Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome
Àngels García‐Cazorla, Edgard Verdura, Natalia Juliá‐Palacios, Eric N. Anderson, Leire Goicoechea, Laura Planas‐Serra, Enkhtuul Tsogtbaatar, Nikita R. Dsouza, Agatha Schlüter, Roser Urreizti, Jessica M. Tarnowski, Ralitza H. Gavrilova, SHMT2 Working Group, Alfonso Oyarzábal, Inés Medina, Aída Ormazábal, Jordi Muchart, Juan Manuel Carretero, Cristina Jou, Mireia del Toro, A. Nascimento, Abraham J. Paredes, Dèlia Yubero, Roser Colomé, Montserrat Ruíz, Agustí Rodríguez‐Palmero, Stéphane Fourcade, Benjamin Cogné, Thomas Besnard, Marie Vincent, Stéphane Bezieau, Clifford D.L. Folmes, Michael T. Zimmermann, Eric W. Klee, Udai Bhan Pandey, Rafael Artuch, Margot A. Cousin, Aurora Pujol
Abstract
Inborn errors of metabolism cause a wide spectrum of neurodevelopmental and neurodegenerative conditions [15]. A pivotal enzyme located at the intersection of the amino acid and folic acid metabolic pathways is SHMT2, the mitochondrial form of serine hydroxymethyltransferase. SHMT2 performs the first step in a series of reactions that provide one-carbon units covalently bound to folate species in mitochondria: it transfers one-carbon units from serine to tetrahydrofolate (THF), generating glycine and 5,10-methylene-THF. Using whole exome sequencing (WES), we identified biallelic SHMT2 variants in five individuals from four different families. All identified variants were located in conserved residues, either absent or extremely rare in control databases (gnomAD, ExAC), and cosegregated based on a recessive mode of inheritance (pRec = 0.9918 for this gene). In family F1, a homozygous missense variant present in two affected siblings was located in a region without heterozygosity (~ 10 Mb, the only region > 1 Mb shared by both siblings) in which no other candidate variants were found, providing a strong genetic evidence of causality for these variants. The missense/in-frame deletion nature of these variants, and the absence of loss-of-function homozygous individuals in control databases, combined with the fact that complete loss of SHMT2 is embryonic lethal in the mouse, suggested that these variants may cause hypomorphic effects. Using 3D molecular dynamics models of the SHMT2 protein, we concluded that these candidate variants probably alter the SHMT2 oligomerization process, and/or disrupt the conformation of the active site, thus inducing deleterious effects on SHMT2 enzymatic function.