Base by Base

• 123: Dominant‑Negative ATP5F1A Variants Uncouple Complex V and Drive Neurological Disease

  ️ Episode 123: Dominant‑Negative ATP5F1A Variants Uncouple Complex V and Drive Neurological Disease In this episode of PaperCast Base by Base, we explore how de novo heterozygous ATP5F1A missense variants disrupt mitochondrial ATP synthase and manifest as pediatric neurological disorders, revealing a dominant‑negative mechanism and an isolated Complex V defect. Study Highlights:The authors describe six probands with developmental delay, dystonia, pyramidal tract signs and failure to thrive, each carrying ATP5F1A variants clustered at the α–β or α–γ interfaces of the F1 sector of ATP synthase. In vivo CRISPR knock‑ins of orthologous variants in C. elegans behaved dominantly, slowed development and locomotion, and activated a mitochondrial stress response that was dose‑dependently suppressed by adding wild‑type gene copies. Patient‑derived cells showed reduced abundance and ATPase activity of Complex V, with increased oxygen consumption but decreased mitochondrial membrane potential and ATP levels, indicating uncoupled oxidative phosphorylation. Structural modeling supported disrupted subunit interactions, and proteomics demonstrated an isolated Complex V deficiency distinct from earlier reports for other ATP5F1A alterations. Conclusion:This work expands the genetic and phenotypic spectrum of ATP5F1A‑related disease and establishes ATP5F1A as a leading nuclear cause of Complex V deficiency while highlighting organismal modeling as a powerful approach to resolve variants of uncertain significance. Reference:Fielder SM, Friederich MW, Hock DH, Zhang JR, Valin LM, Rosenfeld JA, Booth KTA, Brown NJ, Rius R, Sharma T, Semcesen LN, Worley KC, Burrage LC, Treat K, Samson T, Govert S, DaCunha S, Yuan W, Chen J, Lesinski J, Hoang H, Morrison SA, Ladha FA, Van Hove R, Michel CR, Reisdorph R, Tycksen E, Baldridge D, Silverman GA, Soler‑Alfonso C, Conboy E, Vetrini F, Emrick L, Craigen WJ, Undiagnosed Diseases Network, Sykes SM, Stroud DA, Van Hove JLK, Schedl T, Pak SC. Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders. EMBO Molecular Medicine. 2025.  https://doi.org/10.1038/s44321-025-00290-8 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/   On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: ATP5F1A; Complex V; dominant negative; mitochondrial uncoupling; neurological disorders

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• 122: Patient Stratification Reveals the Molecular Basis of Disease Co-Occurrences

  ️ Episode 122: Patient Stratification Reveals the Molecular Basis of Disease Co-Occurrences In this episode of PaperCast Base by Base, we explore a study that investigates the molecular underpinnings of why certain diseases tend to co-occur. By using large-scale RNA sequencing data, the authors present a novel approach to identify disease co-occurrences, revealing a shared molecular basis in many comorbidities, particularly involving the immune system. The study introduces patient stratification based on gene expression profiles, which uncovers known and potential new disease associations, providing a framework for personalized approaches to managing comorbidities. Study Highlights:The researchers developed a Disease Similarity Network (DSN) that uses gene expression data to map disease relationships, explaining 64% of known disease co-occurrences. They demonstrate that many comorbidities, such as inflammatory bowel disease (IBD) and various cancers, share common molecular pathways, particularly immune-related processes. The study also identifies previously underdiagnosed comorbidities, offering insights that could inform therapeutic strategies. A web application is provided for exploring these molecular insights and the relationships between diseases and their associated molecular mechanisms. Conclusion:This work underscores the importance of patient stratification and molecular profiling in understanding disease co-occurrences, potentially improving diagnosis and treatment by revealing hidden connections between diseases. Reference:Urda-García, B., Sánchez-Valle, J., Lepore, R., & Valencia, A. (2025). Patient stratification reveals the molecular basis of disease co-occurrences. *Proceedings of the National Academy of Sciences, 122*(35), e2421060122. https://doi.org/10.1073/pnas.2421060122 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ On PaperCast Base by Base, you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: disease co-occurrence, RNA sequencing, patient stratification, immune system, molecular mechanisms. Chapters (00:00:00) - Deep Dive: The molecular logic of disease co-occurrences(00:04:43) - RNA Sequencing: the game changer(00:06:55) - The Nature of the Disease similarity network(00:09:52) - Discovery of the disease network(00:12:56) - The Social Science Network (SSN) and the Metapat(00:16:56) - Measuring the molecular basis of diseases

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• 121: G-quadruplexes as a Source of Vulnerability in BRCA2-deficient Granule Cell Progenitors and Medulloblastoma

  ️ Episode 121: G-quadruplexes as a Source of Vulnerability in BRCA2-deficient Granule Cell Progenitors and Medulloblastoma In this episode of PaperCast Base by Base, we explore how DNA secondary structures called G-quadruplexes (G4s) contribute to genome instability and tumor development in BRCA2-deficient cerebellar granule cell progenitors, leading to medulloblastoma. Study Highlights:Using a mouse model with Brca2 deletion in the nervous system and Trp53 loss, researchers observed that these animals developed Sonic Hedgehog (SHH) subgroup medulloblastomas with complete penetrance. Whole-genome sequencing revealed that structural variant breakpoints frequently overlapped with predicted G4-forming sequences, suggesting these structures are key drivers of instability in the absence of BRCA2. Experiments showed that BRCA2-deficient cells had slower replication fork progression when exposed to G4-stabilizing compounds, and upregulation of the G4-resolving helicase PIF1 was identified as a mechanism tumors use to cope with replication stress. Targeting PIF1 in primary tumor cells increased genome instability, highlighting its potential as a therapeutic target. Conclusion:This work establishes G-quadruplexes as a critical source of replication stress in BRCA2-deficient progenitor cells and identifies PIF1 helicase as a promising therapeutic vulnerability in medulloblastoma. Reference:Keahi DL, Sanders MA, Paul MR, Webster ALH, Fang Y, Wiley TF, Shalaby S, Carroll TS, Chandrasekharappa SC, Sandoval-Garcia C, MacMillan ML, Wagner JE, Hatten ME, Smogorzewska A. G-quadruplexes as a source of vulnerability in BRCA2-deficient granule cell progenitors and medulloblastoma. Proc Natl Acad Sci U S A. 2025;122(35):e2503872122. doi:10.1073/pnas.2503872122 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Keywords: BRCA2, medulloblastoma, G-quadruplexes, PIF1 helicase, genome instability Chapters (00:00:00) - How DNA defects in children's brains cause cancer(00:02:05) - BRCA2 deficiency in cerebellum cancer(00:07:06) - BRCA2 mutations in brain cancer(00:11:00) - BRCA2 protects the G4(00:12:10) - PIF1 in BRCA2 deficiency medulloblast(00:17:42) - PIF1 and cancer biology

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• 120: Rare BMAL1 Variants Link the Circadian Clock to Neurodevelopment

  ️Episode 120: Rare BMAL1 Variants Link the Circadian Clock to Neurodevelopment In this episode of PaperCast Base by Base, we explore how ultrarare heterozygous variants in BMAL1—a core circadian clock gene—are associated with a neurodevelopmental syndrome featuring developmental delay, autism spectrum disorder, and musculoskeletal findings. Study Highlights:The authors identified ten individuals carrying very rare BMAL1 variants, five of which were de novo, and documented overlapping clinical features including developmental delay and autism spectrum disorder with variably penetrant sleep disturbances and marfanoid traits. Functional assays in U2OS cells using a Per2 promoter–driven luciferase reporter showed that most variants disrupted BMAL1 activity via altered period, phase, or amplitude of molecular rhythms, with frameshift and splice-site changes trending toward loss of function while a PAS1 missense variant (Ile201Thr) enhanced rhythmic output. PER2 and NR1D1 mRNA cycling confirmed variant‑dependent effects on clock-controlled transcription without grossly altering BMAL1 localization or CLOCK binding. In Drosophila, orthologous variants in cycle (cyc) reproduced gain‑ and loss‑of‑function effects on behavioral rhythms and, notably, both classes impaired short‑ and long‑term memory, connecting core clock disruption to neurodevelopment‑relevant phenotypes. Conclusion:These findings implicate rare BMAL1 variants as contributors to a Mendelian neurodevelopmental disorder and suggest that targeting sleep and circadian pathways could be an avenue to mitigate cognitive and developmental impacts. Reference:Cuddapah VA, Chen D, Cho B, Moore R, Suri M, Safraou H, Tran‑Mau‑Them F, Wilson A, Odgis J, Rehman AU, Saunders C, Ganesan S, Jobanputra V, Scherer SW, Helbig I, Sehgal A. Rare variants in BMAL1 are associated with a neurodevelopmental syndrome. PNAS. 2025;122(31):e2427085122. https://doi.org/10.1073/pnas.2427085122 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Keywords: BMAL1; circadian rhythms; neurodevelopmental disorder; autism spectrum disorder; Drosophila memory Chapters (00:00:00) - Sleep disorders and the circadian clock(00:07:06) - BMAL1 variants disrupting the circadian clock(00:11:02) - BMA1 Syndrome in humans(00:16:07) - BMAO1 genetic variants and neurodevelopmental disorders(00:21:03) - Circadian clock gene variants in autism

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• 119: G‑Quadruplex Stabilization Triggers Pericentromeric DNA Breaks in B Cells

  ️ Episode 119: G‑Quadruplex Stabilization Triggers Pericentromeric DNA Breaks in B Cells In this episode of PaperCast Base by Base, we explore how stabilizing G‑quadruplex DNA structures with small molecules reshapes genome stability in B lymphocytes, revealing fragile hotspots in pericentromeric repeats and ribosomal DNA and exposing checkpoint-dependent differences between primary and malignant cells. Study Highlights:Using the G‑quadruplex stabilizer pyridostatin in mouse primary B cells, a lymphoma line (CH12), and human B cell lines, the authors mapped DNA damage with metaphase spreads and FISH and found recurrent breaks and fusions concentrated at major satellite pericentromeres and rDNA arrays. Primary B cells developed abundant dicentric chromosomes and progressed to tetraploid metaphases, whereas CH12 cells mounted a G2/M checkpoint arrest that limited tetraploid metaphases despite increased tetraploid interphases. Pharmacologic manipulation supported a checkpoint-based mechanism: enforcing G2 arrest with CDK1 inhibition reduced tetraploids and dicentrics, while WEE1 inhibition in CH12 released arrest and increased both. Additional G4 ligands (CX‑5461, Phen‑DC3) also induced pericentromeric instability, reinforcing that G‑quadruplex stabilization is the driver rather than off‑target effects. Conclusion:G‑quadruplex stabilization selectively destabilizes pericentromeric and rDNA repeats in B cells and, by interacting with cell‑cycle checkpoints, may be exploitable to suppress tumor growth while sparing normal cells that respond differently. Reference:Waisertreiger I, Ayele K, Elshaikh MH, Barlow JH. G‑quadruplex stabilization induces DNA breaks in pericentromeric repetitive DNA sequences in B lymphocytes. Proceedings of the National Academy of Sciences. 2025;122(34):e2506939122. https://doi.org/10.1073/pnas.2506939122 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Keywords: G-quadruplex, pyridostatin, pericentromeric satellite DNA, B lymphocytes, chromosomal instability Chapters (00:00:00) - G4 stabilizing ligands in B cell cancer(00:06:31) - PDS: Targeted DNA damage in cancer(00:08:24) - PDS causes chromosomal instability in cancer cells(00:13:26) - PDS and BRCA2 deficiency cancers(00:17:59) - Base by base science

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