Please use this identifier to cite or link to this item:
Title: Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome
Author: 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.
SHMT Working Group
Ruiz, Montserrat
Rodríguez Palmero, Agustí
Fourcade, Stéphane
Cogné, Benjamin
Besnard, Thomas
Vincent, Marie
Bézieau, Stéphane
Folmes, Clifford D.
Zimmermann, Michael T.
Klee, Eric W.
Pandey, Udai Bhan
Artuch Iriberri, Rafael
Cousin, Margot A.
Pujol Onofre, Aurora
Keywords: Errors congènits del metabolisme
Malalties neurodegeneratives
Malformacions del cor
Inborn errors of metabolism
Neurodegenerative Diseases
Heart abnormalities
Issue Date: 5-Oct-2020
Publisher: Springer Verlag
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.
Note: Reproducció del document publicat a:
It is part of: Acta Neuropathologica, 2020, num. 140, p. 971-975
Related resource:
ISSN: 0001-6322
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Files in This Item:
File Description SizeFormat 
704083.pdf834.2 kBAdobe PDFView/Open

This item is licensed under a Creative Commons License Creative Commons