ZFIN Image: Vanoevelen et al., 2021, Fig. 1

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Fig. 1

Description of variants and clinical phenotype. a Overview of the dTTP biosynthesis pathway. DTYMK (dTMPK) mediates the penultimate step of the generation of dTTP. Both pathways: salvage pathway and de novo pathway converge before the enzymatic defect in DTYMK. Abbreviations used: DCK deoxycytidine kinase; TK1 thymidine kinase 1; TK2 thymidine kinase 2 (mitochondrial); DTYMK deoxythymidine (monophosphate) kinase; DNDPK deoxynucleotide diphosphate kinase; TS thymidylate synthase; RR ribonucleotide reductase; UMPS uridine monophosphate synthetase; CAD carbamoyl-phosphate synthase 2, aspartate transcarbamylase and dihydroorotase; TP thymidine phosphorylase. b Description of two families carrying variants in DTYMK. Both families share the variant c.242C>T which is homozygous in individual II and indicated in purple. Family I is compound heterozygous and contains the additional variant c.382G>A, indicated in red. Brain MRI and pictures showing microcephaly in both affected individuals. The age of the individuals at which the pictures were taken are 9 months and 26 months for individual I and individual II, respectively. MRI images of individual I at age 6 months and of individual II at 12 months. Both subjects show severe atrophy of the cerebral hemispheres and basal ganglia, whereas the thalamus, brain stem and cerebellum appear normal. Individual I also shows pronounced dilation of the lateral ventricles. c Position of the observed variants in the primary protein sequence of dTMPK and relative position of known functional domains are shown in the upper panel. The variants are labelled in purple (p.(Pro81Leu)) and red (p.Asp128Asn). Known functional domains of DTYMK are: P-loop motif (indicated in green, residues 13–21), DR(Y/H)-motif (yellow, residues 96–98), LID domain (blue, residues 135–150) [26]. In the lower panel, the position of the variants in the 3D structure (PDB code 1e2f) are depicted in purple (p.Pro81Leu) and red (p.Asp128Asn). d Evolutionary conservation of regions in dTMPK containing the described variants. The protein sequences used in the alignment are: H.sapiens: ENSP00000304802; S. cerevisiae: YJR057W; D. melanogaster: FBpp0303030; D. rerio: ENSDARP00000068373; A. carolinensis: ENSACAP00000000660; X. tropicalis: ENSXETP00000044270; G. gallus: ENSGALP00000053279; M. musculus: ENSMUSP00000027503

Acknowledgments

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