Clinical Severity of PGK1 Deficiency Due To a Novel p.E120K Substitution Is Exacerbated by Co-inheritance of a Subclinical Translocation t(3;14)(q26.33;q12), Disrupting NUBPL Gene

David, Dezső; Almeida, Lígia S.; Maggi, Maristella; Carlos, Araújo; Imreh, Stefan; Valentini, Giovanna; Fekete, Gyorgy; Haltrich, Irén

http://hdl.handle.net/10400.18/3279

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Abstract(s)

Carriers of cytogenetically similar, apparentlybalanced familial chromosome translocations not alwaysexhibit the putative translocation-associated disease phenotype.Additional genetic defects, such as genomic imbalanceat breakpoint regions or elsewhere in the genome,have been reported as the most plausible explanation.By means of comprehensive molecular and functionalanalyses, additional to careful dissection of the t(3;14)(q26.33;q12) breakpoints, we unveil a novel X-linkedPGK1 mutation and examine the contribution of these tothe extremely severe clinical phenotype characterized byhemolytic anemia and neuromyopathy.The 3q26.33 breakpoint is 40 kb from the 50 region oftetratricopeptide repeat domain 14 gene (TTC14), whereasthe 14q12 breakpoint is within IVS6 of nucleotide-bindingprotein-like gene (NUBPL) that encodes a mitochondrialcomplex I assembly factor. Disruption of NUBPL intranslocation carriers leads to a decrease in thecorresponding mRNA accompanied by a decrease inprotein level. Exclusion of pathogenic genomic imbalanceand reassessment of familial clinical history indicate theexistence of an additional causal genetic defect. Consequently,by WES a novel mutation, c.358G>A, p.E120K,in the X-linked phosphoglycerate kinase 1 (PGK1) wasidentified that segregates with the phenotype. Specificactivity, kinetic properties, and thermal stability of thisenzyme variant were severely affected. The novel PGK1mutation is the primary genetic alteration underlying thereported phenotype as the translocation per se only resultsin a subclinical phenotype. Nevertheless, its co-inheritancepresumably exacerbates PGK1-deficient phenotype, mostlikely due to a synergistic interaction of the affected genesboth involved in cell energy supply.