Finally, Margot Cousin presents on "Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome" #ASHG20
SHMT2 - encodes mitochondrial serine hydroxymethyltransferase 2. Key roles in amino acid metabolism and folic acid pathways, as well as mitochondrial respiration and protein translocation #ASHG20
Identified 4 individuals with biallelic SHMT2 variants. One individual has a variant disrupting a splice site. Other variants are missense on highly conserved residues, and are absent/extremely rare in gnoMAD. Variable dysmorphic features. Others incl. developmental delay #ASHG20
Brain MRI show all have thin/hypoplastic corpus callosum and perisylvian polymicrogyria in most. Muscle fibres from one patient are consistent with a mitochondrial disorder #ASHG20
3D molecular modelling of SHMT2 indicate mutation effects on the active site or dimerisation interface of the protein. Also appear to affect the average movement and variance in movement of these features over time. Some function likely remain, as LoF is lethal in mice #ASHG20
Functional studies in patient fibroblasts show disrupted Gly/Ser ratio and disruption to folate metabolism. Bioenergetic analyses suggest reduced mitochondrial respiration and bioenergetic failure when cells are dependent on oxidative respiration #ASHG20
Show generation of reactive oxygen species in affected cells. These overall mitochondrial dysfunctions have numerous negative outcomes on the cells #ASHG20
KO of Shmt2 in drosophila motor neurons results in reduced climbing distances and velocity, implying reduced motor function. Functional assays demonstrate increased satellite boutons, indicating abnormal synaptic growth #ASHG20
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