Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities

PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities. METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells. RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells. CONCLUSION: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities

Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities

Purpose: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.Methods: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells.Results: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme alpha-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C > T:p.(Pro189Leu) and c.890C > A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G > A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells.Conclusion: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY licensePeer reviewe

Evaluation of Polycaprolactone Electrospun Nanofiber-Composites for Artificial Skin Based on Dermal Fibroblast Culture

The study’s aim was to develop a dermal equivalent scaffold that can mimic the architecture and biological performance of the human dermis. Poly ε-caprolactone (PCL) electrospun nanofiber material (ENF) was assembled with polyethylene glycol diacrylate (PEGDA), sodium alginate (SA) and type I collagen (CG1) to develop three groups of dermal equivalent scaffolds. These scaffolds were named PEGDA-PCL, SA-PCL and CG1-PCL. Scanning electron microscopy (SEM) images of cell-free scaffolds’ top and cross-sectional surface were collected and analyzed to examine internal morphology, specifically the adhesiveness of PCL fibers with the different scaffolds. Human dermal fibroblasts were cultured on each of the scaffolds. Cell viability studies including cell adhesion, cell differentiation and stress fiber production were conducted on each scaffold. Furthermore, the architectural integrity of each scaffold was verified by degradation analysis for 2 weeks by soaking each scaffold in phosphate-buffered saline (PBS) solution. Finally, we conducted rheological characteristics of each scaffold. Based on our results from the above analysis, the study concluded that CG1-PCL is best suitable for the dermal equivalent model and has potential to be used as a graft for skin repair