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

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

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Citation (Scopus)

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.

Original languageEnglish
Title of host publicationJIMD Reports
PublisherSpringer
Pages55-65
Number of pages11
DOIs
Publication statusPublished - Jan 1 2015

Publication series

NameJIMD Reports
Volume23
ISSN (Print)2192-8304
ISSN (Electronic)2192-8312

Fingerprint

Phosphoglycerate Kinase
Carrier Proteins
Substitution reactions
Nucleotides
Genes
Phenotype
Mutation
Dissection
Defects
Enzyme Stability
Chromosomes
Hemolytic Anemia
Thermodynamic stability
Phosphoglycerate Kinase 1 Deficiency
Hot Temperature
Messenger RNA
Kinetics
Genome
Enzymes
Proteins

Keywords

  • Breakpoint region
  • Genomic imbalance
  • Index subject
  • Junction fragment
  • Translocation carrier

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Cite this

David, D., Almeida, L. S., Maggi, M., Araújo, C., Imreh, S., Valentini, 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. In JIMD Reports (pp. 55-65). (JIMD Reports; Vol. 23). Springer. https://doi.org/10.1007/8904_2015_427

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; Araújo, Carlos; Imreh, Stefan; Valentini, Giovanna; Fekete, G.; Haltrich, Irén.

JIMD Reports. Springer, 2015. p. 55-65 (JIMD Reports; Vol. 23).

Research output: Chapter in Book/Report/Conference proceedingChapter

David, Dezső ; Almeida, Lígia S. ; Maggi, Maristella ; Araújo, Carlos ; Imreh, Stefan ; Valentini, Giovanna ; Fekete, G. ; Haltrich, Irén. / 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. Springer, 2015. pp. 55-65 (JIMD Reports).
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