Glutaric aciduria type 3 is a naturally occurring biochemical trait in inbred mice of 129 substrains

Leandro, João; Bender, Aaron; Dodatko, Tetyana; Argmann, Carmen; Yu, Chunli; Houten, Sander M.

doi:10.1016/j.ymgme.2021.01.004

Cited by 6 publications

(27 citation statements)

References 43 publications

(73 reference statements)

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“…A recent study has demonstrated a decrease of metabolite concentrations in a GA1 mouse model with variants in the SUCGT (succinyl-CoA:glutarate-CoA transferase) gene, but this has not been studied in GA1 patients. 86 In contrast, elevated levels of 3-OH-GA (usually in combination with elevated concentrations of GA) are highly suggestive for GA1. Pitfalls for organic acid analysis should always be considered (Table S4).…”

Section: Confirmation Of a Positive Nbs Resultsmentioning

confidence: 99%

“…Normal urinary or plasma 3‐OH‐GA concentrations are not suggestive but do not reliably exclude GA1 since some LE patients intermittently may show concentrations within the normal range. A recent study has demonstrated a decrease of metabolite concentrations in a GA1 mouse model with variants in the SUCGT (succinyl‐CoA:glutarate‐CoA transferase) gene, but this has not been studied in GA1 patients 86 . In contrast, elevated levels of 3‐OH‐GA (usually in combination with elevated concentrations of GA) are highly suggestive for GA1.…”

Section: Diagnostic Proceduresmentioning

confidence: 99%

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Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Boy

Mühlhausen²,

Maier

et al. 2022

J of Inher Metab Disea

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Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and For affiliation refer to page 29

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Section: Confirmation Of a Positive Nbs Resultsmentioning

confidence: 99%

Section: Diagnostic Proceduresmentioning

confidence: 99%

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Boy

Mühlhausen²,

Maier

et al. 2022

J of Inher Metab Disea

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show abstract

“…13,14 Aberrations in SUGCT have been linked with Glutaric Aciduria III and Trichothiodystrophy. 15 Collectively, these insights shed light on potential molecular mechanisms underpinning the observed pathomics features.…”

Section: Gene-linked Spatial Patterns Of Differential Morphomic Featuresmentioning

confidence: 95%

Spatial pathomics toolkit for quantitative analysis of podocyte nuclei with histology and spatial transcriptomics data in renal pathology

Chen,

Wang,

Deng

et al. 2024

Medical Imaging 2024: Digital and Computational Pathology

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Podocytes, specialized epithelial cells that envelop the glomerular capillaries, play a pivotal role in maintaining renal health. The current description and quantification of features on pathology slides are limited, prompting the need for innovative solutions to comprehensively assess diverse phenotypic attributes within Whole Slide Images (WSIs). In particular, understanding the morphological characteristics of podocytes, terminally differentiated glomerular epithelial cells, is crucial for studying glomerular injury. This paper introduces the Spatial Pathomics Toolkit (SPT) and applies it to podocyte pathomics. The SPT consists of three main components: (1) instance object segmentation, enabling precise identification of podocyte nuclei; (2) pathomics feature generation, extracting a comprehensive array of quantitative features from the identified nuclei; and (3) robust statistical analyses, facilitating a comprehensive exploration of spatial relationships between morphological and spatial transcriptomics features. The SPT successfully extracted and analyzed morphological and textural features from podocyte nuclei, revealing a multitude of podocyte morphomic features through statistical analysis. Additionally, we demonstrated the SPT's ability to unravel spatial information inherent to podocyte distribution, shedding light on spatial patterns associated with glomerular injury. By disseminating the SPT, our goal is to provide the research community with a powerful and user-friendly resource that advances cellular spatial pathomics in renal pathology. The toolkit's implementation and its complete source code are made openly accessible at the GitHub repository: https://github.com/hrlblab/spatial_pathomics.

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“…The main biochemical abnormality of GA3 patients and SUGCT deficient mice is increased urine levels of glutaric acid [4, 12, 13]. Glutaryl-CoA is an intermediate of lysine degradation.…”

Section: Introductionmentioning

confidence: 99%

“…The association of GA3 with clinical symptoms is likely due to ascertainment bias. Similarly, SUGCT deficiency in mice does lead to a recognizable clinical phenotype [12, 13].…”

Section: Introductionmentioning

confidence: 99%

Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1

Khamrui,

Dodatko,

et al. 2024

Preprint

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Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or non-toxic metabolites. Here, we report a novel target, SUGCT, which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA. We report the structure of SUGCT, the first eukaryotic structure of a type III CoA transferase, develop a high-throughput enzyme assay and a cell-based assay, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme validating the screening approach. These results may form the basis for future development of new pharmacological intervention to treat GA1.

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Glutaric aciduria type 3 is a naturally occurring biochemical trait in inbred mice of 129 substrains

Cited by 6 publications

References 43 publications

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Spatial pathomics toolkit for quantitative analysis of podocyte nuclei with histology and spatial transcriptomics data in renal pathology

Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1

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