Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation

Radenkovic, Silvia; Fitzpatrick-Schmidt, Taylor; Byeon, Seul Kee; Madugundu, Anil K.; Saraswat, Mayank; Lichty, Angie; Wong, Sunnie; McGee, Stephen J.; Kubiak, Katharine; Ligęzka, Anna; Ranatunga, Wasantha; Zhang, Yuebo; Wood, Tim; Friez, Michael J.; Clarkson, Katie; Pandey, Akhilesh; Jones, Julie R.; Morava, Éva

doi:10.1016/j.ymgme.2020.10.007

Cited by 12 publications

(13 citation statements)

References 30 publications

(16 reference statements)

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“…We used immunoblotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) to measure intercellular adhesion molecule 1 (ICAM-1), lysosomal associated membrane protein 2 (LAMP-2) protein, and mRNA expression levels, respectively, as cellular markers of N-glycosylation [18][19][20][21] in 10 PMM-deficient fibroblast lines (P1-P6, P8, P17, P19, and P24 [P10 was excluded from this analysis due to inappropriate cell condition]) and controls. Fibroblasts were treated with 10 μM epalrestat (optimal dose based on PMM enzyme activity) as described above.…”

Section: Effect Of Epalrestat On Glycosylation Biomarkers In Vitromentioning

confidence: 99%

Sorbitol Is a Severity Biomarker for PMM2‐CDG with Therapeutic Implications

Ligęzka

Radenkovic

Saraswat

et al. 2021

Annals of Neurology

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Objective: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. Methods: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. Results: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein Nglycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months.

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Section: Effect Of Epalrestat On Glycosylation Biomarkers In Vitromentioning

confidence: 99%

Sorbitol Is a Severity Biomarker for PMM2‐CDG with Therapeutic Implications

Ligęzka

Radenkovic

Saraswat

et al. 2021

Annals of Neurology

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“…Moreover, CD36 was found to promote sterile inflammation and activate the protumor ability of tumor-associated immune cells ( Wang and Li, 2019 ). DPM2 (Dolichyl-Phosphate Mannosyltransferase Subunit 2) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum ( Radenkovic et al, 2021 ). A total of 19 lipid metabolism-related genes were used to establish the risk predictive score model as a potential prognostic indicator of gastric cancer, including DPM2 ( Wei et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel lipid metabolism-related gene signature for predicting colorectal cancer survival

et al. 2022

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Colorectal cancer (CRC) is a common malignant tumor worldwide. Lipid metabolism is a prerequisite for the growth, proliferation and invasion of cancer cells. However, the lipid metabolism-related gene signature and its underlying molecular mechanisms remain unclear. The aim of this study was to establish a lipid metabolism signature risk model for survival prediction in CRC and to investigate the effect of gene signature on the immune microenvironment. Lipid metabolism-mediated genes (LMGs) were obtained from the Molecular Signatures Database. The consensus molecular subtypes were established using “ConsensusClusterPlus” based on LMGs and the cancer genome atlas (TCGA) data. The risk model was established using univariate and multivariate Cox regression with TCGA database and independently validated in the international cancer genome consortium (ICGC) datasets. Immune infiltration in the risk model was developed using CIBERSORT and xCell analyses. A total of 267 differentially expressed genes (DEGs) were identified between subtype 1 and subtype 2 from consensus molecular subtypes, including 153 upregulated DEGs and 114 downregulated DEGs. 21 DEGs associated with overall survival (OS) were selected using univariate Cox regression analysis. Furthermore, a prognostic risk model was constructed using the risk coefficients and gene expression of eleven-gene signature. Patients with a high-risk score had poorer OS compared with patients in the low-risk score group (p = 3.36e-07) in the TCGA cohort and the validationdatasets (p = 4.03e-05). Analysis of immune infiltration identified multiple T cells were associated with better prognosis in the low-risk group, including Th2 cells (p = 0.0208), regulatory T cells (p = 0.0425), and gammadelta T cells (p = 0.0112). A nomogram integrating the risk model and clinical characteristics was further developed to predict the prognosis of patients with CRC. In conclusion, our study revealed that the expression of lipid-metabolism genes were correlated with the immune microenvironment. The eleven-gene signature might be useful for prediction the prognosis of CRC patients.

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“… 11 Additional studies in fibroblasts included OCR by seahorse, and lipidomic studies (Figures 3 and S1 ). 12 , 13 , 14 , 15 …”

Section: Novel Patients and Methodsmentioning

confidence: 99%

TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and normal lactate levels

Muylle

Jiang

Johnsen

et al. 2022

J of Inher Metab Disea

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TRIT1 defect is a rare, autosomal-recessive disorder of transcription, initially described as a condition with developmental delay, myoclonic seizures, and abnormal mitochondrial function. Currently, only 13 patients have been reported. We reviewed the genetic, clinical, and metabolic aspects of the disease in all known patients, including two novel, unrelated TRIT1 cases with abnormalities in oxidative phosphorylation complexes I and IV in fibroblasts. Taken together the features of all 15 patients, TRIT1 defect could be identified as a potentially recognizable syndrome including myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and variable microcephaly, with normal lactate levels. Half of the patients had oxidative phosphorylation complex measurements and had multiple complex abnormalities.

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Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation

Cited by 12 publications

References 30 publications

Sorbitol Is a Severity Biomarker for PMM2‐CDG with Therapeutic Implications

Sorbitol Is a Severity Biomarker for PMM2‐CDG with Therapeutic Implications

Identification of a novel lipid metabolism-related gene signature for predicting colorectal cancer survival

TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and normal lactate levels

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