Common ALDH3A1 Gene Variant Associated with Keratoconus Risk in the Polish Population

Berdyński, Mariusz; Krawczyk, Piotr; Safranow, Krzysztof; Borzemska, Beata; Szaflik, Jacek P.; Nowakowska-Żawrocka, Karolina; Żekanowski, Cezary; Giebułtowicz, Joanna

doi:10.3390/jcm11010008

Cited by 3 publications

(2 citation statements)

References 30 publications

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“…In contrast to α-SMA, the expression of ALDH3A1 in quiescent form cornea keratocytes notably reduced, deactivating the pathway to trigger ALDH3A1 under high curvature. ALDH3A1 is a known crystalline protein that maintains the transparency of the cornea stroma 36 . This downregulation of ALDH3A1 in cornea keratocytes under high curvature conditions may be associated with the stromal cloudiness observed in keratoconus.…”

Section: Discussionmentioning

confidence: 99%

“…Our findings show that mechanical stimuli can stimulate TGF-β/Smad2/3 signaling pathways, which can be explained by exploring crosstalk between Rho/ROCK and Smad2/3 pathways 33 34, 35 . Even though recent studies have shown the possible crosstalk between mechanical strain influences the Rho/ROCK pathway 33 and the Smad2/3 signaling pathway 34,35 in lung, kidney, and sclera [33][34][35][36][37][38] , the precise mechanisms by which ROCK influences the expression of TGF-βinduced profibrotic mediators are yet to be uncovered. To accurately determine the impact of these phenotypic changes in corneal keratocytes, further in-depth analyses at the protein and gene levels are required to dissect the signaling pathways involved.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Corneal Stromal Cell Behavior by Modulating Curvature Using a Hydraulically Controlled Organ Chip Array

Kim,

Choi

et al. 2024

Preprint

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Curvature is a critical factor in cornea mechanobiology, but its impact on phenotypic alterations and extracellular matrix remodeling of cornea stroma remains unclear. In this work, we investigated how curvature influences the corneal stroma using a hydraulically controlled curvature array chip. The responses of stromal cells to low, medium, and high curvatures were observed by preparing three phenotypes of corneal stromal cells: corneal keratocytes, fibroblasts, and myofibroblasts. Keratocytes exhibited phenotypic alterations in response to curvature changes, notably including a decrease in ALDH3 expression and an increase in α-SMA expression. For focal adhesion, corneal fibroblast and myofibroblasts showed enhanced vinculin localization in response to curvature, while corneal keratocytes presented reduced vinculin expression. For cell alignment and ECM expression, most stromal cells under all curvatures showed a radially organized f-actin and collagen fibrils. Interestingly, for corneal fibroblast under medium curvature, we observed orthogonal cell alignment, which is linked to the unique hoop and meridional stress profiles of the curved surface. Furthermore, lumican expression was upregulated in corneal keratocytes, and keratocan expression was increased in corneal fibroblasts and myofibroblasts due to curvature. These results demonstrate that curvature influences both the phenotype of corneal stromal cells and the structural organization of corneal stroma tissue without any external stimuli. This curvature-dependent behavior of corneal stromal cells presents potential opportunities for creating therapeutic strategies for corneal shape dysfunctions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of Corneal Stromal Cell Behavior by Modulating Curvature Using a Hydraulically Controlled Organ Chip Array

Kim,

Choi

et al. 2024

Preprint

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Identification of genetic variants in two families with Keratoconus

Lin,

Wang,

Han

et al. 2023

BMC Med Genomics

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Background This research investigated the genetic characteristic of two Chinese families with keratoconus (KC). Methods For all people in the two families with KC, their history, clinical data, and peripheral blood were collected. One hundred healthy participants without KC and 112 sporadic KC patients were recruited as the controls. Whole exome sequencing of the genomic DNA and polymerase chain reaction were conducted for all the controls and family members to verify the variants. Functional analyses of the variants was performed using the software programs. Results A missense tuberous sclerosis 1 (TSC1) variant g.135797247A > G (c.622A > G, p.Ser208Gly) was detected in family 1. A single nucleotide polymorphism (SNP) rs761232139 (p.Gly235Arg) in aldehyde dehydrogenase 3 family member A1 (ALDH3A1) gene was detected in family 2. The variant c.622A > G in TSC1 and the SNP rs761232139 in ALDH3A1 were predicted as being probably damaging. Conclusions Novel variant c.622A > G in TSC1 and SNP rs761232139 in ALDH3A1 have been detected in families with KC. These two findings may play a role in the pathogenesis of KC.

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The Applicability and Limitations of the Spectrofluorometric Method for Determination of ALDH1 Activity in Serum and Plasma

Michorowska,

Wiśniewska,

Wolinowska

et al. 2024

Diagnostics

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Background: Aldehyde dehydrogenase class 1 (ALDH1) is an enzyme that is ubiquitously distributed in adult tissues and may serve as a prognostic marker in various cancer types. In blood, 99% of ALDH1 is found in erythrocytes; although, it was also demonstrated that leukocytes and platelets exhibit ALDH activity. No ALDH activity was detected in plasma, even when employing the highly sensitive fluorometric method with 7-methoxy-1-naphthaldehyde as a substrate. However, some reports have been released describing stable and measurable ALDH1 activity in the serum of healthy subjects using 6-methoxy-2-naphthaldehyde as a substrate and a Shimadzu RF—5301 spectrofluorometer. Methods: Our study aimed to verify whether ALDH1 activity can be measured in plasma or serum (n = 80) using 6-methoxy-2-naphthaldehyde as a substrate and a highly sensitive Hitachi F7000 spectrofluorometer, which offers a higher signal-to-noise ratio compared to the Shimadzu RF-5301. Additionally, HPLC with fluorometric detection was used to validate the results (n = 25) and analyze the influence of hemolysis (n = 5) and liver cell damage (n = 15) on ALDH1 activity in serum. Results: Measurable ALDH activity in serum/plasma was very rarely detected using a spectrofluorometer (2 cases out of 80). However, background drift in assays without coenzyme addition was observed, and it may be easily mistaken for ALDH or oxidase activity. Therefore, the spectrofluorometer drift observed in blank assays and modified by a matrix, e.g., enhanced in protein-rich samples, should be considered in ALDH1 activity assays. Conclusions: The spectrofluorometric method has limited applicability for determining ALDH activity in plasma and serum. HPLC can measure ALDH1 activity in plasma or serum; however, factors like hemolysis and elevated liver enzymes significantly affect activity and must be considered in diagnostic interpretations. To enhance research quality on ALDH1 as a biomarker for diseases, including cancers, we recommend using control samples, reference materials, and purifying commercially available aldehyde substrates to improve method sensitivity.

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Common ALDH3A1 Gene Variant Associated with Keratoconus Risk in the Polish Population

Cited by 3 publications

References 30 publications

Regulation of Corneal Stromal Cell Behavior by Modulating Curvature Using a Hydraulically Controlled Organ Chip Array

Regulation of Corneal Stromal Cell Behavior by Modulating Curvature Using a Hydraulically Controlled Organ Chip Array

Identification of genetic variants in two families with Keratoconus

The Applicability and Limitations of the Spectrofluorometric Method for Determination of ALDH1 Activity in Serum and Plasma

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