International Journal of Molecular Sciences

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Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants

by András Salamon, Zsófia Flóra Nagy, Margit Pál, Máté Szabó, Ádám Csősz, László Szpisjak, Gabriella Gárdián, Dénes Zádori, Márta Széll and Péter Klivényi

Int. J. Mol. Sci. 2023, 24(13), 10745; https://doi.org/10.3390/ijms241310745 - 28 Jun 2023

Cited by 2 | Viewed by 931

Abstract

Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A [...] Read more.

Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A total of 121 patients (CD, 74; BSP, 47) were included in the study. The average age of the patients was 64 years. For the next-generation sequencing (NGS) approach, 30 genes were selected on the basis of a thorough search of the scientific literature. Assessment of 30 CD- and BSP-associated genes from 121 patients revealed a total of 209 different heterozygous variants in 24 genes. Established clinical and genetic validity was determined for nine heterozygous variations (three likely pathogenic and six variants of uncertain significance). Detailed genetic examination is an important part of the work-up for focal dystonia forms. To our knowledge, our investigation is the first such study to be carried out in the Middle-European region. Full article

(This article belongs to the Special Issue Unraveling the Genetic Background of Neurological Disorders)

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18 pages, 1533 KiB

Open AccessArticle

Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies

by Rowida Almomani, Maurice Sopacua, Margherita Marchi, Milena Ślęczkowska, Patrick Lindsey, Bianca T. A. de Greef, Janneke G. J. Hoeijmakers, Erika Salvi, Ingemar S. J. Merkies, Maryam Ferdousi, Rayaz A. Malik, Dan Ziegler, Kasper W. J. Derks, Gidon Boenhof, Filippo Martinelli-Boneschi, Daniele Cazzato, Raffaella Lombardi, Sulayman Dib-Hajj, Stephen G. Waxman, Hubert J. M. Smeets, Monique M. Gerrits, Catharina G. Faber, Giuseppe Lauria and on behalf of the PROPANE Study Group Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(9), 8278; https://doi.org/10.3390/ijms24098278 - 5 May 2023

Cited by 5 | Viewed by 2076

Abstract

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes [...] Read more.

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments. Full article

(This article belongs to the Special Issue Unraveling the Genetic Background of Neurological Disorders)

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39 pages, 10359 KiB

Open AccessArticle

Genome-Wide Gene-Set Analysis Identifies Molecular Mechanisms Associated with ALS

by Christina Vasilopoulou, Sarah L. McDaid-McCloskey, Gavin McCluskey, Stephanie Duguez, Andrew P. Morris and William Duddy

Int. J. Mol. Sci. 2023, 24(4), 4021; https://doi.org/10.3390/ijms24044021 - 16 Feb 2023

Cited by 1 | Viewed by 2408

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset motor neuron disease characterized by the loss of the upper and lower motor neurons. Our understanding of the molecular basis of ALS pathology remains elusive, complicating the development of efficient treatment. Gene-set analyses of genome-wide [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset motor neuron disease characterized by the loss of the upper and lower motor neurons. Our understanding of the molecular basis of ALS pathology remains elusive, complicating the development of efficient treatment. Gene-set analyses of genome-wide data have offered insight into the biological processes and pathways of complex diseases and can suggest new hypotheses regarding causal mechanisms. Our aim in this study was to identify and explore biological pathways and other gene sets having genomic association to ALS. Two cohorts of genomic data from the dbGaP repository were combined: (a) the largest available ALS individual-level genotype dataset (N = 12,319), and (b) a similarly sized control cohort (N = 13,210). Following comprehensive quality control pipelines, imputation and meta-analysis, we assembled a large European descent ALS-control cohort of 9244 ALS cases and 12,795 healthy controls represented by genetic variants of 19,242 genes. Multi-marker analysis of genomic annotation (MAGMA) gene-set analysis was applied to an extensive collection of 31,454 gene sets from the molecular signatures database (MSigDB). Statistically significant associations were observed for gene sets related to immune response, apoptosis, lipid metabolism, neuron differentiation, muscle cell function, synaptic plasticity and development. We also report novel interactions between gene sets, suggestive of mechanistic overlaps. A manual meta-categorization and enrichment mapping approach is used to explore the overlap of gene membership between significant gene sets, revealing a number of shared mechanisms. Full article

(This article belongs to the Special Issue Unraveling the Genetic Background of Neurological Disorders)

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11 pages, 3973 KiB

Open AccessArticle

Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder

by Martje G. Pauly, Norbert Brüggemann, Stephanie Efthymiou, Anne Grözinger, Sokhna Haissatou Diaw, Viorica Chelban, Valentina Turchetti, Barbara Vona, Vera Tadic, Henry Houlden, Alexander Münchau and Katja Lohmann

Int. J. Mol. Sci. 2023, 24(3), 1874; https://doi.org/10.3390/ijms24031874 - 18 Jan 2023

Cited by 6 | Viewed by 1674

Abstract

VPS13D is one of four human homologs of the vacuolar sorting protein 13 gene (VPS13). Biallelic pathogenic variants in the gene are associated with spastic ataxia or spastic paraplegia. Here, we report two patients with intronic pathogenic variants: one patient with [...] Read more.

VPS13D is one of four human homologs of the vacuolar sorting protein 13 gene (VPS13). Biallelic pathogenic variants in the gene are associated with spastic ataxia or spastic paraplegia. Here, we report two patients with intronic pathogenic variants: one patient with early onset severe spastic ataxia and debilitating tremor, which is compound-heterozygous for a canonical (NM_018156.4: c.2237−1G > A) and a non-canonical (NM_018156.4: c.941+3G>A) splice site variant. The second patient carries the same non-canonical splice site variant in the homozygous state and is affected by late-onset spastic paraplegia. We confirmed altered splicing as a result of the intronic variants and demonstrated disturbed mitochondrial integrity. Notably, tremor in the first patient improved significantly by bilateral deep brain stimulation (DBS) in the ventralis intermedius (VIM) nucleus of the thalamus. We also conducted a literature review and summarized the phenotypical spectrum of reported VPS13D-related disorders. Our study underscores that looking for mutations outside the canonical splice sites is important not to miss a genetic diagnosis, especially in disorders with a highly heterogeneous presentation without specific red flags. Full article

(This article belongs to the Special Issue Unraveling the Genetic Background of Neurological Disorders)

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17 pages, 4289 KiB

Open AccessArticle

A Paternal Methylation Error in the Congenital Hydrocephalic Texas (H-Tx) Rat Is Partially Rescued with Natural Folate Supplements

by Naila Naz, Ghazaleh Moshkdanian, Salma Miyan, Sereen Eljabri, Charlotte James and Jaleel Miyan

Int. J. Mol. Sci. 2023, 24(2), 1638; https://doi.org/10.3390/ijms24021638 - 13 Jan 2023

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Abstract

Folate deficiencies, folate imbalance and associated abnormal methylation are associated with birth defects, developmental delays, neurological conditions and diseases. In the hydrocephalic Texas (H-Tx) rat, 10-formyl tetrahydrofolate dehydrogenase (FDH) is reduced or absent from the CSF and the nuclei of cells in the [...] Read more.

Folate deficiencies, folate imbalance and associated abnormal methylation are associated with birth defects, developmental delays, neurological conditions and diseases. In the hydrocephalic Texas (H-Tx) rat, 10-formyl tetrahydrofolate dehydrogenase (FDH) is reduced or absent from the CSF and the nuclei of cells in the brain and liver and this is correlated with decreased DNA methylation. In the present study, we tested whether impaired folate metabolism or methylation exists in sexually mature, unaffected H-Tx rats, which may explain the propagation of hydrocephalus in their offspring. We compared normal Sprague Dawley (SD, n = 6) rats with untreated H-Tx (uH-Tx, n = 6 and folate-treated H-Tx (TrH-Tx, n = 4). Structural abnormalities were observed in the testis of uH-Tx rats, with decreased methylation, increased demethylation, and cell death, particularly of sperm. FDH and FRα protein expression was increased in uH-Tx males but not in folate-treated males but tissue folate levels were unchanged. 5-Methylcytosine was significantly reduced in untreated and partially restored in treated individuals, while 5-hydroxymethylcytosine was not significantly changed. Similarly, a decrease in DNA-methyltransferase-1 expression in uH-Tx rats was partially reversed with treatment. The data expose a significant germline methylation error in unaffected adult male H-Tx rats from which hydrocephalic offspring are obtained. Reduced methylation in the testis and sperm was partially recovered by treatment with folate supplements leading us to conclude that this neurological disorder may not be completely eradicated by maternal supplementation alone. Full article

(This article belongs to the Special Issue Unraveling the Genetic Background of Neurological Disorders)

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Graphical abstract

10 pages, 594 KiB

Open AccessCommunication

Two Single Nucleotide Polymorphisms in the Purinergic Receptor P2X7 Gene Are Associated with Disease Severity in Multiple Sclerosis

by Franca Rosa Guerini, Cristina Agliardi, Elisabetta Bolognesi, Milena Zanzottera, Domenico Caputo, Maria Barbara Pasanisi, Marco Rovaris and Mario Clerici

Int. J. Mol. Sci. 2022, 23(23), 15381; https://doi.org/10.3390/ijms232315381 - 6 Dec 2022

Cited by 3 | Viewed by 1247

Abstract

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) that leads to progressive physical disability. Recent evidence has suggested that P2X7 receptor (P2X7R)-mediated purinergic signalling pathways play a role in MS-associated neuroinflammation, possibly contributing to disease pathogenesis. [...] Read more.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) that leads to progressive physical disability. Recent evidence has suggested that P2X7 receptor (P2X7R)-mediated purinergic signalling pathways play a role in MS-associated neuroinflammation, possibly contributing to disease pathogenesis. To evaluate possible associations between P2X7R polymorphisms and MS disease severity, we performed an association study of five non-synonymous SNPs coding variants of the P2X7R gene: rs1718119 Ala348Thr, rs2230911 Thr357Ser, rs2230912 Gln460Arg, rs3751143 Glu496Ala, and rs28360457 Arg307Gln, modulating P2X7R expression in 128 MS patients (relapsing remitting MS, RRMS: n = 94; secondary progressive, SPMS: n = 34). All patients were genotyped, and multiple sclerosis severity score (MSSS) was evaluated in every case; 189 healthy subjects were enrolled as well as controls. Results showed that P2X7R rs1718119(A) 348Thr and rs22390912(G) 464Arg, two SNPs of minor allele frequency (MAF) known to confer gain of function to the P2X7R protein, were associated with significantly higher MSSS in RRMS patients alone (SMRR (p < 0.001, p = 0.01, respectively)). Interestingly, two whole haplotypes resulted in having significant association with MSSS in these same patients. Thus: (1) the P2X7R-4 “ACGAG” haplotype, characterized by the co-presence of the rs1718119-rs2230912 AG MAF alleles, was associated with higher MSSS (Beta: 1.11 p = 0.04), and (2) the P2X7R-1 “GCAAG” complementary haplotype, which contains the rs1718119 and rs2230912 GA wild-type alleles, was more frequently carried by patients with lower MSSS and less severe disease (Beta: −1.54 p < 0.001). Although being preliminary and needing confirmation in an ampler cohort, these results suggest that 348Thr and 464Arg variants have a role as modulators of disease severity in RRMS patients. Full article

(This article belongs to the Special Issue Unraveling the Genetic Background of Neurological Disorders)

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Review

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18 pages, 1047 KiB

Open AccessReview

Can Genetic Markers Predict the Sporadic Form of Alzheimer’s Disease? An Updated Review on Genetic Peripheral Markers

by Danelda Theron, Lloyd N. Hopkins, Heidi G. Sutherland, Lyn R. Griffiths and Francesca Fernandez

Int. J. Mol. Sci. 2023, 24(17), 13480; https://doi.org/10.3390/ijms241713480 - 30 Aug 2023

Viewed by 1335

Abstract

Alzheimer’s disease (AD) is the most common form of dementia that affects millions of individuals worldwide. Although the research over the last decades has provided new insight into AD pathophysiology, there is currently no cure for the disease. AD is often only diagnosed [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia that affects millions of individuals worldwide. Although the research over the last decades has provided new insight into AD pathophysiology, there is currently no cure for the disease. AD is often only diagnosed once the symptoms have become prominent, particularly in the late-onset (sporadic) form of AD. Consequently, it is essential to further new avenues for early diagnosis. With recent advances in genomic analysis and a lower cost of use, the exploration of genetic markers alongside RNA molecules can offer a key avenue for early diagnosis. We have here provided a brief overview of potential genetic markers differentially expressed in peripheral tissues in AD cases compared to controls, as well as considering the changes to the dynamics of RNA molecules. By integrating both genotype and RNA changes reported in AD, biomarker profiling can be key for developing reliable AD diagnostic tools. Full article

(This article belongs to the Special Issue Unraveling the Genetic Background of Neurological Disorders)

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Other

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5 pages, 572 KiB

Open AccessCase Report

Identification of the Third Case of PSEN1 Tyr389His Variant in Early-Onset Alzheimer’s Disease in Korea

by Kyu Hwan Shim, Sangjoon Kang, Seong Soo A. An and Min Ju Kang

Int. J. Mol. Sci. 2022, 23(24), 16192; https://doi.org/10.3390/ijms232416192 - 19 Dec 2022

Cited by 1 | Viewed by 1157

Abstract

Amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are associated with autosomal-dominant early-onset Alzheimer’s disease (AD). Most mutations have been identified in the PSEN1 gene. We discovered a PSEN1 mutation (Tyr389His) in a Korean [...] Read more.

Amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are associated with autosomal-dominant early-onset Alzheimer’s disease (AD). Most mutations have been identified in the PSEN1 gene. We discovered a PSEN1 mutation (Tyr389His) in a Korean patient with early-onset AD who presented memory decline at 41 years of age followed by language, memory, and visuospatial dysfunctions. As this is the third such patient identified in Korea, this mutation may be involved in AD pathogenesis, suggesting that routine screening is necessary in this population. Altered intra-molecular interactions with the mutated amino acid may result in the destabilization of γ-secretase. In the future, a panel incorporating genes with relatively high-frequency rare variants, along with the APOE4 gene, may predict the onset of AD and facilitate customized treatment. Full article

(This article belongs to the Special Issue Unraveling the Genetic Background of Neurological Disorders)

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