Complex genetic findings in a female patient with pyruvate dehydrogenase complex deficiency: Null mutations in the PDHX gene associated with unusual expression of the testis-specific PDHA2 gene in her somatic cells

Pinheiro, António N.; Silva, Maria João; Pavlu-Pereira, Hana; Florindo, Cristina; Barroso, Madalena; Marques, Bárbara; Correia, Hildeberto; Oliveira, Anjolina Grisi de; Gaspar, Ana; Almeida, Isabel Tavares de; Rivera, Isabel

doi:10.1016/j.gene.2016.06.041

Cited by 5 publications

(5 citation statements)

References 38 publications

(43 reference statements)

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“…The most striking evidence is the relatively high incidence of E3BP deficiency, mostly caused by a p.R284X E3BP variant, half the cases originating from the Azores Islands, thus denoting a founder effect. This E3BP variant was first described by our group [27] and, until now, only another Portuguese patient has been reported to carry this mutation [28]. Furthermore, the mutational spectrum of E3BP deficiency in Portugal includes very severe mutations, leading to null alleles.…”

Section: Discussionmentioning

confidence: 81%

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients

Pavlu-Pereira

Silva

Florindo

et al. 2020

Orphanet J Rare Dis

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Background The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype–phenotype correlations. Results The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1α subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying what seems to be a private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas the lactate/pyruvate ratio was below 16; enzymatic activities, when compared to control values, indicated to be independent from the genotype and ranged from 8.5% to 30%, the latter being considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed psychomotor retardation/developmental delay, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially include the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, in silico analysis of the missense mutations present in this PDC deficient population allowed to envisage the molecular mechanism underlying these pathogenic variants. Conclusion The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allow to obtain an insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.

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Section: Discussionmentioning

confidence: 81%

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients

Pavlu-Pereira

Silva

Florindo

et al. 2020

Orphanet J Rare Dis

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“…The most striking evidence is the relatively high incidence of E3BP de ciency, mostly caused by a single PDHX variant, p.R284X, half the cases originating from the Azores Islands. This E3BP variant was rst described by our group (25) and, until now, only another Portuguese patient has been reported to carry this mutation (26). Furthermore, the mutational spectrum of E3BP de ciency in Portugal includes very severe mutations, leading to null alleles.…”

Section: Discussionmentioning

confidence: 91%

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes

Pavlu-Pereira

Silva

Florindo

et al. 2020

Preprint

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Background : Pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA which ultimately generates ATP. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits, and the resulting phenotype, though very heterogeneous, mainly affects the neuro-encephalic system. The aim of this study is to describe and discuss the clinic, metabolic and genotypic profiles of thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results : The mutational spectrum revealed that seven patients (54 %) carry mutations in the PDHA1 gene , encoding the E1α subunit, five patients (38 %) carry mutations in the PDHX gene, encoding the E3 binding protein, and the remaining patient (8 %) harbors mutations in the DLD gene, encoding the E3 subunit. These data corroborate PDHA1 mutations as the predominant cause of PDC deficiency, though revealing a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying a seemingly private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas de ratio L/P was under 16; enzymatic activities, when compared to control values, revealed to be independent from the genotype and ranged from 8.5% to 30% which may be considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed developmental delay/psychomotor retardation, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially go through the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, the in silico analysis of the missense mutations present in this PDC deficient population allowed to understand the molecular mechanism underlying these pathogenic variants. Conclusion : The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allows to get insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.

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“…PDHA1 and PDHA2 transcriptional levels were evaluated by quantitative real time RT-PCR under conditions previously described [1] .…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

“…The copy number of PDHA1 gene was evaluated by two methods, quantitative real time PCR and microarray analysis, as previously described [1] .…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

“…In addition, two different experimental approaches were used to elucidate the copy number of PDHA1 gene in the patient and her mother. The interpretation and discussion of these data, along with further extensive experiments concerning the origin of this altered gene expression and its potential therapeutic consequences, can be found in “Complex genetic findings in a female patient with pyruvate dehydrogenase complex deficiency: null mutations in the PDHX gene associated with unusual expression of the testis-specific PDHA2 gene in her somatic cells” (A. Pinheiro, M.J. Silva, C. Florindo, et al, 2016) [1] .…”

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confidence: 99%

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Data supporting the co-expression of PDHA1 gene and of its paralogue PDHA2 in somatic cells of a family

et al. 2016

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This article presents a dataset proving the simultaneous presence of a 5′UTR-truncated PDHA1 mRNA and a full-length PDHA2 mRNA in the somatic cells of a PDC-deficient female patient and all members of her immediate family (parents and brother).We have designed a large set of primer pairs in order to perform detailed RT-PCR assays allowing the clear identification of both PDHA1 and PDHA2 mRNA species in somatic cells. In addition, two different experimental approaches were used to elucidate the copy number of PDHA1 gene in the patient and her mother.The interpretation and discussion of these data, along with further extensive experiments concerning the origin of this altered gene expression and its potential therapeutic consequences, can be found in “Complex genetic findings in a female patient with pyruvate dehydrogenase complex deficiency: null mutations in the PDHX gene associated with unusual expression of the testis-specific PDHA2 gene in her somatic cells” (A. Pinheiro, M.J. Silva, C. Florindo, et al., 2016) [1].

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Complex genetic findings in a female patient with pyruvate dehydrogenase complex deficiency: Null mutations in the PDHX gene associated with unusual expression of the testis-specific PDHA2 gene in her somatic cells

Cited by 5 publications

References 38 publications

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes

Data supporting the co-expression of PDHA1 gene and of its paralogue PDHA2 in somatic cells of a family

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