Biology subjects

Rocca, C.

Publications and source records attributed to Rocca, C..

6 recordsLinked to original sources

bioRxiv2026

Sex-biased gene expression shapes sex differences in gene essentiality

Sex differences in disease incidence and progression are well documented, yet their underlying molecular mechanisms remain poorly understood. Multiple models suggest that baseline gene expression levels shape the impact of gene disruption, raising the possibility that sex-biased expression itself contributes to sex differences in cellular vulnerability. Here, we test this hypothesis by integrating sex-biased transcriptomic profiles with large-scale CRISPR loss-of-function screens to determine whether sex-biased expression predicts sex-biased gene essentiality across the genome. We find that gene expression level and sex chromosome dosage each explain a modest fraction of variance in essentiality, with substantially larger effects for sex chromosome genes than for autosomes. Across genes, sex effects on expression and essentiality are small in magnitude but directionally aligned, suggesting that sex differences in transcription can influence functional dependency. To resolve how these relationships arise, we applied gene-level mediation analyses to decompose sex effects on essentiality into expression-mediated and expression-independent components. This approach revealed multiple mechanistic architectures. On autosomes, most genes exhibited either sex-biased essentiality from direct sex effects (independent of expression) or sex-biased expression without functional consequence, while expression-mediated sex differences accounted for a smaller but substantial fraction of genes. In contrast, X chromosome genes were dominated by direct, expression-independent sex differences, consistent with strong effects of sex chromosome dosage, but also showed enrichment of expression-mediated architectures, particularly among X gametologs. Together, our results demonstrate that while sex-biased expression can generate sex-biased gene essentiality, this mechanism is not the default. Instead, sex-biased functional dependency is often driven by direct, expression-independent effects, particularly on the X chromosome, where dosage and compensatory mechanisms play a dominant role.

bioinformatics↗

bioRxiv2025

Aging promotes escape from X chromosome inactivation in human tissues

Age-related diseases often show sex differences, yet their molecular bases remain unclear. Animal models suggest that age-related disruption of X-chromosome inactivation (XCI) occurs in female mice. We test whether this phenomenon extends to humans using bulk and single-cell datasets. We find that age-dependent escape from XCI also occurs in human females, particularly among genes at the distal ends of the X-chromosome and those involved in genome stability. These findings provide preliminary evidence that XCI erosion represents a human female-specific aging process.

bioinformatics↗

bioRxiv2025

Cystinosin is involved in Na+/H+ Exchanger 3 trafficking in the proximal tubular cells: new insights in the renal Fanconi syndrome in cystinosis

Cystinosis is a systemic lysosomal storage disease resulting from a defective CTNS gene, leading to the accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, the renal Fanconi syndrome (FS) is the first manifestation of cystinosis that presents early in life of the patients while other complications appear years later. Additionally, the cystine reduction therapy, cysteamine, does not prevent the FS. While the matter is still unresolved, it is apparent that specific function(s) of cystinosin in the proximal tubular cells (PTCs) beyond cystine transport explain the early tubular defects in cystinosis. Here, we report a novel interaction of cystinosin with the sodium/hydrogen (Na+/H+) exchanger proteins in the endosomes in both yeast and mammalian cells. One isoform of Na+/H+ exchanger, NHE3, is a major absorptive sodium transporter at the apical membrane of the proximal tubules. Cystinosin was found to play a significant role in NHE3 subcellular localization, trafficking, and resulting sodium uptake in PTCs. Interestingly, introduction of CTNS successfully rescued these defects in CTNS-deficient PTCs, whereas CTNS-LKG, the lysosomal and plasma membrane isoform of cystinosin, did not. NHE3 mislocalization was confirmed in Ctns-/- mice and cystinosis patient kidney. Interestingly, transplantation of wild-type hematopoietic stem and progenitor cells in Ctns-/- mice restored NHE3 expression at the brush border membrane. This study uncovers a new role of cystinosin in the trafficking of NHE3 in the PTCs that is evolutionary conserved, offering new insights in the pathogenesis of the renal FS in cystinosis and potential new therapeutic avenue for this pathology. SignificanceThis study reveals a new role of cystinosin in the trafficking of NHE3, the Na+/H+ exchanger in the proximal tubular cells (PTCs) in the kidney. NHE3 contributes to the majority of renal sodium absorption and is essential for maintaining the homeostasis of the PTCs. Thus, this study offers new molecular insights in the endosomal trafficking of NHE3 and provides a new mechanism that may explain the underlying pathogenesis and early onset of the renal Fanconi syndrome in cystinosis. Additionally, these findings provide potential new drug targets for this pathology and are also relevant to our ongoing stem cell gene therapy clinical trial for cystinosis, offering valuable information on the potential impact of hematopoietic stem cell transplantation on renal Fanconi syndrome.

molecular biology↗

bioRxiv2025

Transcriptomic analysis of repeat expansion-ataxias uncovers distinct non-neuronal cell type-specific signatures of disease across the human brain

Hereditary ataxias are a heterogeneous group of neurogenetic conditions characterised by the clinical syndrome of progressive loss of coordination from neurodegeneration of the cerebellum. A commonality across the most prevalent ataxias is the underlying disease mechanism secondary to expansions of short tandem DNA repeats. There is currently an incomplete understanding of the pathogenic mechanisms of these repeat expansion disorders, a core feature of which revolves around RNA-dysregulation. In this study, we used both bulk and single nuclear RNA-sequencing to study post-mortem brain tissue of human donors with a range of repeat-expansion ataxias to reveal further mechanistic insights. We compared post-mortem paired cerebellar and frontal cortex tissue bulk RNA-sequencing data from 23 ataxia patients and 22 sex-, age-matched controls from two brain banks (spinocerebellar ataxia (SCA)1, SCA2, SCA6, SCA7, SCA17, Friedreichs ataxia (FRDA), and 7 cases with unknown molecular diagnoses). We analysed bulk RNA-sequencing data for transcript usage, differential and cell-type-specific expression to transcriptomically profile these diseases. We also generated single nuclear RNA-sequencing data of the cerebellum from donors with SCA1, SCA2, SCA6 and FRDA to decipher changes in cell type proportions in the disease state. Using this approach, we found that: (i) despite the commonalities in the genetics of ataxia, there were components of their transcriptional signatures which were distinct; (ii) there were extensive transcriptional changes evident not only in the cerebellum but also the frontal cortex in ataxia cases; (iii) activation of immune and inflammatory pathways, as well as involvement of non-neuronal cell types was a feature of all ataxias to a lesser or greater extent. This study provides a novel resource to understand the mechanisms of disease in ataxia. Furthermore, taken together, these results highlight immune pathways and the role of non-neuronal cell types as early and potentially important therapeutic targets. These findings provide a map of transcriptomic changes in ataxia to further understanding of the underlying pathogenesis.

neuroscience↗

bioRxiv2024

Ide copy number variant does not influence lesion size and mortality in two C57BL/6J mouse models of cerebrovascular ischemia nor in human cerebrovascular disease. An exploratory study

Contrary to the common belief, the most commonly used laboratory mouse inbred strains are shaped by a distinctive genetic and phenotypic diversity. In the past 10 years next generation sequencing unveiled a wide spectrum of genetic variants in different mouse inbred strains and the meticulous observation of researchers pointed to a variegate intra-and inter-strain phenotypic diversity. Although a genotype-phenotype correlation has been described for some traits, the relationship between several endophenotypes and causative genetic variability remains still unknown. Recently, we characterized the brain collateral plasticity in two brain ischemia C57BL/6J mouse models (i.e bilateral common carotid artery stenosis [BCCAS] and 60-min transient unilateral middle cerebral artery occlusion [MCAO]) and observed a Mendelian-like fashion of inheritance of the posterior communicating artery (PcomA) plasticity. Interestingly, a copy number variant (CNV) spanning Ide locus was reported to segregate in an analogous Mendelian-like pattern in the C57BL/6J colonies of the Jackson Laboratory. Given the critical role of Ide in vascular plasticity, Ide CNV was an excellent candidate to explain PcomA variability in C57BL/6J inbred mice. To investigate this hypothesis, we applied a combination of complementary techniques (i.e T2-weighted magnetic resonance imaging [MRI], time of flight [TOF] angiography [MRA], cerebral blood flow [CBF] imaging and histology) to characterize the collaterome in C57BL/6J BCCAS and MCAO mice and performed on these Taqman genotyping, exome sequencing, and RNA sequencing. We report an Ide CNV in a BCCAS mouse with 2 patent PcomAs. We then investigated the hypothesis that IDE gain and loss of function mutations may have influenced the vascular phenotype in a cohort of 438,250 cases and controls (UK Biobank) and 15,790 neurological patients (Genomics England), respectively. We identified four IDE CNVs resulting in a loss of function (LoF) in one patient with hereditary ataxia, a patient with hereditary congenital heart disease and two healthy individuals. In addition, we report four IDE LoF point mutations (p.Leu5X, p.Met394ValfsX29, p.Pro14SerfsX26, p.Leu889X) present in controls or inherited from healthy parents. Ide CNV and LoF variants do not crucially influence PcomA variability in C57BL/6J inbred mice and do not cause a vascular phenotype in humans.

genetics↗

bioRxiv2022

Human mutations in SLITRK3 implicated in GABAergic synapse development in mice

We report on biallelic homozygous and monoallelic de-novo variants in SLITRK3 in 3 unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3-/-) mice, we bring additional evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG, as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, our results exhibit impaired development of peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. Our study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.

genetics↗