Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome

García‐Cazorla, Àngels; Verdura, Edgard; Juliá‐Palacios, Natalia; Anderson, Eric N.; Goicoechea, Leire; Planas‐Serra, Laura; Tsogtbaatar, Enkhtuul; Dsouza, Nikita R.; Schlüter, Agatha; Urreizti, Roser; Tarnowski, Jessica M.; Gavrilova, Ralitza H.; Ruíz, Montserrat; Rodríguez‐Palmero, Agustí; Fourcade, Stéphane; Cogné, Benjamin; Besnard, Thomas; Vincent, Marie; Bézieau, Stéphane; Folmes, Clifford D.L.; Zimmermann, Michael T.; Klee, Eric W.; Pandey, Udai Bhan; Artuch, Rafael; Cousin, Margot A.; Pujol, Aurora

doi:10.1007/s00401-020-02223-w

Cited by 30 publications

(28 citation statements)

References 19 publications

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“…This data is consistent with other MEF and immortalized cells models of homozygous SHMT2 loss or folate deficiency that exhibit decreased oxidative capacity and impaired mitochondrial complex I activity and protein levels, suggesting FOCM and the oxidative phosphorylation system are functionally coordinated (26,(31)(32)(33)(34). Furthermore, the reduced membrane potential is consistent with the observations in human cells with biallelic SHMT2 variants (28). In immortalized cell models, SHMT2-induced energy metabolism changes are thought to be a result of impaired mitochondrial translation (32), reduced complex I protein levels (26,31), or decreased NADPH production (34).…”

Section: Discussionsupporting

confidence: 90%

“…al., homozygous Shmt2 knockouts are embryonic lethal, demonstrating the essentiality of Shmt2 (Table 2) (26). Biallelic human variants in SHMT2 have recently been identified in a small number of patients using whole-exome sequencing (28). Most of these variants are hypothesized to affect substrate binding and/or SHMT2 protein oligomerization and ultimately protein function (28).…”

Section: Discussionmentioning

confidence: 99%

“…Biallelic human variants in SHMT2 have recently been identified in a small number of patients using whole-exome sequencing (28). Most of these variants are hypothesized to affect substrate binding and/or SHMT2 protein oligomerization and ultimately protein function (28). Biallelic SHMT2 variants result in neurological complications, among other phenotypes, in affected individuals.…”

Section: Discussionmentioning

confidence: 99%

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ReducedShmt2expression impairs mitochondrial folate accumulation and respiration, and leads to uracil accumulation in mouse mitochondrial DNA

Fiddler

Xiu

Blum

et al. 2021

Preprint

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Background. Adequate cellular thymidylate (dTMP) pools are essential for preservation of nuclear and mitochondrial genome stability. Previous studies have indicated that disruption in dTMP synthesis in the nucleus leads to increased uracil misincorporation into DNA affecting genome stability. To date, the effects of impaired mitochondrial dTMP synthesis in non-transformed tissues have been understudied. Objective. This study aimed to determine the effects of decreased serine hydroxymethyltransferase 2 (Shmt2) expression and dietary folate deficiency on mitochondrial DNA integrity and mitochondrial function in mouse tissues. Methods. Liver mitochondrial DNA (mtDNA) content, and uracil content in liver mtDNA was measured in Shmt2+/- and Shmt2+/+ mice weaned onto either a folate-sufficient control diet (2 mg/kg folic acid, C) or a modified diet lacking folic acid (0 mg/kg folic acid, FD) for 7 wks. Shmt2+/- and Shmt2+/+ mouse embryonic fibroblasts (MEF cells) were cultured in defined culture medium containing either 0 or 25 nM folate to assess proliferative capacity and mitochondrial function. Results. Shmt2+/- mice exhibited 48-67% reduction in SHMT2 protein levels in tissues. Interestingly, Shmt2+/- mice consuming the folate-sufficient C diet exhibited a 25% reduction in total folate in liver mitochondria. There was also a >20-fold increase in uracil in liver mtDNA in Shmt2+/- mice consuming the C diet, and dietary folate deficiency also increased uracil content in mouse liver mtDNA from both Shmt2+/+ and Shmt2+/- mice. Furthermore, decreased Shmt2 expression in MEF cells reduced cell proliferation, mitochondrial membrane potential, and oxygen consumption rate. Conclusions. This study demonstrates that Shmt2 heterozygosity and dietary folate deficiency impair mitochondrial dTMP synthesis, as evidenced by the increased uracil in mtDNA. In addition, Shmt2 heterozygosity impairs mitochondrial function in MEF cells. These findings suggest that elevated uracil in mtDNA may impair mitochondrial function.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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ReducedShmt2expression impairs mitochondrial folate accumulation and respiration, and leads to uracil accumulation in mouse mitochondrial DNA

Fiddler

Xiu

Blum

et al. 2021

Preprint

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“…Of the variant-phenotype associations uncovered by our study, only the association between BCL2L13 and cancer has been previously reported 51 , 52 . Interestingly, bi-allelic loss-of-function mutations in SHMT2 have recently been described in a novel brain and heart developmental syndrome involving spastic paraparesis and ataxias 53 . Indeed, in addition to the phenome-wide significant association with diseases of the salivary gland uncovered in our study, the SHMT2 uORF stop-strengthening variant was nominally associated with several Phecodes related to cardiac and movement disorders in the PMBB (Supplementary Table 6 ), including congenital anomalies of the great vessels (ICD 747.13, P = 0.0117), abnormal involuntary movements (350.1, P = 0.0238), abnormality of gait (350.2, P = 0.02575), Mobitz II AV block (426.22, P = 0.03432), and Arrhythmia (cardiac) NOS (427.5, P = 0.04977).…”

Section: Discussionmentioning

confidence: 99%

Disrupting upstream translation in mRNAs is associated with human disease

et al. 2021

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Ribosome-profiling has uncovered pervasive translation in non-canonical open reading frames, however the biological significance of this phenomenon remains unclear. Using genetic variation from 71,702 human genomes, we assess patterns of selection in translated upstream open reading frames (uORFs) in 5’UTRs. We show that uORF variants introducing new stop codons, or strengthening existing stop codons, are under strong negative selection comparable to protein-coding missense variants. Using these variants, we map and validate gene-disease associations in two independent biobanks containing exome sequencing from 10,900 and 32,268 individuals, respectively, and elucidate their impact on protein expression in human cells. Our results suggest translation disrupting mechanisms relating uORF variation to reduced protein expression, and demonstrate that translation at uORFs is genetically constrained in 50% of human genes.

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“…On the one hand, an increased expression of the active metabolic enzyme SHMT2 is associated with various types of cancer [ 74 , 75 ]. On the other hand, overexpression of SHMT2 is reported to induce neurodegeneration driven by excessive cerebral glycine production [ 76 ], and mutations in the SHMT2 gene are known to cause brain and cardiac developmental disorders [ 77 ]. In correlation, transgenic htra2 mnd 2 mice with a deficient HTRA2 activity also showed an inefficient mitochondrial respiration accompanied by ATP depletion [ 78 ], and might reflect the important interaction between SHMT2 and HTRA2 for the proper regulation of the cellular energy metabolism.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the HTRA2 Protease Activity by an Inhibitory Antibody-Derived Peptide Ligand and the Influence on HTRA2-Specific Protein Interaction Networks in Retinal Tissues

et al. 2021

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The mitochondrial serine protease HTRA2 has many versatile biological functions ranging from being an important regulator of apoptosis to being an essential component for neuronal cell survival and mitochondrial homeostasis. Loss of HTRA2 protease function is known to cause neurodegeneration, whereas overactivation of its proteolytic function is associated with cell death and inflammation. In accordance with this, our group verified in a recent study that the synthetic peptide ASGYTFTNYGLSWVR, encoding the hypervariable sequence part of an antibody, showed a high affinity for the target protein HTRA2 and triggered neuroprotection in an in vitro organ culture model for glaucoma. To unravel this neuroprotective mechanism, the present study showed for the first time that the synthetic CDR1 peptide significantly (p < 0.01) inhibited the proteolytic activity of HTRA2 up to 50% using a specific protease function assay. Furthermore, using state-of-the-art co-immunoprecipitation technologies in combination with highresolution MS, we identified 50 significant protein interaction partners of HTRA2 in the retina of house swine (p < 0.01; log2 fold change > 1.5). Interestingly, 72% of the HTRA2-specific interactions (23 of 31 binders) were inhibited by additional treatment with UCF-101 (HTRA2 protease inhibitor) or the synthetic CDR peptide. On the other hand, the remaining 19 binders of HTRA2 were exclusively identified in the UCF101 and/or CDR group. However, many of the interactors were involved in the ER to Golgi anterograde transport (e.g., AP3D1), aggrephagy (e.g., PSMC1), and the pyruvate metabolism/citric acid cycle (e.g., SHMT2), and illustrated the complex protein interaction networks of HTRA2 in neurological tissues. In conclusion, the present study provides, for the first time, a comprehensive protein catalogue of HTRA2-specific interaction partners in the retina, and will serve as reference map in the future for studies focusing on HTRA2mediated neurodegeneration.

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Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome

Cited by 30 publications

References 19 publications

ReducedShmt2expression impairs mitochondrial folate accumulation and respiration, and leads to uracil accumulation in mouse mitochondrial DNA

ReducedShmt2expression impairs mitochondrial folate accumulation and respiration, and leads to uracil accumulation in mouse mitochondrial DNA

Disrupting upstream translation in mRNAs is associated with human disease

Regulation of the HTRA2 Protease Activity by an Inhibitory Antibody-Derived Peptide Ligand and the Influence on HTRA2-Specific Protein Interaction Networks in Retinal Tissues

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