A Novel <i>SUCLA2</i> Mutation in a Portuguese Child Associated With “Mild” Methylmalonic Aciduria

Nogueira, Célia; Meschini, Maria Chiara; Nesti, Claudia; Garcia, Paula; Diogo, Luísa; Valongo, Carla; Costa, Ricardo; Videira, Arnaldo; Vilarinho, Laura; Santorelli, Filippo M.

doi:10.1177/0883073814527158

Cited by 16 publications

(20 citation statements)

References 14 publications

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“…To date, 51 patients have been reported with SUCLA2 deficiency [6,7,20,24,29,41,44,46,49,50,52,54], and 21 patients with SUCLG1 deficiency, due to different mutations [7]. Patients with SUCLG1 mutations may have an extremely severe phenotype with antenatal manifestations of the disorder, severe acidosis with lactic aciduria in the first day of life and death within 2–4 days [53] or a phenotype similar to those of patients with SUCLA2 mutations.…”

Section: Introductionmentioning

confidence: 99%

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Kacso

Ravasz

Dóczi

et al. 2016

Biochemical Journal

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Succinate-CoA ligase (SUCL) is a heterodimer enzyme composed of Suclg1 α-subunit and a substrate-specific Sucla2 or Suclg2 β-subunit yielding ATP or GTP, respectively. In humans, the deficiency of this enzyme leads to encephalomyopathy with or without methylmalonyl aciduria, in addition to resulting in mitochondrial DNA depletion. We generated mice lacking either one Sucla2 or Suclg2 allele. Sucla2 heterozygote mice exhibited tissue- and age-dependent decreases in Sucla2 expression associated with decreases in ATP-forming activity, but rebound increases in cardiac Suclg2 expression and GTP-forming activity. Bioenergetic parameters including substrate-level phosphorylation (SLP) were not different between wild-type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of SUCL was concomitantly present. mtDNA contents were moderately decreased, but blood carnitine esters were significantly elevated. Suclg2 heterozygote mice exhibited decreases in Suclg2 expression but no rebound increases in Sucla2 expression or changes in bioenergetic parameters. Surprisingly, deletion of one Suclg2 allele in Sucla2 heterozygote mice still led to a rebound but protracted increase in Suclg2 expression, yielding double heterozygote mice with no alterations in GTP-forming activity or SLP, but more pronounced changes in mtDNA content and blood carnitine esters, and an increase in succinate dehydrogenase activity. We conclude that a partial reduction in Sucla2 elicits rebound increases in Suclg2 expression, which is sufficiently dominant to overcome even a concomitant deletion of one Suclg2 allele, pleiotropically affecting metabolic pathways associated with SUCL. These results as well as the availability of the transgenic mouse colonies will be of value in understanding SUCL deficiency.

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Section: Introductionmentioning

confidence: 99%

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Kacso

Ravasz

Dóczi

et al. 2016

Biochemical Journal

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“…The defects in the SUCLA2 gene can result in myopathic mitochondrial DNA depletion syndrome, which is characterized by a significant reduction in mtDNA content [1]. In a culture medium of fibroblasts from a patient with SUCLA2 mutation, Western blotting showed a significant decrease in Sucla2 protein and mitochondrial ATP contents and enhanced levels of ROS [6].…”

Section: Discussionmentioning

confidence: 99%

“…Our present data indicate that Sucla2 most likely serves as a link between mitochondrial function and apoptosis of germ cells, and may be one of the targeting markers affected by some stress stimulators. Most studies on Sucla2 focused on the mutation in the SUCLA2 nuclear gene and its relationship with the clinical syndromes of patients [1,3,6,26]. On the other hand, the majority of studies on the apoptosis of germ cells were focused on the detection of markers of mitochondrial dysfunction or apoptosis, such as ATP production, ROS level, Bcl2, or caspase 3/9 [8,18,35,36].…”

Section: Discussionmentioning

confidence: 99%

“…Defects in the SUCLA2 gene result in myopathic mtDNA depletion syndrome, characterized by a significant reduction in mtDNA levels and mitochondrial dysfunction [3][4][5]. In patients with SUCLA2 mutation, impaired production of ATP and high levels of reactive oxygen species (ROS) were found in fibroblasts [6]. Only a few authors have studied Sucla2 expression in males.…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis through injury of the mitochondrial function of cells

Huang

Wang

2016

Folia Histochem Cytobiol.

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Introduction. Sucla2, a b subunit of succinyl coenzyme A synthase, is located in the mitochondrial matrix. Sucla2 catalyzes the reversible synthesis of succinate and adenosine triphosphate (ATP) in the tricarboxylic acid cycle. Sucla2 expression was found to be correlated with the capacitation of boar spermatozoa. We have previously reported that Sucla2 was decreased in the testes of rats with spermatogenesis failure after exposure to endocrine disruptor BDE47. Yet, the expression model of Sucla2 in spermatogenesis and the function of Sucla2 in spermatogenic cells are still unclear. Our objective was to explore the localization of Sucla2 during mouse spermatogenesis and its function in the mouse spermatocyte line (GC2). Material and methods. The localization of Sucla2 in the mouse testis was explored through immunohistochemistry (IHC). Sucla2 was knocked down in GC2 cells and its expression was detected by Western blot (WB) to verify the efficiency of the siRNA transfection. Mitochondrial membrane potential (MMP), apoptosis and ROS of GC2 were detected by flow cytometry. ATP production was measured by the luminometric method and the presence of Bcl2 of GC2 was detected by WB. Results. Sucla2 is highly expressed in all germ cells but not in interstitial cells. Coarse Sucla2 signals are found in spermatocytes in stages VII-XII of mouse spermatogenesis. In GC2 cells, knockdown of Sucla2 decreased cell viability and MMP, induced apoptosis of GC2 cells, decreased ATP production, and Bcl2 expression, and increased ROS levels. Conclusions. Sucla2 is related to the developmental stages of mouse spermatogenesis. Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis via decreased mitochondrial function of the cells.

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“…A total of 28 patients were reported in literature (Carrozzo et al 2007;Elpeleg et al 2005;Jaberi et al 2013;Lamperti et al 2012;Matilainen et al 2014;Morava et al 2009;Nogueira et al 2015;Ostergaard et al 2007b) of whom nine were female.…”

Section: Review Of Patients Reported In the Literaturementioning

confidence: 99%

SUCLA2 Deficiency: A Deafness-Dystonia Syndrome with Distinctive Metabolic Findings (Report of a New Patient and Review of the Literature)

Maas

Marina²,

Brouwer

et al. 2015

JIMD Reports

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SUCLA2 encodes for a subunit of succinylcoenzyme A synthase, the enzyme that reversibly synthesises succinyl-coenzyme A and ATP from succinate, coenzyme A and ADP in the Krebs cycle. Disruption of SUCLA2 function can lead to mitochondrial DNA depletion. Patients with a SUCLA2 mutation present with a rare but distinctive deafness-dystonia syndrome. Additionally, they exhibit elevated levels of the characteristic biochemical markers: methylmalonate, C4-dicarboxylic carnitine and lactate are increased in both plasma and urine. Thus far, eight different disease-causing SUCLA2 mutations, of which six missense mutations and two splice site mutations, have been described in the literature. Here, we present the first patient with an intragenic deletion in SUCLA2 and review the patients described in literature.

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A Novel SUCLA2 Mutation in a Portuguese Child Associated With “Mild” Methylmalonic Aciduria

Cited by 16 publications

References 14 publications

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis through injury of the mitochondrial function of cells

SUCLA2 Deficiency: A Deafness-Dystonia Syndrome with Distinctive Metabolic Findings (Report of a New Patient and Review of the Literature)

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