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20 pages, 3412 KiB

Open AccessArticle

Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy

by Dolores Martínez-Rubio, Isabel Hinarejos, Herminia Argente-Escrig, Clara Marco-Marín, María Ana Lozano, Nerea Gorría-Redondo, Vincenzo Lupo, Itxaso Martí-Carrera, Concepción Miranda, María Vázquez-López, Asunción García-Pérez, Ana Victoria Marco-Hernández, Miguel Tomás-Vila, Sergio Aguilera-Albesa and Carmen Espinós

Int. J. Mol. Sci. 2023, 24(22), 16400; https://doi.org/10.3390/ijms242216400 - 16 Nov 2023

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Abstract

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with [...] Read more.

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity. Full article

(This article belongs to the Special Issue Molecular Genetics in Neurodegenerative Disorders)

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13 pages, 744 KiB

Open AccessArticle

TREML2 Gene Expression and Its Missense Variant rs3747742 Associate with White Matter Hyperintensity Volume and Alzheimer’s Disease-Related Brain Atrophy in the General Population

by Annemarie Luise Kühn, Stefan Frenzel, Alexander Teumer, Katharina Wittfeld, Linda Garvert, Antoine Weihs, Georg Homuth, Holger Prokisch, Robin Bülow, Matthias Nauck, Uwe Völker, Henry Völzke, Hans Jörgen Grabe and Sandra Van der Auwera

Int. J. Mol. Sci. 2022, 23(22), 13764; https://doi.org/10.3390/ijms232213764 - 09 Nov 2022

Cited by 1 | Viewed by 1430

Abstract

Although the common pathology of Alzheimer’s disease (AD) and white matter hyperintensities (WMH) is disputed, the gene TREML2 has been implicated in both conditions: its whole-blood gene expression was associated with WMH volume and its missense variant rs3747742 with AD risk. We re-examined [...] Read more.

Although the common pathology of Alzheimer’s disease (AD) and white matter hyperintensities (WMH) is disputed, the gene TREML2 has been implicated in both conditions: its whole-blood gene expression was associated with WMH volume and its missense variant rs3747742 with AD risk. We re-examined those associations within one comprehensive dataset of the general population, additionally searched for cross-relations and illuminated the role of the apolipoprotein E (APOE) ε4 status in the associations. For our linear regression and linear mixed effect models, we used 1949 participants from the Study of Health in Pomerania (Germany). AD was assessed using a continuous pre-symptomatic MRI-based score evaluating a participant’s AD-related brain atrophy. In our study, increased whole-blood TREML2 gene expression was significantly associated with reduced WMH volume but not with the AD score. Conversely, rs3747742-C was significantly associated with a reduced AD score but not with WMH volume. The APOE status did not influence the associations. In sum, TREML2 robustly associated with WMH volume and AD-related brain atrophy on different molecular levels. Our results thus underpin TREML2’s role in neurodegeneration, might point to its involvement in AD and WMH via different biological mechanisms, and highlight TREML2 as a worthwhile target for disentangling the two pathologies. Full article

(This article belongs to the Special Issue Molecular Genetics in Neurodegenerative Disorders)

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14 pages, 978 KiB

Open AccessArticle

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration

by Giacomina Rossi, Erika Salvi, Luisa Benussi, Elkadia Mehmeti, Andrea Geviti, Sonia Bellini, Antonio Longobardi, Alessandro Facconi, Matteo Carrara, Cristian Bonvicini, Roland Nicsanu, Claudia Saraceno, Martina Ricci, Giorgio Giaccone, Giuliano Binetti and Roberta Ghidoni

Int. J. Mol. Sci. 2022, 23(21), 12847; https://doi.org/10.3390/ijms232112847 - 25 Oct 2022

Cited by 1 | Viewed by 1634

Abstract

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN [...] Read more.

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10–12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (−5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease. Full article

(This article belongs to the Special Issue Molecular Genetics in Neurodegenerative Disorders)

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26 pages, 4009 KiB

Open AccessArticle

Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias

by Dolores Martínez-Rubio, Isabel Hinarejos, Paula Sancho, Nerea Gorría-Redondo, Raquel Bernadó-Fonz, Cristina Tello, Clara Marco-Marín, Itxaso Martí-Carrera, María Jesús Martínez-González, Ainhoa García-Ribes, Raquel Baviera-Muñoz, Isabel Sastre-Bataller, Irene Martínez-Torres, Anna Duat-Rodríguez, Patrícia Janeiro, Esther Moreno, Leticia Pías-Peleteiro, Mar O’Callaghan Gordo, Ángeles Ruiz-Gómez, Esteban Muñoz, Maria Josep Martí, Ana Sánchez-Monteagudo, Candela Fuster, Amparo Andrés-Bordería, Roser Maria Pons, Silvia Jesús-Maestre, Pablo Mir, Vincenzo Lupo, Belén Pérez-Dueñas, Alejandra Darling, Sergio Aguilera-Albesa and Carmen Espinós Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(19), 11847; https://doi.org/10.3390/ijms231911847 - 06 Oct 2022

Cited by 5 | Viewed by 3258

Abstract

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are [...] Read more.

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype. Full article

(This article belongs to the Special Issue Molecular Genetics in Neurodegenerative Disorders)

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Review

Jump to: Research

24 pages, 1525 KiB

Open AccessReview

Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives

by Jan Lejman, Kinga Panuciak, Emilia Nowicka, Angelika Mastalerczyk, Katarzyna Wojciechowska and Monika Lejman

Int. J. Mol. Sci. 2023, 24(2), 1130; https://doi.org/10.3390/ijms24021130 - 06 Jan 2023

Cited by 9 | Viewed by 4892

Abstract

Gene therapy is defined as the administration of genetic material to modify, manipulate gene expression or alter the properties of living cells for therapeutic purposes. Recent advances and improvements in this field have led to many breakthroughs in the treatment of various diseases. [...] Read more.

Gene therapy is defined as the administration of genetic material to modify, manipulate gene expression or alter the properties of living cells for therapeutic purposes. Recent advances and improvements in this field have led to many breakthroughs in the treatment of various diseases. As a result, there has been an increasing interest in the use of these therapies to treat motor neuron diseases (MNDs), for which many potential molecular targets have been discovered. MNDs are neurodegenerative disorders that, in their most severe forms, can lead to respiratory failure and death, for instance, spinal muscular atrophy (SMA) or amyotrophic lateral sclerosis (ALS). Despite the fact that SMA has been known for many years, it is still one of the most common genetic diseases causing infant mortality. The introduction of drugs based on ASOs—nusinersen; small molecules—risdiplam; and replacement therapy (GRT)—Zolgensma has shown a significant improvement in both event-free survival and the quality of life of patients after using these therapies in the available trial results. Although there is still no drug that would effectively alleviate the course of the disease in ALS, the experience gained from SMA gene therapy gives hope for a positive outcome of the efforts to produce an effective and safe drug. The aim of this review is to present current progress and prospects for the use of gene therapy in the treatment of both SMA and ALS. Full article

(This article belongs to the Special Issue Molecular Genetics in Neurodegenerative Disorders)

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22 pages, 444 KiB

Open AccessReview

Recent Insight into the Genetic Basis, Clinical Features, and Diagnostic Methods for Neuronal Ceroid Lipofuscinosis

by Konrad Kaminiów, Sylwia Kozak and Justyna Paprocka

Int. J. Mol. Sci. 2022, 23(10), 5729; https://doi.org/10.3390/ijms23105729 - 20 May 2022

Cited by 8 | Viewed by 2869

Abstract

Neuronal ceroid lipofuscinoses (NCLs) are a group of rare, inherited, neurodegenerative lysosomal storage disorders that affect children and adults. They are traditionally grouped together, based on shared clinical symptoms and pathological ground. To date, 13 autosomal recessive gene variants, as well as one [...] Read more.

Neuronal ceroid lipofuscinoses (NCLs) are a group of rare, inherited, neurodegenerative lysosomal storage disorders that affect children and adults. They are traditionally grouped together, based on shared clinical symptoms and pathological ground. To date, 13 autosomal recessive gene variants, as well as one autosomal dominant gene variant, of NCL have been described. These genes encode a variety of proteins, whose functions have not been fully defined; most are lysosomal enzymes, transmembrane proteins of the lysosome, or other organelles. Common symptoms of NCLs include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and, in rare adult-onset cases, dementia. Depending on the mutation, these symptoms can vary, with respect to the severity and onset of symptoms by age. Currently, all forms of NCL are fatal, and no curative treatments are available. Herein, we provide an overview to summarize the current knowledge regarding the pathophysiology, genetics, and clinical manifestation of these conditions, as well as the approach to diagnosis. Full article

(This article belongs to the Special Issue Molecular Genetics in Neurodegenerative Disorders)

18 pages, 1431 KiB

Open AccessReview

Valosin Containing Protein (VCP): A Multistep Regulator of Autophagy

by Veronica Ferrari, Riccardo Cristofani, Barbara Tedesco, Valeria Crippa, Marta Chierichetti, Elena Casarotto, Marta Cozzi, Francesco Mina, Margherita Piccolella, Mariarita Galbiati, Paola Rusmini and Angelo Poletti

Int. J. Mol. Sci. 2022, 23(4), 1939; https://doi.org/10.3390/ijms23041939 - 09 Feb 2022

Cited by 20 | Viewed by 3857

Abstract

Valosin containing protein (VCP) has emerged as a central protein in the regulation of the protein quality control (PQC) system. VCP mutations are causative of multisystem proteinopathies, which include neurodegenerative diseases (NDs), and share various signs of altered proteostasis, mainly associated with autophagy [...] Read more.

Valosin containing protein (VCP) has emerged as a central protein in the regulation of the protein quality control (PQC) system. VCP mutations are causative of multisystem proteinopathies, which include neurodegenerative diseases (NDs), and share various signs of altered proteostasis, mainly associated with autophagy malfunctioning. Autophagy is a complex multistep degradative system essential for the maintenance of cell viability, especially in post-mitotic cells as neurons and differentiated skeletal muscle cells. Interestingly, many studies concerning NDs have focused on autophagy impairment as a pathological mechanism or autophagy activity boosting to rescue the pathological phenotype. The role of VCP in autophagy has been widely debated, but recent findings have defined new mechanisms associated with VCP activity in the regulation of autophagy, showing that VCP is involved in different steps of this pathway. Here we will discuss the multiple activity of VCP in the autophagic pathway underlying its leading role either in physiological or pathological conditions. A better understanding of VCP complexes and mechanisms in regulating autophagy could define the altered mechanisms by which VCP directly or indirectly causes or modulates different human diseases and revealing possible new therapeutic approaches for NDs. Full article

(This article belongs to the Special Issue Molecular Genetics in Neurodegenerative Disorders)

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39 pages, 4273 KiB

Open AccessReview

Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

by Jaya Bagaria, Eva Bagyinszky and Seong Soo A. An

Int. J. Mol. Sci. 2022, 23(1), 552; https://doi.org/10.3390/ijms23010552 - 04 Jan 2022

Cited by 9 | Viewed by 7483

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also [...] Read more.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases. Full article

(This article belongs to the Special Issue Molecular Genetics in Neurodegenerative Disorders)

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