411. An evolutionarily conserved role for CTNNB1/ β-CATENIN in regulating the development of the corpus callosumArpan Parichha, Debarpita Datta, Amrita Singh, Ishita Talwar, Shreya Yadav, Špela Miroševič, Nina Žakelj, David Gosar, Damjan Osredkar, 2025, izvirni znanstveni članek Povzetek: The corpus callosum (CC) is a major nerve bundle that connects the two hemispheres of the brain. Dysgenesis of the CC is associated with neurodevelopmental disorders such as the CTNNB1 syndrome. We identified that five individuals carrying CTNNB1 mutations displayed CC deficits. To explore CTNNB1/β-CATENIN-dependent mechanisms that regulate CC midline crossing, we examined mice with Ctnnb1 gain-of-function (GOF) or loss-of-function (LOF) selectively targeted to the early embryonic central nervous system midline using an Lmx1aCre driver. We identify that the Lmx1a lineage contributes to midline cell populations known to regulate CC pathfinding: the glial wedge, the indusium griseum glia, and a population of midline glutamatergic neurons. We find that each of these structures are affected in both GOF and LOF embryos, resulting in a profound disruption of CC crossing and formation of Probst bundles. Thus, regulated β-CATENIN function in midline cell populations is critical for CC development and its dysregulation may underlie the CC deficits associated with CTNNB1 syndrome.
Ključne besede: neurodevelopment, molecular neuroscience, CTNNB1 syndrome, corpus callosum development
Objavljeno v DiRROS: 24.11.2025; Ogledov: 172; Prenosov: 77
 Celotno besedilo (27,02 MB)
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420. Severe clinical phenotype in Alport syndrome due to two COL4A4 exon skipping eventsJerica Pleško, Nika Kojc, Špela Kert, Sara Petrin, Alenka Matjašič, Anamarija Meglič, Andrej Zupan, 2025, drugi znanstveni članki Povzetek: Alport syndrome (AS) is a genetically heterogeneous disorder caused by mutations in COL4A3, COL4A4, or COL4A5, leading to progressive renal dysfunction. While genetic screening has advanced, many cases remain undiagnosed due to deep intronic splice site variants. We report a male patient diagnosed with autosomal recessive AS, characterized by hematuria, proteinuria, and chronic kidney disease progression. Initial kidney biopsy at age 10 revealed glomerular basement membrane thinning and focal sclerosis, while targeted DNA sequencing failed to detect pathogenic variants. Over 15 years, renal function declined, and a second biopsy showed severe GBM abnormalities with multilamellated structures. Whole-transcriptome sequencing revealed two events of exon skipping, specifically at exons 27 and 38 of the COL4A4 gene, which were verified by exon-specific PCR and Sanger sequencing. Intronic regions analysis revealed two heterozygous variants positioned 78 bp downstream of exon 27 and 8 bp upstream of exon 38, though their role in aberrant splicing remains uncertain. Immunofluorescence analysis confirmed disrupted α3α4α5(IV) heterotrimer assembly. This is the first documented case of dual exon-skipping events in COL4A4, highlighting their contribution to disease severity. Our findings emphasize the need for RNA-based diagnostics and raise questions about potential benefit of exon-skipping therapy in autosomal recessive AS.
Ključne besede: Alport syndrome, exon skipping, whole transcriptome sequencing, kidney, COL4A4
Objavljeno v DiRROS: 24.11.2025; Ogledov: 112; Prenosov: 52
Celotno besedilo (3,18 MB)
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