Unexpectedly High Prevalence of Low Alpha-Galactosidase A Enzyme Activity in Patients with Focal Segmental Glomerulosclerosis

Hasbal, Nuri Barış; Caglayan, Feyza Bayrakdar; Şakacı, Tamer; Ahbap, Elbis; Koç, Yener; Sevinc, Mustafa; Uçar, Zuhal Atan; Ünsal, Abdülkadir; Baştürk, Taner

doi:10.6061/clinics/2020/e1811

Cited by 9 publications

(9 citation statements)

References 25 publications

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“…Meanwhile, increased levels of renal HO-1 and Nrf2 proteins were noted on day 7 after UUO, suggesting that levels of these antioxidant proteins might not be enough to reverse the extensive renal injury induced by UUO. In Fabry disease, accumulated Gb3 has been suggested to be associated with oxidative stress [ 4 ]. However, our experiment's results rejected the initial hypothesis that Fabry disease would have more highly augmented oxidant stress and more impaired antioxidants under the stimulus of UUO.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical manifestations of Fabry disease are consequences of such Gb3 accumulation in various tissues and organs, including the heart, liver, spleen, and kidney [ 1 , 3 ]. Renal involvement is observed in approximately 55% of patients with Fabry disease [ 4 ]. In males with the classical form of Fabry disease, renal manifestation can start with microalbuminuria in infancy.…”

Section: Introductionmentioning

confidence: 99%

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Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis

Chung

Son

Chae

et al. 2021

Kidney Res Clin Pract

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Background Fabry disease is a rare X-linked genetic lysosomal disorder caused by mutations in the GLA gene encoding alpha-galactosidase A. Despite some data showing that profibrotic and proinflammatory cytokines and oxidative stress could be involved in Fabry disease-related renal injury, the pathogenic link between metabolic derangement within cells and renal injury remains unclear. Methods Renal fibrosis was triggered by unilateral ureteral obstruction (UUO) in mice with Fabry disease to investigate the pathogenic mechanism leading to fibrosis in diseased kidneys. Results Compared to kidneys of wild-type mice, lamellar inclusion bodies were recognized in proximal tubules of mice with Fabry disease. Sirius red and trichrome staining revealed significantly increased fibrosis in all UUO kidneys, though it was more prominent in obstructed Fabry kidneys. Renal messenger RNA levels of inflammatory cytokines and profibrotic factors were increased in all UUO kidneys compared to sham-operated kidneys but were not significantly different between UUO control and UUO Fabry mice. Protein levels of Nox2, Nox4, NQO1, catalase, SOD1, SOD2, and Nrf2 were not significantly different between UUO control and UUO Fabry kidneys, while the protein contents of LC3-II and LC3-I and expression of Beclin1 were significantly decreased in UUO kidneys of Fabry disease mouse models compared with wild-type mice. Notably, TUNEL-positive cells were elevated in obstructed kidneys of Fabry disease mice compared to wild-type control and UUO mice. Conclusion These findings suggest that impaired autophagy and enhanced apoptosis are probable mechanisms involved in enhanced renal fibrosis under the stimulus of UUO in Fabry disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis

Chung

Son

Chae

et al. 2021

Kidney Res Clin Pract

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“…Such relatively high REA was also observed in other renal variant patients associated with GLA missense mutations (Met42Leu [5]; Pro210Ser [11]), in whom renal involvement was limited to podocyte pathology. Interestingly, one recent study found that low α-GalA activity may be associated with patients with focal segmental glomerulosclerosis [33]. Taking together, these evidences suggest the vulnerability of podocytes to α-GalA de ciency.…”

Section: Discussionmentioning

confidence: 97%

Identification and Functional Characterization of the First Deep Intronic GLA Mutation (IVS4+1326C>T) Causing Renal Variant of Fabry Disease

Dai

Zong

Pan

et al. 2022

Preprint

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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.

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“…IVS4+1326C>T identified in our case was associated with mild α-GalA enzyme deficiency that manifested predominantly as Fabry podocytopathy. One recent study also found that slightly decreased α-GalA activity may be associated with patients with focal segmental glomerulosclerosis [ 33 ]. However, residual α-GalA activity analyzed in peripheral leukocytes of our patient of 75% of normal activity was much higher than the cut-off value for defining a ‘mild’ GLA mutation (≥ 20% of mean normal level of α-GalA activity) [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and functional characterization of the first deep intronic GLA mutation (IVS4+1326C>T) causing renal variant of Fabry disease

Dai

Zong

Pan

et al. 2022

Orphanet J Rare Dis

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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.

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Unexpectedly High Prevalence of Low Alpha-Galactosidase A Enzyme Activity in Patients with Focal Segmental Glomerulosclerosis

Cited by 9 publications

References 25 publications

Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis

Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis

Identification and Functional Characterization of the First Deep Intronic GLA Mutation (IVS4+1326C>T) Causing Renal Variant of Fabry Disease

Identification and functional characterization of the first deep intronic GLA mutation (IVS4+1326C>T) causing renal variant of Fabry disease

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Unexpectedly High Prevalence of Low Alpha-Galactosidase A Enzyme Activity in Patients with Focal Segmental Glomerulosclerosis

Cited by 9 publications

References 25 publications

Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis

Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis

Identification and Functional Characterization of the First Deep Intronic GLA Mutation (IVS4+1326C&gt;T) Causing Renal Variant of Fabry Disease

Identification and functional characterization of the first deep intronic GLA mutation (IVS4+1326C>T) causing renal variant of Fabry disease

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Identification and Functional Characterization of the First Deep Intronic GLA Mutation (IVS4+1326C>T) Causing Renal Variant of Fabry Disease