Biology subjects

Delatycki, M.

Publications and source records attributed to Delatycki, M..

5 recordsLinked to original sources

bioRxiv2026

Autonomic neurons are intrinsically hyperexcitable in a Friedreich ataxia iPSC model

Friedreich ataxia (FRDA) is an inherited multisystem disorder caused by a GAA repeat expansion in the FXN gene and consequent frataxin deficiency, causing progressive neurodegeneration and heart disease. Clinical studies have documented autonomic dysfunction in FRDA, including elevated resting heart rate, raised plasma catecholamines and a high burden of urinary, bowel and sexual symptoms. Consistent with this, autopsy studies show degeneration of the cardiac conduction system and its associated ganglia in FRDA. Whether these features are intrinsic to FRDA autonomic neurons has been untestable without a human cellular model. Here, a human model of FRDA autonomic neurons was established by differentiating induced pluripotent stem cells (iPSCs) from individuals with FRDA and from their CRISPR/Cas9-corrected isogenic controls. FRDA autonomic neurons expressed canonical autonomic lineage markers and retained reduced FXN mRNA and frataxin protein levels. Electrophysiological analysis revealed pronounced hyperexcitability, with an approximately five-fold increase in spike number, shortened interspike intervals, and longer bursts. FRDA autonomic neurons also exhibited increased cell death, elevated mitochondrial reactive oxygen species, and a shift from networked to tubular mitochondrial morphology. Bulk RNA sequencing of all three isogenic pairs revealed loss of extracellular matrix programs and activation of stress response pathways. The top differentially expressed gene was MEG3, a maternally imprinted long noncoding RNA, which was consistently upregulated across all three isogenic pairs. MEG3 sits within the imprinted 14q32 DLK1-DIO3 locus, whose maternally expressed noncoding transcripts were co-ordinately de-repressed in FRDA autonomic neurons. Competitive gene-set testing of 43 imprinted genes across 20 domains showed this to be specific to 14q32: no other imprinted domain was co-ordinately altered. Together, these findings establish hyperexcitability of autonomic neurons as a cell autonomous consequence of frataxin deficiency, accompanied by mitochondrial dysfunction. This provides a cellular basis for the increased sympathetic tone observed in clinical studies.

neuroscience↗

bioRxiv2025

Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model

Friedreich ataxia (FRDA) is a progressive neuromuscular degenerative disorder caused by GAA repeat expansions in the FXN gene, leading to frataxin deficiency and multisystem pathology. Cardiomyopathy is the leading cause of mortality in individuals with FRDA. To investigate the cellular and molecular mechanisms underlying FRDA-associated cardiac dysfunction, we employed induced pluripotent stem cell (iPSC) lines derived from three individuals with FRDA, each paired with an isogenic control line generated through CRISPR/Cas9-mediated excision of the pathogenic GAA repeat expansion. Correction of the mutation restored FXN expression to levels comparable to healthy donor iPSCs, and all lines differentiated efficiently into cardiomyocytes. Functional analysis revealed significant contractile abnormalities in FRDA cardiomyocytes and multicellular cardiac microtissues, including prolonged contraction and relaxation times and faster beating rates, consistent with clinical observations of cardiac contractile dysfunction. FRDA cardiomyocytes also exhibited pathological features such as increased cell size, irregular calcium transients, elevated mitochondrial reactive oxygen species levels, increased mitochondrial fission and increased cell death. These phenotypes were exacerbated by pathological levels of iron supplementation in culture media, highlighting the heightened sensitivity of frataxin-deficient cardiomyocytes to iron-induced metabolic stress. RNA sequencing revealed a distinct transcriptional profile associated with frataxin deficiency. MEG3 and PCDHGA10 were consistently dysregulated across all three FRDA-iPSC lines and may represent early molecular markers of FRDA cardiomyopathy. Together, these findings establish a robust human iPSC model of FRDA cardiomyopathy that captures early disease phenotypes and reveals novel molecular targets. This preclinical human model provides valuable insight into the pathogenesis of FRDA and provides a platform for developing early-stage therapeutic interventions.

pathology↗

bioRxiv2019

Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data

BackgroundSpinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats (STRs). Recent methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. ObjectivesTo determine the genetic basis of ataxia in a multigenerational Australian pedigree, with autosomal dominant inheritance. Methods and ResultsWGS was performed on three affected relatives. The sequence data was screened for known pathogenic REs using two repeat expansion detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis (<five days from receiving the sequencing data) of SCA36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56. Conclusionsthe that diagnosis of rare ataxias caused by REs is highly feasible and cost effective with WGS. We propose that WGS be implemented as the frontline, cost effective methodology for molecular testing of individuals with a clinical diagnosis of ataxia.

genomics↗

bioRxiv2019

Tracing Autism Traits in Large Multiplex Families to Identify Endophenotypes of the Broader Autism Phenotype

Families comprising many individuals with Autism Spectrum Disorder (ASD) may carry a dominant predisposing mutation. Our aim was to use rigorous phenotyping of the Broader Autism Phenotype (BAP) in large multiplex ASD families to identify endophenotypes of the BAP for future genetic studies. We evaluated ASD/BAP features using standardised tests and a semi-structured interview to assess social, intellectual, executive and adaptive functioning in 109 individuals, including two large multiplex families (Family A: 30; Family B: 34) and an independent sample of small families (n=45). Our protocol identified four psychological endophenotypes of the BAP that were evident in both samples, and showed high sensitivity (97%) and specificity (82%) for individuals classified with the BAP. The patterns of inheritance of these endophenotypes varied in the two large families, supporting their utility for identifying genes in autism.

neuroscience↗

bioRxiv2019

Validation of new tools to identify expanded repeats: an intronic pentamer expansion in RFC1 causes CANVAS

Genomic technologies such as Next Generation Sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS families and identified a core ancestral haplotype, estimated to have arisen in Europe over twenty-five thousand years ago. WGS of the four RFC1 negative CANVAS families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

genetics↗