Biology subjects

Pellerin, D.

Publications and source records attributed to Pellerin, D..

4 recordsLinked to original sources

bioRxiv2025

SynTEF1 restores the functional disease phenotype of SCA27B in an hiPSC-derived neuronal disease model

Spinocerebellar Ataxia 27B (SCA27B), caused by a deep-intronic GAA repeat expansion in the first intron of the FGF14 gene, is one of the most frequent genetic ataxias. Its underlying disease mechanisms remain largely unknown, and disease-modifying therapies targeting upstream processes are lacking. Here we hypothesized that (i) SCA27B is driven by transcriptional repression of FGF14, which encodes a protein regulating ion channels at the axon initial segment (AIS), resulting in reduced Na+ channel availability and neuronal excitability, and that (ii) these defects can be restored by a synthetic elongation transcription factor (Syn-TEF1). We assessed FGF14 mRNA levels by qPCR and neuronal function by whole-cell patch-clamp recordings in iPSC-derived neurons from two SCA27B patients and two healthy controls. Patients carried GAA repeat expansions that were either monoallelic (391/16 repeats) or biallelic (315/290 repeats), exceeding the common pathogenicity threshold of >250 repeats. FGF14 mRNA levels were reduced approximately to 60% and 70% of control levels in monoallelic and biallelic SCA27B neurons, respectively. This was accompanied by impaired excitability, with cumulative action potential (AP) firing reduced to 38% and 45% of control levels in monoallelic and biallelic lines, respectively, and peak Na current density reduced to 46% and 41%, while voltage-dependent gating of Na channels remained unchanged. Treatment with Syn-TEF1 significantly increased FGF14 mRNA expression and restored cumulative AP firing to 83% and 135% of control levels in monoallelic and biallelic neurons, respectively, and Na peak current density to 95% and 138%. These findings strongly suggest that the pathophysiological cascade in SCA27B - from FGF14 repression to impaired Na+ currents and decreased neuronal excitability - can be reversed by an elongation transcription factor. Our results thus provide a rationale for further exploring Syn-TEF1 as a first gene-targeted, disease-modifying therapeutic approach for SCA27B.

neuroscience↗

bioRxiv2025

The Genetic and Evolutionary Landscape of Pentanucleotide Tandem Repeats in Human Genomes

Tandem repeats are a class of genetic variation characterized by repetitions of DNA motifs of diverse sequences and lengths. Pentameric motifs, in particular, do not align with the protein-coding reading frames, often confining them to the less extensively studied non-coding portion of the genome. Intronic pentanucleotide tandem repeats are associated with 11 neurological disorders. Their pathogenic genotypes are primarily characterized by large length expansion and, unlike most repeat expansion disorders, have required a deviation from the reference motif. The population-level variability of pentameric repeats remains poorly understood due to technical limitations of short-read sequencing technologies. To address this knowledge gap, we genotyped 28,446 pentanucleotide repeat loci in 1,027 long-read PacBio HiFi samples from self-identified Black and African American participants in the All of Us Research Program. We developed new algorithms for tandem repeat decomposition, characterization, and visualization to facilitate this analysis. Our findings reveal extensive genome-wide heterogeneity in repeat length and sequence composition. Alleles with DNA sequences containing segments of distinct motifs were observed in 15% of loci. Additionally, 8% of loci exhibited multimodal repeat length distributions, in which distinct sequence compositions were often associated with distinct length ranges. Repeat loci were highly enriched in proximity to transposable elements, including 68% mapping to Alu elements, a retrotransposon specific to primates. Comparative analysis of the reference sequences from 30 species, including 27 primates, suggests that most pentanucleotide repeats fully emerged in a common ancestor of humans and other ape species, or even within more closely related hominin lineages. As an example, we describe a highly polymorphic and recently evolved repeat locus in the ABCA1 gene, a major regulator of cellular cholesterol and phospholipid homeostasis. This study provides novel and comprehensive insights into the evolutionary formation of pentamer tandem repeat loci and their extensive variability across human genomes.

genetics↗

bioRxiv2025

Detailed tandem repeat allele profiling in 1,027 long-read genomes reveals genome-wide patterns of pathogenicity

Short tandem repeat (STR) instability is a major cause of disease association, yet their full length-distributions and sequence content have been difficult to resolve with short-read sequencing. By analyzing long-read sequencing genomes from 2,645 participants of the All of Us Research Program, we establish a comprehensive STR resource of 23 billion alleles covering a catalog of 4.4 million loci. We find that known disease-associated STR loci exhibit markedly elevated allelic variability relative to genome-wide distributions, which is most pronounced when based on the length of uninterrupted, pure repeat motifs (Odds Ratio: 244, p=1.62e-29). We establish the Pure Length Variability Index (PLVI) as a measure of this instability, which is robust across ancestries and replicated in 500 samples from the 1000 Genomes Project (Odds Ratio: 84, p=2.72e-28). To illustrate, we identify 55 unstable coding CAG and 5-UTR CGG STR loci with this metric, 60% of which have not been associated with disease. From this set, we document potential pathogenic repeat expansions for FAM193B and EP400 by integrating PLVI with single-genome length outlier analysis. These data establish a population-scale framework for STR discovery in rare and common diseases using long-read sequencing cohorts.

genomics↗

bioRxiv2023

A common flanking variant is associated with enhanced meiotic stability of the FGF14-SCA27B locus

The factors driving initiation of pathological expansion of tandem repeats remain largely unknown. Here, we assessed the FGF14-SCA27B (GAA)*(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a 5-flanking 17-bp deletion-insertion in 70.34% of alleles (3,463/4,923). This common sequence variation was present nearly exclusively on alleles with fewer than 30 GAA-pure repeats and was associated with enhanced meiotic stability of the repeat locus.

genetics↗