variations within ABCB1 gene have been proposed to affect drug efflux and have been previously associated with depression. In this context, we aimed to evaluate the role of C1236T, G2677TA and C3435T ABCB1 genetic polymorphisms in antidepressant treatment phenotypes from a cohort of patients harboring Major Depressive Disorder. Patients enrolled in the study consisted of 80 individuals with Major Depressive Disorder, who took part in a 27-month follow-up study at HML, Portugal. To investigate the correlation between ABCB1 polymorphisms and antidepressant response phenotypes, DNA was extracted from peripheral blood, and C1236T, C3435T and G2677TA polymorphisms were genotyped with TaqMan^® SNP Genotyping Assays. Despite the fact that the evaluated polymorphisms (C1236T, C3435T and G2677TA) were not associated with treatment resistant depression, or relapse, we observed that patients carrying TT genotype of the C3435T polymorphism remit earlier than the ones carrying CC or CT genotypes (10.2 weeks vs. 14.9 and 21.3, respectively, p = 0.028, Log-rank test). Since we found an association with C3435T and time to remission, and not to the absence of remission, we suggest that this polymorphism could have an impact on antidepressant drug distribution, and thus influence on the time to remission will occur, without influencing the risk of remission itself. Full article

(This article belongs to the Special Issue Genetic Variants in Neurological and Psychiatric Diseases)

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13 pages, 4135 KiB

Open AccessArticle

Novel Genetic and Phenotypic Expansion in Ameliorated PUF60-Related Disorders

by Emily Baum, Wenming Huang, Catherine Vincent-Delorme, Perrine Brunelle, Adam Antebi and Hormos Salimi Dafsari

Int. J. Mol. Sci. 2024, 25(4), 2053; https://doi.org/10.3390/ijms25042053 - 8 Feb 2024

Viewed by 1602

Abstract

Heterozygous variants in the Poly(U) Binding Splicing Factor 60kDa gene (PUF60) have been associated with Verheij syndrome, which has the key features of coloboma, short stature, skeletal abnormalities, developmental delay, palatal abnormalities, and congenital heart and kidney defects. Here, we report five novel patients from unrelated families with PUF60-related disorders exhibiting novel genetic and clinical findings with three truncating variants, one splice-site variant with likely reduced protein expression, and one missense variant. Protein modeling of the patient’s missense variant in the PUF60 AlphaFold structure revealed a loss of polar bonds to the surrounding residues. Neurodevelopmental disorders were present in all patients, with variability in speech, motor, cognitive, social-emotional and behavioral features. Novel phenotypic expansions included movement disorders as well as immunological findings with recurrent respiratory, urinary and ear infections, atopic diseases, and skin abnormalities. We discuss the role of PUF60 in immunity with and without infection based on recent organismic and cellular studies. As our five patients showed less-severe phenotypes than classical Verheij syndrome, particularly with the absence of key features such as coloboma or palatal abnormalities, we propose a reclassification as PUF60-related neurodevelopmental disorders with multi-system involvement. These findings will aid in the genetic counseling of patients and families. Full article

(This article belongs to the Special Issue Genetic Variants in Neurological and Psychiatric Diseases)

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16 pages, 783 KiB

Open AccessArticle

Genetic and Epigenetic Regulation in Lingo-1: Effects on Cognitive Function and White Matter Microstructure in a Case-Control Study for Schizophrenia

by Jessica L. Andrews, Andrew Zalesky, Shalima Nair, Ryan P. Sullivan, Melissa J. Green, Christos Pantelis, Kelly A. Newell and Francesca Fernandez

Int. J. Mol. Sci. 2023, 24(21), 15624; https://doi.org/10.3390/ijms242115624 - 26 Oct 2023

Cited by 2 | Viewed by 1242

Abstract

Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) plays a vital role in a large number of neuronal processes underlying learning and memory, which are known to be disrupted in schizophrenia. However, Lingo-1 has never been examined in the context of schizophrenia. The genetic association of a single-nucleotide polymorphism (SNP, rs3144) and methylation (CpG sites) in the Lingo-1 3′-UTR region was examined, with the testing of cognitive dysfunction and white matter (WM) integrity in a schizophrenia case-control cohort (n = 268/group). A large subset of subjects (97 control and 161 schizophrenia subjects) underwent structural magnetic resonance imaging (MRI) brain scans to assess WM integrity. Frequency of the rs3144 minor allele was overrepresented in the schizophrenia population (p = 0.03), with an odds ratio of 1.39 (95% CI 1.016–1.901). CpG sites surrounding rs3144 were hypermethylated in the control population (p = 0.032) compared to the schizophrenia group. rs3144 genotype was predictive of membership to a subclass of schizophrenia subjects with generalized cognitive deficits (p < 0.05), in addition to having associations with WM integrity (p = 0.018). This is the first study reporting a potential implication of genetic and epigenetic risk factors in Lingo-1 in schizophrenia. Both of these genetic and epigenetic alterations may also have associations with cognitive dysfunction and WM integrity in the context of the schizophrenia pathophysiology. Full article

(This article belongs to the Special Issue Genetic Variants in Neurological and Psychiatric Diseases)

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8 pages, 770 KiB

Open AccessCase Report

Hereditary Spastic Paraplegia Type 11—Clinical, Genetic and Neuroimaging Characteristics

by Justyna Chojdak-Łukasiewicz, Katarzyna Sulima, Anna Zimny, Marta Waliszewska-Prosół and Sławomir Budrewicz

Int. J. Mol. Sci. 2023, 24(24), 17530; https://doi.org/10.3390/ijms242417530 - 15 Dec 2023

Viewed by 1349

Abstract

Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetically determined diseases, characterised by progressive spastic paraparesis of the lower limbs, associated with degeneration of the corticospinal tract and the posterior column of the spinal cord. HSP occurs worldwide and the estimated prevalence is about 1–10/100,000, depending on the geographic localisation. More than 70 genes responsible for HSP have been identified to date, and reports of new potentially pathogenic variants appear regularly. All possible patterns of inheritance (autosomal dominant, autosomal recessive, X-linked and mitochondrial) have been described in families of HSP patients. Among the autosomal recessive forms of HSP (AR-HSP), hereditary spastic paraplegia type 11 is the most common one. We present a patient with diagnosed HSP 11, with a typical clinical picture and characteristic features in additional diagnostic tests. Full article

(This article belongs to the Special Issue Genetic Variants in Neurological and Psychiatric Diseases)

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