RÉSUMÉ
Biallelic intronic expansions (AAGGG)exp in intron 2 of the RFC1 gene have been shown to be a common cause of late-onset ataxia. Since their first description, the phenotypes, neurological damage, and pathogenic variants associated with the RFC1 gene have been frequently updated. Here, we review the various motifs, genetic variants, and phenotypes associated with the RFC1 gene. We searched PubMed for scientific articles published between March 1st, 2019, and January 15th, 2024. The motifs and phenotypes associated with the RFC1 gene are highly heterogeneous, making molecular diagnosis and clinical screening and investigation challenging. In this review we will provide clues to give a better understanding of RFC1 disease. We briefly discuss new methods for molecular diagnosis, the origin of cough in RFC1 disease, and research perspectives.
Sujet(s)
Phénotype , Protéine C de réplication , Humains , Protéine C de réplication/génétique , Ataxie/génétique , Ataxie/diagnostic , Introns/génétiqueRÉSUMÉ
Inherited neuropathies are a heterogeneous group of slowly progressive disorders affecting either motor, sensory, and/or autonomic nerves. Peripheral neuropathy may be the major component of a disease such as Charcot-Marie-Tooth disease or a feature of a more complex multisystemic disease involving the central nervous system and other organs. The goal of this review is to provide the clinical clues orientating the genetic diagnosis in a patient with inherited peripheral neuropathy. This review focuses on primary inherited neuropathies, amyloidosis, inherited metabolic diseases, while detailing clinical, neurophysiological and potential treatment of these diseases.
Sujet(s)
Maladie de Charcot-Marie-Tooth , Neuropathie héréditaire motrice et sensitive , Humains , Maladie de Charcot-Marie-Tooth/diagnostic , Maladie de Charcot-Marie-Tooth/génétique , Neuropathie héréditaire motrice et sensitive/diagnostic , Neuropathie héréditaire motrice et sensitive/génétiqueRÉSUMÉ
INTRODUCTION: Hereditary transthyretin related amyloidosis (h-ATTR) classically presents as a small fiber neuropathy with positive family history, but can also be revealed by various other types of peripheral neuropathy. OBJECTIVE: To describe the initial electro-clinical presentation of patients from in a single region (northern France) of h-ATTR when it presents as a polyneuropathy of unknown origin. METHOD: We reviewed the records of patients referred to two neuromuscular centers from northern France with a peripheral neuropathy of unknown origin who were subsequently diagnosed with h-ATTR. RESULTS: Among 26 h-ATTR patients (10 Val30Met, 16 Ser77Tyr), only 14 patients had a suspicious family history (53.8%). The electro-clinical presentation was mostly a large-fiber sensory motor polyneuropathy (92.3%), which could be symmetric or not, length-dependent or not, or associated with nerve entrapment or not. Demyelinating signs were observed in 17 patients (70.8%), among whom nine fulfilled the criteria for a definite diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (37.5%). CONCLUSION: h-ATTR may have a wide spectrum of clinical profiles, and should be considered in the screening of polyneuropathies of unknown origin.
Sujet(s)
Neuropathies amyloïdes familiales , Polyneuropathies , Polyradiculonévrite inflammatoire démyélinisante chronique , Neuropathies amyloïdes familiales/complications , Neuropathies amyloïdes familiales/diagnostic , Neuropathies amyloïdes familiales/épidémiologie , France/épidémiologie , Humains , Polyneuropathies/diagnostic , Polyneuropathies/épidémiologie , Polyneuropathies/étiologie , Préalbumine/génétiqueSujet(s)
Récepteurs nucléaires orphelins/génétique , Polymorphisme de nucléotide simple , Rétine/imagerie diagnostique , Dégénérescence de la rétine/diagnostic , Dystrophies rétiniennes/diagnostic , Adolescent , Substitution d'acide aminé , Arginine/génétique , Femelle , Fluorescence , Glycine/génétique , Humains , Imagerie optique , Rétine/anatomopathologie , Rétine/physiologie , Dégénérescence de la rétine/génétique , Dystrophies rétiniennes/génétique , Tomographie par cohérence optiqueRÉSUMÉ
The splicing of the microtubule-associated protein Tau is regulated during development and is found to be deregulated in a growing number of pathological conditions such as myotonic dystrophy type I (DM1), in which a reduced number of isoforms is expressed in the adult brain. DM1 is caused by a dynamic and unstable CTG repeat expansion in the DMPK gene, resulting in an RNA bearing long CUG repeats (n>50) that accumulates in nuclear foci and sequesters CUG-binding splicing factors of the muscle blind-like (MBNL) family, involved in the splicing of Tau pre-mRNA among others. However, the precise mechanism leading to Tau mis-splicing and the role of MBNL splicing factors in this process are poorly understood. We therefore used new Tau minigenes that we developed for this purpose to determine how MBNL1 and MBNL2 interact to regulate Tau exon 2 splicing. We demonstrate that an intronic region 250 nucleotides downstream of Tau exon 2 contains cis-regulatory splicing enhancers that are sensitive to MBNL and that bind directly to MBNL1. Both MBNL1 and MBNL2 act as enhancers of Tau exon 2 inclusion. Intriguingly, the interaction of MBNL1 and MBNL2 is required to fully reverse the mis-splicing of Tau exon 2 induced by the trans-dominant effect of long CUG repeats, similar to the DM1 condition. In conclusion, both MBNL1 and MBNL2 are involved in the regulation of Tau exon 2 splicing and the mis-splicing of Tau in DM1 is due to the combined inactivation of both.
Sujet(s)
Exons , Dystrophie myotonique/génétique , Protéines de liaison à l'ARN/physiologie , Éléments de réponse , Protéines tau/génétique , Séquence nucléotidique , Lignée cellulaire tumorale , Humains , Données de séquences moléculaires , Épissage des ARNRÉSUMÉ
Tau is the proteinaceous component of intraneuronal aggregates common to neurodegenerative diseases called Tauopathies, including myotonic dystrophy type 1. In myotonic dystrophy type 1, the presence of microtubule-associated protein Tau aggregates is associated with a mis-splicing of Tau. A toxic gain-of-function at the ribonucleic acid level is a major etiological factor responsible for the mis-splicing of several transcripts in myotonic dystrophy type 1. These are probably the consequence of a loss of muscleblind-like 1 (MBNL1) function or gain of CUGBP1 and ETR3-like factor 1 (CELF1) splicing function. Whether these two dysfunctions occur together or separately and whether all mis-splicing events in myotonic dystrophy type 1 brain result from one or both of these dysfunctions remains unknown. Here, we analyzed the splicing of Tau exons 2 and 10 in the brain of myotonic dystrophy type 1 patients. Two myotonic dystrophy type 1 patients showed a mis-splicing of exon 10 whereas exon 2-inclusion was reduced in all myotonic dystrophy type 1 patients. In order to determine the potential factors responsible for exon 10 mis-splicing, we studied the effect of the splicing factors muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1), CUGBP1 and ETR3-like factor 2 (CELF2), and CUGBP1 and ETR3-like factor 4 (CELF4) or a dominant-negative CUGBP1 and ETR-3 like factor (CELF) factor on Tau exon 10 splicing by ectopic expression or siRNA. Interestingly, the inclusion of Tau exon 10 is reduced by CUGBP1 and ETR3-like factor 2 (CELF2) whereas it is insensitive to the loss-of-function of muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1) gain-of-function, or a dominant-negative of CUGBP1 and ETR-3 like factor (CELF) factor. Moreover, we observed an increased expression of CUGBP1 and ETR3-like factor 2 (CELF2) only in the brain of myotonic dystrophy type 1 patients with a mis-splicing of exon 10. Taken together, our results indicate the occurrence of a mis-splicing event in myotonic dystrophy type 1 that is induced neither by a loss of muscleblind-like 1 (MBNL1) function nor by a gain of CUGBP1 and ETR3-like factor 1 (CELF1) function but is rather associated to CUGBP1 and ETR3-like factor 2 (CELF2) gain-of-function.
Sujet(s)
Exons , Extinction de l'expression des gènes , Protéines de tissu nerveux/génétique , Protéines de liaison à l'ARN/génétique , Protéines tau/génétique , Séquence nucléotidique , Encéphale/métabolisme , Protéines CELF , Amorces ADN , Humains , Dystrophie myotonique/génétique , Dystrophie myotonique/métabolisme , Protéines de tissu nerveux/métabolisme , Protéines de liaison à l'ARN/métabolisme , Protéines tau/métabolismeSujet(s)
Maladie d'Alzheimer/sang , Maladie d'Alzheimer/diagnostic , Peptides bêta-amyloïdes/sang , Marqueurs biologiques/sang , Maladie d'Alzheimer/liquide cérébrospinal , Maladie d'Alzheimer/génétique , Peptides bêta-amyloïdes/liquide cérébrospinal , Apolipoprotéines E/génétique , Diagnostic différentiel , HumainsSujet(s)
Noyaux gris centraux/anatomopathologie , Cortex cérébral/anatomopathologie , Maladie de Huntington/métabolisme , Maladies neurodégénératives/métabolisme , Maladies neurodégénératives/anatomopathologie , Protéines tau/métabolisme , Sujet âgé , Femelle , Humains , Protéine huntingtine , Maladie de Huntington/complications , Maladie de Huntington/anatomopathologie , Protéines de tissu nerveux/métabolisme , Maladies neurodégénératives/complications , Protéines nucléaires/métabolismeRÉSUMÉ
Neurofibrillary degeneration is often observed in the brain of patients with type 1 myotonic dystrophy (DM1). It consists principally of the aggregation of Tau isoforms that lack exon 2/3 encoded sequences, and is the consequence of the modified splicing of Tau pre-mRNA. In experimental models of DM1, the splicing of several transcripts is modified due to the loss of Muscleblind-like 1 (MBNL1) function. In the present study, we demonstrate that the MBNL1 protein is also present in the human brain, and consists of several isoforms, as shown by RT-PCR and sequencing. In comparison with controls, we show that the adult DM1 brain exhibits modifications in the splicing of MBNL1, with the preferential expression of long MBNL1 isoforms--a splicing pattern similar to that seen in the fetal human brain. In cultured HeLa cells, the presence of long CUG repeats, such as those found in the DM1 mutation, leads to similar changes in the splicing pattern of MBNL1, and the localization of MBNL1 in nuclear RNA foci. Long CUG repeats also reproduce the repression of Tau exon 2/3 inclusion, as in the human disease, suggesting that their effect on MBNL1 expression may lead to changes in Tau splicing. However, while an overall reduction in the expression of MBNL1 mimics the effect of the DM1 mutation, none of the MBNL1 isoforms tested so far modulates the endogenous splicing of Tau. The modified splicing of Tau thus results from a possibly CUG-mediated loss of function of MBNL1, but not from changes in the MBNL1 expression pattern.