This synthesis supports a conceptual model in which intrinsic sequence-dependent mutational susceptibility at the human PKD1 locus may interact with localized inflammatory microenvironments characterized by oxidative stress and epithelial proliferation to contribute to recurrent somatic second-hit formation.
Abstract
In ADPKD renal function is corrupted by the accumulation and growth of fluid-filled cysts. Disruption of the PKD1 gene product, polycystin-1, is the most frequent cause of ADPKD, but the mechanisms that predispose PKD1 to recurrent somatic mutation remain poorly understood. Because current evidence for sequence- and structure-dependent mutational susceptibility is strongest at the human PKD1 locus, we will focus here on mechanisms that may promote somatic PKD1 inactivation. Experimental evidence for polycistin-1 inactivation supports a two-hit pathway, with the first hit being an inherited germline pathogenic mutation in PKD1 and the second hit mutation arising later in a somatic cell to inactivate the gene or lower the gene's dosage to lift a barrier to cyst initiation. An affected kidney can have thousands of cysts, each of which is a clonal lineage arising from an independent mutational second-hit event. Why human PKD1 is prone to inactivation and why the rodent orthologs escape similar mutagenesis is a mystery that, once solved, promises to provide important insights into the molecular mechanisms governing cyst initiation. A step toward that goal came from the characterization of the guanine-rich sequence architecture of human PKD1 that distinguishes it from rodent Pkd1. These guanine-rich tracts are intrinsically susceptible to oxidative damage and can adopt non-duplex secondary structures such as guanine-quadruplex DNA. Although guanine quadruplexes serve important regulatory functions, both oxidized guanine lesions and guanine quadruplex structures can interfere with faithful DNA replication and repair, thereby increasing mutation risk. Here, we discuss PKD1 mutagenesis in the context of the renal inflammatory microenvironment, integrating established principles of sequence-dependent mutagenesis and guanine-rich DNA structure biology with mechanisms of cyst initiation in ADPKD. This synthesis supports a conceptual model in which intrinsic sequence-dependent mutational susceptibility at the human PKD1 locus may interact with localized inflammatory microenvironments characterized by oxidative stress and epithelial proliferation to contribute to recurrent somatic second-hit formation.
It is concluded that PC2C331S may perturb protein stability and/or polycystin complex formation prior to ciliary/EV trafficking and a C. elegans pipeline for mechanistic classification of conserved ADPKD-associated missense variants is established.
Juan Wang, Carlos Nava Cruz, Jonathon D. Walsh et al.· Genetics· 0 citations
The role of the PI3K/AKT pathway in the PIK3CA-related overgrowth is clarified, with one pediatric patient carrying a novel mosaic de novo in-frame deletion mutation in the PIK3CA gene identified.
Jing-Heng Wu, Shan-Lin Chen, Yunhao Xue et al.· Yi chuan = Hereditas· 0 citations
The complex formed between Wiskott-Aldrich syndrome protein (WASP) and WASP-Interacting Protein (WIP) is a potent regulator of cytoskeletal changes in hematopoietic cells. Mutations in the WASP N-terminal domain cause the primary immunodeficiencies Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). Using NMR we determine the structure of the WASP/WIP complex and provide a first molecular view of this key biochemical junction. The central feature of this complex is the extensive binding interface formed by four WIP epitopes that wrap around the canonical EVH1 domain. Phosphoregulation of the WIP chaperone function occurs on two tyrosine residues, and not a distal serine residue as suggested earlier, and involves selective dissociation of the fourth epitope (epiIV), thereby exposing two established WASP ubiquitylation sites. Single-residue WAS-inducing mutations with mild phenotypes all influence the same WASP-epiIV interface, suggesting this is the molecular mechanism behind WAS. This structural viewpoint of WASP/WIP biology creates a much-needed molecular context for understanding hematopoietic cytoskeletal regulation in homeostasis and in WAS/XLT and is expected to be invaluable in the search for new therapeutic approaches to these rare diseases.
Inna Sasson, Saja Baluom, Adi Halle-Bikovski et al.· Journal of Structural Biolog...· 0 citations
These findings identify a primate-specific cascade linking Alu-mediated genomic rearrangements to zinc dyshomeostasis and Golgi pathology and suggest that dysregulation of the ZnT6–Golgi axis may represent a vulnerability and therapeutic target in structural variant–driven neurodegeneration and possibly in a subset of sporadic cases.
Youngsun Lee, Onju Ham, Hana Lee et al.· Signal Transduction and Targ...· 0 citations
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging, with a life expectancy of less than two decades. HGPS is commonly caused by a point mutation in the LMNA gene which codes for lamin A, a vital component of the nuclear lamina. The HGPS mutation activates a cryptic splice site and leads to production of a truncated, farnesylated form of lamin A referred to as "progerin." Progerin is also produced in small amounts in healthy individuals and has been implicated in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks (DSBs), and alterations in DSB repair. DSB repair in mammalian cells normally occurs by either homologous recombination (HR), an accurate, templated form of repair, or by DNA end-joining (EJ), a non-templated rejoining of DNA ends. EJ is error-prone, although a portion of EJ events occurs precisely with no alteration to joined sequences. Previously, we reported that over-expression of progerin increased EJ relative to HR and decreased the precision of EJ. In our current work, we designed a novel model experimental system using derivatives of thymidine kinase (tk)-deficient mouse fibroblasts and incorporating a loss-of-function assay to further explore progerin’s impact on EJ. We established cell lines containing an integrated copy of a functional herpes tk gene with an embedded recognition site for endonuclease I-SceI. We examined EJ at the nucleotide level following induction of a DSB within the tk gene by expression of I-SceI and subsequent selection for cells that lost tk gene function. Comparison of EJ products recovered from cells expressing progerin versus from cells not expressing progerin revealed that progerin expression provoked larger DNA deletions associated with DSB repair as well as recovery of multiple repair products from individual cells, suggesting progerin impedes re-joining of DNA ends.
Aubrey A. Bondurant, Emma K. Grove, Nina M. Van et al.· bioRxiv· 0 citations
DICER1 is an endoribonuclease that plays a critical role in microRNA (miRNA) biogenesis. DICER1 contains two catalytic ribonuclease domains: RNase IIIa and RNase IIIb, which cleave the bound precursor miRNA to generate 3p and 5p strands, respectively, of the miRNA. One strand is loaded into the RNA-induced silencing complex to mediate gene silencing. Germline loss-of-function (LOF) mutations in DICER1 are associated with DICER1-related tumor predisposition (DRTP), a rare hereditary tumour predisposition syndrome affecting mainly children and young adults. DRTP is associated with a broad spectrum of benign and malignant tumors, including pleuropulmonary blastoma (PPB), Sertoli-Leydig cell tumors, and aggressive sarcomas at multiple sites, the most common being gynecological and intra-cranial. Unlike the classical Knudson two-hit model involving biallelic inactivation, DRTP tumors typically carry a germline LOF mutation with a hotspot somatic missense mutation in the RNase IIIb catalytic domain. These somatic mutations affecting residues (e.g. D1709, E1813) selectively disrupt cleavage of 5p miRNAs, while preserving most 3p miRNA production. This creates an miRNA imbalance marked by depletion of 5p miRNAs, including tumor suppressors such as the let-7 family, which contributes to oncogenesis. We examined the effects of two of these variants using Dicer1-floxed mouse mesenchymal stem cells: the canonical RNase IIIb mutant E1813K and the non-canonical RNase IIIa mutant S1344L, which also impairs RNase IIIb activity. We show that while both variants impair 5p miRNA production and enhance 3p miRNA levels, S1344L affects only a subset of 5p miRNAs. Consistent with their differential effects on 5p miRNA production, E1813K and S1344L induce partially overlapping gene expression changes relative to wild-type DICER1 cells. When compared with a DICER1 mutant–initiated pituitary blastoma, we identify a discrete set of stabilized mRNAs, many of which promote cell proliferation. Conversely, several mRNAs encoding pro-apoptotic factors exhibit reduced stability in DICER1 mutant cells. One of the most aggressive DRTP cancers is primary intracranial sarcoma (PIS), which lacks effective therapies. Using a longitudinal primary and recurrent DRTP PIS patient tumour pair, we characterize elevated expression of myogenic transcription factor MYOD1 and concomitant downregulation of neural gene signatures in recurrent PIS. We also establish patient-derived xenograft (PDX) and primary cell models of DRTP PIS, that recapitulate human tumor biology. We demonstrate that inhibitors of MEK and CDK4/6 strongly suppressed tumour growth of DRTP PIS PDXs and induced upregulation of genes associated with neuronal differentiation. Our results suggest that disrupted neural differentiation program is associated with DRTP PIS progression and inhibition of MEK and CDK4/6 can be used to induce neural differentiation and suppress growth of DRTP PIS. Taken together, these studies have begun to identify the key pathways and vulnerabilities that characterise tumors that arise in DRTP.
William D. Foulkes, Anne-Laure Chong, Hannah D. Hosein, Anais Gagne, Sidong Huang, Marc R. Fabian. DICER1-related tumor predisposition: genotypes, phenotypes and mechanisms [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr IA003.
William D. Foulkes, Anne-Laure Chong, Hannah D. Hosein et al.· Cancer Research· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
