Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis

Bhoj, Elizabeth; Li, M.; Ahrens‐Nicklas, Rebecca C.; Pyle, Louise C.; Wang, J.; Zhang, V. W.; Clarke, Colleen; Wong, Lee‐Jun; Sondheimer, Neal; Fıçıcıoğlu, Can

doi:10.1007/8904_2014_364

Cited by 34 publications

(38 citation statements)

References 9 publications

(12 reference statements)

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“…Remarkably the c.158-9A>G mutation, which results in a gain of a spliceacceptor, was also reported in a family of Guatemalan origin [67], suggesting that at least this mutation has a widespread prevalence. Furthermore, mutations in regions outside of exon 3 have also been described, which affect both PiC-A and B isoforms [67]. Every patient presented mainly with cardiomyopathy regardless of the involvement of only the A or A and B isoforms.…”

Section: Pathogenic Mutations In the Human Pic Genementioning

confidence: 89%

“…Two different mutations that affect only exon 3A and therefore the PiC-A isoform [42,66,67] were first observed in two different families of Turkish origin [42,66]. More recently, one of these mutations (c.215G>A) was found in a third Turkish family (Mayr J.A.…”

Section: Pathogenic Mutations In the Human Pic Genementioning

confidence: 99%

“…One remarkable feature common to patients with SLC25A3 mutations is the lack of neurocognitive involvement, when compared to other mitochondrial disorders causing cardiomyopathy [66,67].…”

Section: Pathogenic Mutations In the Human Pic Genementioning

confidence: 99%

“…It is also known that the transport affinity for Pi of PiC-A is 3-fold higher than that of PiC-B, whereas the maximal transport rate of PiC-B is 3-fold higher compared to PiC-A [24]. However, it is unknown how tissue function is affected by changes in the ratio of these two isoforms [67].…”

Section: Pathogenic Mutations In the Human Pic Genementioning

confidence: 99%

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The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

Seifert

Ligeti

Mayr

et al. 2015

Biochemical and Biophysical Research Communications

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The mitochondrial phosphate carrier (PiC) is a mitochondrial solute carrier protein, which is encoded by SLC25A3 in humans. PiC delivers phosphate, a key substrate of oxidative phosphorylation, across the inner mitochondrial membrane. This transport activity is also relevant for allowing effective mitochondrial calcium handling.Furthermore, PiC has also been described to affect cell survival mechanisms via interactions with cyclophilin D and the viral mitochondrial-localized inhibitor of apoptosis (vMIA). The significance of PiC has been supported by the recent discovery of a fatal human condition associated with PiC mutations. Here, we present first the early studies that lead to the discovery and molecular characterization of the PiC, then discuss the very recently developed mouse models for PiC and pathological mutations in the human SLC25A3 gene.

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Section: Pathogenic Mutations In the Human Pic Genementioning

confidence: 89%

Section: Pathogenic Mutations In the Human Pic Genementioning

confidence: 99%

“…One remarkable feature common to patients with SLC25A3 mutations is the lack of neurocognitive involvement, when compared to other mitochondrial disorders causing cardiomyopathy [66,67].…”

Section: Pathogenic Mutations In the Human Pic Genementioning

confidence: 99%

Section: Pathogenic Mutations In the Human Pic Genementioning

confidence: 99%

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The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

Seifert

Ligeti

Mayr

et al. 2015

Biochemical and Biophysical Research Communications

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“…cells (10) and through the discovery of pathologic variants in the human gene (11)(12)(13). These variants are both in exon 3A, specifically c.158 -9A3 G and c.215G3 A, which each cause a frameshift and absence of protein.…”

mentioning

confidence: 99%

Natural and Induced Mitochondrial Phosphate Carrier Loss

Seifert

Gál

Acoba

et al. 2016

Journal of Biological Chemistry

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Edited by F. Anne StephensonThe relevance of mitochondrial phosphate carrier (PiC), encoded by SLC25A3, in bioenergetics is well accepted. However, little is known about the mechanisms mediating the cellular impairments induced by pathological SLC25A3 variants. To this end, we investigated the pathogenicity of a novel compound heterozygous mutation in SLC25A3. First, each variant was modeled in yeast, revealing that substituting GSSAS for QIP within the fifth matrix loop is incompatible with survival on non-fermentable substrate, whereas the L200W variant is functionally neutral. Next, using skin fibroblasts from an individual expressing these variants and HeLa cells with varying degrees of PiC depletion, PiC loss of ϳ60% was still compatible with uncompromised maximal oxidative phosphorylation (oxphos), whereas lower maximal oxphos was evident at ϳ85% PiC depletion. Furthermore, intact mutant fibroblasts displayed suppressed mitochondrial bioenergetics consistent with a lower substrate availability rather than phosphate limitation. This was accompanied by slowed proliferation in glucose-replete medium; however, proliferation ceased when only mitochondrial substrate was provided. Both mutant fibroblasts and HeLa cells with 60% PiC loss showed a less interconnected mitochondrial network and a mitochondrial fusion defect that is not explained by altered abundance of OPA1 or MFN1/2 or relative amount of different OPA1 forms. Altogether these results indicate that PiC depletion may need to be profound (>85%) to substantially affect maximal oxphos and that pathogenesis associated with PiC depletion or loss of function may be independent of phosphate limitation when ATP requirements are not high.

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Association of Genetic Variant at Chromosome 12q23.1 With Neuropathic Pain Susceptibility

et al. 2021

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Key Points Question Are genetic variants associated with neuropathic pain (NP) susceptibility? Findings This genetic association study included a meta-analysis of 3 genome-wide association studies, with 4512 individuals with NP and 428 489 without, all with European descent, and identified a novel genome-wide significant locus at chromosome 12q23.1 near SLC25A3 and a suggestive locus at chromosome 13q14.2 near CAB39L . These mitochondrial phosphate carriers and calcium binding genes are expressed in tissues associated with the generation of NP, including the brain and dorsal root ganglia. Meaning These findings may provide a better understanding of genetic predisposition to NP, and this may inform the development of new treatment strategies.

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Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis

Cited by 34 publications

References 9 publications

The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

Natural and Induced Mitochondrial Phosphate Carrier Loss

Association of Genetic Variant at Chromosome 12q23.1 With Neuropathic Pain Susceptibility

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