Background Fabry disease (FD, OMIM #301500) is an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A (α-GalA), encoded by the GLA gene. Among more than 1100 reported GLA mutations, few were deep intronic mutations which have been linked to classic and cardiac variants of FD. Methods and results We report a novel hemizygous deep intronic GLA mutation (IVS4+1326C>T) in a 33-year-old Chinese man with a mild α-GalA deficiency phenotype involving isolated proteinuria and predominant globotriaosylceramide deposits in podocytes. IVS4+1326C>T, which appears to be the first deep intronic GLA mutation associated with renal variant of FD, was identified by Sanger sequencing the entire GLA genomic DNA sequence of the patient’s peripheral mononuclear blood lymphocytes (PBMCs). Further sequencing of cDNA from PBMCs of the patient revealed a minor full-length GLA transcript accounting for about 25% of total GLA transcript, along with two major aberrantly spliced GLA transcripts encoding mutant forms of α-GalA with little enzyme activity characterized by in vitro α-GalA overexpression system in the HEK293T cells. Thus, the combined clinical phenotype, genetic analysis and functional studies verified the pathogenicity of IVS4+1326C>T. Conclusions The identification of IVS4+1326C>T establishes a link between deep intronic GLA mutation and the renal variant of FD, which extends the mutation spectrum in GLA gene and justifies further study of how IVS4+1326C>T and potentially other deep intronic GLA mutations contribute to Fabry podocytopathy through aberrant splicing. Future studies should also assess the true incidence of IVS4+1326C>T in patients with different variants of FD, which may improve early genetic diagnosis to allow timely treatment that can prevent disease progression and improve survival.
Significance Statement Causes of congenital anomalies of the kidney and urinary tract (CAKUT) remain unclear. The authors investigated whether and how inactivation of Ash2l—which encodes a subunit of the COMPASS methyltransferase responsible for genome-wide histone H3 lysine K4 (H3K4) methylation—might contribute to CAKUT. In a mouse model, inactivation of Ash2l in the ureteric bud (UB) lineage led to CAKUT-like phenotypes. Removal of ASH2L led to deficient H3K4 trimethylation, which slowed cell proliferation at the UB tip, delaying budding and impairing branching morphogenesis. The absence of ASH2L also downregulated the expression of Ret, Gfra1, and Wnt11 genes involved in RET/GFRA1 signaling. These findings identify ASH2L-mediated H3K4 methylation as an upstream epigenetic regulator of signaling crucial for UB morphogenesis and indicate that deficiency or dysregulation of these processes may lead to CAKUT. Background Ureteric bud (UB) induction and branching morphogenesis are fundamental to the establishment of the renal architecture and are key determinants of nephron number. Defective UB morphogenesis could give rise to a spectrum of malformations associated with congenital anomalies of the kidney and urinary tract (CAKUT). Signaling involving glial cell line–derived neurotrophic factor and its receptor rearranged during transfection (RET) and coreceptor GFRA1 seems to be particularly important in UB development. Recent epigenome profiling studies have uncovered dynamic changes of histone H3 lysine K4 (H3K4) methylation during metanephros development, and dysregulated H3K4 methylation has been associated with a syndromic human CAKUT. Methods To investigate whether and how inactivation of Ash2l, which encodes a subunit of the COMPASS methyltransferase responsible for genome-wide H3K4 methylation, might contribute to CAKUT, we inactivated Ash2l specifically from the UB lineage in C57BL/6 mice and examined the effects on genome-wide H3K4 methylation and metanephros development. Genes and epigenome changes potentially involved in these effects were screened using RNA-seq combined with Cleavage Under Targets and Tagmentation sequencing. Results UB-specific inactivation of Ash2l caused CAKUT-like phenotypes mainly involving renal dysplasia at birth, which were associated with deficient H3K4 trimethylation. Ash2l inactivation slowed proliferation of cells at the UB tip, delaying budding and impairing UB branching morphogenesis. These effects were associated with downregulation of Ret, Gfra1, and Wnt11, which participate in RET/GFRA1 signaling. Conclusions These experiments identify ASH2L-dependent H3K4 methylation in the UB lineage as an upstream epigenetic regulator of RET/GFRA1 signaling in UB morphogenesis, which, if deficient, may lead to CAKUT.
Background: Fabry disease (FD, OMIM #301500) is an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A (α-GalA), encoded by the GLA gene. Among more than 1100 reported GLA mutations, few were deep intronic mutations which have been linked to classic and cardiac variants of FD. Methods and results: We report a novel hemizygous deep intronic GLA mutation (IVS4+1326C>T) in a 33-year-old Chinese man with a mild α-GalA deficiency phenotype involving isolated proteinuria and predominant globotriaosylceramide deposits in podocytes. IVS4+1326C>T, which appears to be the first deep intronic GLA mutation associated with renal variant of FD, was identified by Sanger sequencing the entire GLA DNA sequence of the patient’s peripheral mononuclear blood lymphocytes (PBMCs). Further sequencing of cDNA from PBMCs of the patient revealed a minor full-length GLA transcript accounting for about 25% of total GLA transcript, along with two major aberrantly spliced GLA transcripts both encoding deficient α-GalA, as determined by in vitro functional assay. As a result, our patient had a high residual α-GalA activity of 75% of normal activity, highlighting the vulnerability of podocytes to α-GalA deficiency. The combined clinical phenotype, genetic analysis and functional studies verified the pathogenicity of IVS4+1326C>T.Conclusions: The identification of IVS4+1326C>T establishes a link between deep intronic GLA mutation and the renal variant of FD, which extends the mutation spectrum in GLA gene and justifies further study of how IVS4+1326C>T and potentially other deep intronic GLA mutations contribute to Fabry podocytopathy through aberrant splicing. Future studies should also assess the true incidence of IVS4+1326C>T in patients with different variants of FD, which may improve early genetic diagnosis to allow timely treatment that can prevent disease progression and improve survival.
Objective: To investigate the clinical characteristics and prognosis of pregnancy-related acute kidney injury (PR-AKI) and provide a basis for improving maternal and infant outcomes. Methods: Seventy pregnant women admitted to the surgical intensive care unit of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine from January 2010 to December 2020 were included; 31 were screened out according to KDIGO-AKI criteria. We retrospectively analyzed their clinical characteristics and prognosis and analyzed risk factors for different pregnancy outcomes with logistic regression analysis. Results: A total of 31 PR-AKI patients were enrolled. The mean age of onset was 30.08±0.63 years, and the mean gestational age was 33.02±7.64 weeks. Six cases (19.45%) were in stage 1, six cases (19.35%) were in stage 2, and 19 cases (61.29%) were in stage 3. The continuous renal replacement therapy (CRRT) group comprised 13 cases (41.94%): one (7.69%) in stage 1, one (7.69%) in stage 2, and 11 (84.62%) in stage 3. The non-CRRT group comprised 18 cases (58.06%): five (27.78%) in stage 1, five (27.78%) in stage 2, and eight (44.44%) in stage 3. The mean time of commencing renal replacement therapy was 2.08±1.26 days after admission, and the serum creatinine (SCr) level at the beginning of treatment was 352.68±196.58 μmol/L. Renal function recovered completely in 18 cases (58.06%), comprising four (22.22%) in the CRRT group and 14 (77.78%) in the non-CRRT group, and three cases of partial renal function recovery occurred in the CRRT group. Eventually, seven patients (22.58%) died, of whom four (57.14%) were in the non-CRRT group, and all were in stage 3. The causes of death were postpartum hemorrhage, septic shock, and acute fatty liver during pregnancy. Three patients (42.86%) died in the non-CRRT group: two in stage 3 and one case in stage 1. The causes of death were severe preeclampsia and acute fatty liver during pregnancy. Multi-factor logistic regression analysis showed that gestational weeks (OR=0.456, P=0.023), platelet count (OR=0.989, P=0.02), hemoglobin (OR=1.017, P=0.022), and uric acid (OR=1.017, P=0.022) were associated risk factors for maternal adverse pregnancy outcomes of PR-AKI (P<0.05). Conclusions: The incidence of PR-AKI is high, the outcomes of maternal renal function are better, and the proportion of adverse fetal outcomes is higher. CRRT can effectively improve the prognosis of patients with PR-AKI, stabilize the internal environment, and affect hemodynamics slightly. It is currently one of the main ways to treat severe PR-AKI. Maternal and infant outcomes are related to the severity of PR-AKI.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.