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David D, Almeida LS, Maggi M, et al. 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. JIMD Rep. 2015;23:55-65doi: 10.1007/8904_2015_427.
David, D., Almeida, L. S., Maggi, M., Araújo, C., Imreh, S., Valentini, G., Fekete, G., & Haltrich, I. (2015). 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. JIMD reports, 2355-65. https://doi.org/10.1007/8904_2015_427
David, Dezső, et al. "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." JIMD reports vol. 23 (2015): 55-65. doi: https://doi.org/10.1007/8904_2015_427
David D, Almeida LS, Maggi M, Araújo C, Imreh S, Valentini G, Fekete G, Haltrich I. 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. JIMD Rep. 2015;23:55-65. doi: 10.1007/8904_2015_427. Epub 2015 Mar 27. PMID: 25814383; PMCID: PMC4484905.
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JIMD Rep. 2015;23:55-65. doi: 10.1007/8904_2015_427. Epub 2015 Mar 27.

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.

JIMD reports

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

Affiliations

  1. Department of Human Genetics, National Institute of Health Dr Ricardo Jorge, Lisbon, Portugal, [email protected].

PMID: 25814383 PMCID: PMC4484905 DOI: 10.1007/8904_2015_427

Abstract

Carriers of cytogenetically similar, apparently balanced familial chromosome translocations not always exhibit the putative translocation-associated disease phenotype. Additional genetic defects, such as genomic imbalance at breakpoint regions or elsewhere in the genome, have been reported as the most plausible explanation.By means of comprehensive molecular and functional analyses, additional to careful dissection of the t(3;14)(q26.33;q12) breakpoints, we unveil a novel X-linked PGK1 mutation and examine the contribution of these to the extremely severe clinical phenotype characterized by hemolytic anemia and neuromyopathy.The 3q26.33 breakpoint is 40 kb from the 5' region of tetratricopeptide repeat domain 14 gene (TTC14), whereas the 14q12 breakpoint is within IVS6 of nucleotide-binding protein-like gene (NUBPL) that encodes a mitochondrial complex I assembly factor. Disruption of NUBPL in translocation carriers leads to a decrease in the corresponding mRNA accompanied by a decrease in protein level. Exclusion of pathogenic genomic imbalance and reassessment of familial clinical history indicate the existence 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) was identified that segregates with the phenotype. Specific activity, kinetic properties, and thermal stability of this enzyme variant were severely affected. The novel PGK1 mutation is the primary genetic alteration underlying the reported phenotype as the translocation per se only results in a subclinical phenotype. Nevertheless, its co-inheritance presumably exacerbates PGK1-deficient phenotype, most likely due to a synergistic interaction of the affected genes both involved in cell energy supply.

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