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Background: Globally, the most common form of arrhythmias is atrial fibrillation (AF), which causes severe morbidity, mortality, and socioeconomic burden. The application of machine learning algorithms in combination with weighted gene co-expression network analysis (WGCNA) can be used to screen genes, therefore, we aimed to screen for potential biomarkers associated with AF development using this integrated bioinformatics approach. Methods: On the basis of the AF endocardium gene expression profiles GSE79768 and GSE115574 from the Gene Expression Omnibus database, differentially expressed genes (DEGs) between AF and sinus rhythm samples were identified. DEGs enrichment analysis and transcription factor screening were then performed. Hub genes for AF were screened using WGCNA and machine learning algorithms, and the diagnostic accuracy was assessed by the receiver operating characteristic (ROC) curves. GSE41177 was used as the validation set for verification. Subsequently, we identified the specific signaling pathways in which the key biomarkers were involved, using gene set enrichment analysis and reverse prediction of mRNA-miRNA interaction pairs. Finally, we explored the associations between the hub genes and immune microenvironment and immune regulation. Results: Fifty-seven DEGs were identified, and the two hub genes, hypoxia inducible factor 1 subunit alpha inhibitor (HIF1AN) and mitochondrial inner membrane protein MPV17 (MPV17), were screened using WGCNA combined with machine learning algorithms. The areas under the receiver operating characteristic curves for MPV17 and HIF1AN validated that two genes predicted AF development, and the differential expression of the hub genes was verified in the external validation dataset. Enrichment analysis showed that MPV17 and HIF1AN affect mitochondrial dysfunction, oxidative stress, gap junctions, and other signaling pathway functions. Immune cell infiltration and immunomodulatory correlation analyses showed that MPV17 and HIF1AN are strongly correlated with the content of immune cells and significantly correlated with HLA expression. Conclusion: The identification of hub genes associated with AF using WGCNA combined with machine learning algorithms and their correlation with immune cells and immune gene expression can elucidate the molecular mechanisms underlying AF occurrence. This may further identify more accurate and effective biomarkers and therapeutic targets for the diagnosis and treatment of AF. [ABSTRACT FROM AUTHOR]

Charcot–Marie–Tooth disease (CMT) and autosomal recessive spastic ataxia of Charlevoix–Saguenay type (ARSACS) are large heterogeneous groups of sensory, neurological genetic disorders characterized by sensory neuropathies, muscular atrophies, abnormal sensory conduction velocities, and ataxia. CMT2EE (OMIM: 618400) is caused by mutations in MPV17 (OMIM: 137960), CMT4F (OMIM: 614895) is caused by PRX (OMIM: 605725), CMTX1 (OMIM: 302800) is caused by mutations in GJB1 (OMIM: 304040), and ARSACS (OMIM: 270550) is caused by mutations in SACS (OMIM: 604490). In this study, we enrolled four families: DG-01, BD-06, MR-01, and ICP-RD11, with 16 affected individuals, for clinical and molecular diagnoses. One patient from each family was analyzed for whole exome sequencing and Sanger sequencing was done for the rest of the family members. Affected individuals of families BD-06 and MR-01 show complete CMT phenotypes and family ICP-RD11 shows ARSACS type. Family DG-01 shows complete phenotypes for both CMT and ARSACS types. The affected individuals have walking difficulties, ataxia, distal limb weakness, axonal sensorimotor neuropathies, delayed motor development, pes cavus, and speech articulations with minor variations. The WES analysis in an indexed patient of family DG-01 identified two novel variants: c.83G>T (p.Gly28Val) in MPV17 and c.4934G>C (p.Arg1645Pro) in SACS. In family ICP-RD11, a recurrent mutation that causes ARSACS, c.262C>T (p.Arg88Ter) in SACS, was identified. Another novel variant, c.231C>A (p.Arg77Ter) in PRX, which causes CMT4F, was identified in family BD-06. In family MR-01, a hemizygous missense variant c.61G>C (p.Gly21Arg) in GJB1 was identified in the indexed patient. To the best of our knowledge, there are very few reports on MPV17, SACS, PRX, and GJB1 causing CMT and ARSACS phenotypes in the Pakistani population. Our study cohort suggests that whole exome sequencing can be a useful tool in diagnosing complex multigenic and phenotypically overlapping genetic disorders such as Charcot–Marie–Tooth disease (CMT) and spastic ataxia of Charlevoix–Saguenay type. [ABSTRACT FROM AUTHOR]

Background: MPV17‐related mitochondrial DNA maintenance defect (MPV17 deficiency) is a rare, autosomal recessive mitochondrial DNA depletion syndrome with a high mortality rate in infancy and early childhood due to progression to liver failure. Liver transplantation for children with MPV17 deficiency has been considered controversial due to uncertainty about the potential progression of extrahepatic manifestations following liver transplantation. Methods: We describe our institution's experience for two infants diagnosed with infantile MPV17 deficiency who presented in acute on chronic liver failure, but with normal development and normal neurological status who successfully underwent liver transplantation. Results: Both patients underwent successful liver transplantation with normal development and neurological status at 3 years and 16 months post‐transplant, respectively. Conclusions: In this rare disease population, we describe two infants with MPV17 deficiency who underwent liver transplantation for acute on chronic liver failure who continue to have normal development, without progression of neurological disease. MPV17 deficiency should not be considered a contraindication to liver transplantation. [ABSTRACT FROM AUTHOR]

Charcot–Marie–Tooth disease (CMT) and autosomal recessive spastic ataxia of Charlevoix–Saguenay type (ARSACS) are large heterogeneous groups of sensory, neurological genetic disorders characterized by sensory neuropathies, muscular atrophies, abnormal sensory conduction velocities, and ataxia. CMT2EE (OMIM: 618400) is caused by mutations in MPV17 (OMIM: 137960), CMT4F (OMIM: 614895) is caused by PRX (OMIM: 605725), CMTX1 (OMIM: 302800) is caused by mutations in GJB1 (OMIM: 304040), and ARSACS (OMIM: 270550) is caused by mutations in SACS (OMIM: 604490). In this study, we enrolled four families: DG-01, BD-06, MR-01, and ICP-RD11, with 16 affected individuals, for clinical and molecular diagnoses. One patient from each family was analyzed for whole exome sequencing and Sanger sequencing was done for the rest of the family members. Affected individuals of families BD-06 and MR-01 show complete CMT phenotypes and family ICP-RD11 shows ARSACS type. Family DG-01 shows complete phenotypes for both CMT and ARSACS types. The affected individuals have walking difficulties, ataxia, distal limb weakness, axonal sensorimotor neuropathies, delayed motor development, pes cavus, and speech articulations with minor variations. The WES analysis in an indexed patient of family DG-01 identified two novel variants: c.83G>T (p.Gly28Val) in MPV17 and c.4934G>C (p.Arg1645Pro) in SACS. In family ICP-RD11, a recurrent mutation that causes ARSACS, c.262C>T (p.Arg88Ter) in SACS, was identified. Another novel variant, c.231C>A (p.Arg77Ter) in PRX, which causes CMT4F, was identified in family BD-06. In family MR-01, a hemizygous missense variant c.61G>C (p.Gly21Arg) in GJB1 was identified in the indexed patient. To the best of our knowledge, there are very few reports on MPV17, SACS, PRX, and GJB1 causing CMT and ARSACS phenotypes in the Pakistani population. Our study cohort suggests that whole exome sequencing can be a useful tool in diagnosing complex multigenic and phenotypically overlapping genetic disorders such as Charcot–Marie–Tooth disease (CMT) and spastic ataxia of Charlevoix–Saguenay type.

Abstract Background Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan. Results We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 18 of 23 patients: MPV17 (n = 13), DGUOK (n = 3), POLG (n = 1), and MICOS13 (n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive (n = 13, 56.5%). The most frequent liver symptom was cholestasis (n = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G > A or c.293C > T. Conclusions MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboring MPV17 mutations associated with mild phenotypes such as c.149G > A or c.293C > T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.

Abstract Background Mitochondrial DNA depletion syndromes (MDS) are clinically and phenotypically heterogeneous disorders resulting from nuclear gene mutations. The affected individuals represent a notable reduction in mitochondrial DNA (mtDNA) content, which leads to malfunction of the components of the respiratory chain. MDS is classified according to the type of affected tissue; the most common type is hepatocerebral form, which is attributed to mutations in nuclear genes such as DGUOK and MPV17. These two genes encode mitochondrial proteins and play major roles in mtDNA synthesis. Case presentation In this investigation patients in three families affected by hepatocerebral form of MDS who were initially diagnosed with tyrosinemia underwent full clinical evaluation. Furthermore, the causative mutations were identified using next generation sequencing and were subsequently validated using sanger sequencing. The effect of the mutations on the gene expression was also studied using real-time PCR. A pathogenic heterozygous frameshift deletion mutation in DGUOK gene was identified in parents of two affected patients (c.706–707 + 2 del: p.k236 fs) presenting with jaundice, impaired fetal growth, low-birth weight, and failure to thrive who died at the age of 3 and 6 months in family I. Moreover, a novel splice site mutation in MPV17 gene (c.461 + 1G > C) was identified in a patient with jaundice, muscle weakness, and failure to thrive who died due to hepatic failure at the age of 4 months. A 5-month-old infant presenting with jaundice, dark urine, poor sucking, and feeding problems was also identified to have another novel mutation in MPV17 gene leading to stop gain mutation (c.277C > T: p.(Gln93*)). Conclusions These patients had overlapping clinical features with tyrosinemia. MDS should be considered a differential diagnosis in patients presenting with signs and symptoms of tyrosinemia.

Noise exposure is particularly stressful to hair-cell mitochondria, which must produce enough energy to meet high metabolic demands as well as regulate local intracellular Ca2+ concentrations. Mitochondrial Inner Membrane Protein 17 (Mpv17) functions as a non-selective cation channel and plays a role in maintaining mitochondrial homeostasis. In zebrafish, hair cells in mpv17a9/a9 mutants displayed elevated levels of reactive oxygen species (ROS), elevated mitochondrial calcium, hyperpolarized transmembrane potential, and greater vulnerability to neomycin, indicating impaired mitochondrial function. Using a strong water current to overstimulate hair cells in the zebrafish lateral line, we observed mpv17a9/a9 mutant hair cells were more vulnerable to morphological disruption than wild type (WT) siblings simultaneously exposed to the same stimulus. To determine the role of mitochondrial homeostasis on hair-cell synapse integrity, we surveyed synapse number in mpv17a9/a9 mutants and WT siblings as well as the sizes of presynaptic dense bodies (ribbons) and postsynaptic densities immediately following stimulus exposure. We observed mechanically injured mpv17a9/a9 neuromasts were not more vulnerable to synapse loss; they lost a similar number of synapses per hair cell relative to WT. Additionally, we quantified the size of hair cell pre- and postsynaptic structures following stimulation and observed significantly enlarged WT postsynaptic densities, yet relatively little change in the size of mpv17a9/a9 postsynaptic densities following stimulation. These results suggest chronically impaired hair-cell mitochondrial activity influences postsynaptic size under homeostatic conditions but does not exacerbate synapse loss following mechanical injury. [ABSTRACT FROM AUTHOR]

Noise exposure is particularly stressful to hair-cell mitochondria, which must produce enough energy to meet high metabolic demands as well as regulate local intracellular Ca2+ concentrations. Mitochondrial Inner Membrane Protein 17 (Mpv17) functions as a non-selective cation channel and plays a role in maintaining mitochondrial homeostasis. In zebrafish, hair cells in mpv17a9/a9 mutants displayed elevated levels of reactive oxygen species (ROS), elevated mitochondrial calcium, hyperpolarized transmembrane potential, and greater vulnerability to neomycin, indicating impaired mitochondrial function. Using a strong water current to overstimulate hair cells in the zebrafish lateral line, we observed mpv17a9/a9 mutant hair cells were more vulnerable to morphological disruption than wild type (WT) siblings simultaneously exposed to the same stimulus. To determine the role of mitochondrial homeostasis on hair-cell synapse integrity, we surveyed synapse number in mpv17a9/a9 mutants and WT siblings as well as the sizes of presynaptic dense bodies (ribbons) and postsynaptic densities immediately following stimulus exposure. We observed mechanically injured mpv17a9/a9 neuromasts were not more vulnerable to synapse loss; they lost a similar number of synapses per hair cell relative to WT. Additionally, we quantified the size of hair cell pre- and postsynaptic structures following stimulation and observed significantly enlarged WT postsynaptic densities, yet relatively little change in the size of mpv17a9/a9 postsynaptic densities following stimulation. These results suggest chronically impaired hair-cell mitochondrial activity influences postsynaptic size under homeostatic conditions but does not exacerbate synapse loss following mechanical injury.

Mitochondrial DNA depletion consisting of the systemic reduction of mtDNA copy number in cells may have a heterogenous genetic basis, resulting from a pathogenic change in the nuclear genes involved in mtDNA synthesis. The mode of inheritance is autosomal recessive. Severe hepatocerebral disease represents one of many different clinical forms of so-called mitochondrial depletion syndrome (MDS). We present the liver histopathology of 13 children who eventually died in the course of hepatocerebral MDS confirmed molecularly, harbouring mutations of DGUOK , MPV17 , and POLG genes. Material comprising eight autopsy and five liver biopsy specimens showed a moderately reproducible pattern of parenchymal damage, which we consider potentially helpful in the differential diagnosis and planning of the diagnostic investigation in families of children who died due to early-onset acute liver failure and encephalopathy.

Background: Globally, the most common form of arrhythmias is atrial fibrillation (AF), which causes severe morbidity, mortality, and socioeconomic burden. The application of machine learning algorithms in combination with weighted gene co-expression network analysis (WGCNA) can be used to screen genes, therefore, we aimed to screen for potential biomarkers associated with AF development using this integrated bioinformatics approach. Methods: On the basis of the AF endocardium gene expression profiles GSE79768 and GSE115574 from the Gene Expression Omnibus database, differentially expressed genes (DEGs) between AF and sinus rhythm samples were identified. DEGs enrichment analysis and transcription factor screening were then performed. Hub genes for AF were screened using WGCNA and machine learning algorithms, and the diagnostic accuracy was assessed by the receiver operating characteristic (ROC) curves. GSE41177 was used as the validation set for verification. Subsequently, we identified the specific signaling pathways in which the key biomarkers were involved, using gene set enrichment analysis and reverse prediction of mRNA-miRNA interaction pairs. Finally, we explored the associations between the hub genes and immune microenvironment and immune regulation. Results: Fifty-seven DEGs were identified, and the two hub genes, hypoxia inducible factor 1 subunit alpha inhibitor ( HIF1AN ) and mitochondrial inner membrane protein MPV17 ( MPV17 ), were screened using WGCNA combined with machine learning algorithms. The areas under the receiver operating characteristic curves for MPV17 and HIF1AN validated that two genes predicted AF development, and the differential expression of the hub genes was verified in the external validation dataset. Enrichment analysis showed that MPV17 and HIF1AN affect mitochondrial dysfunction, oxidative stress, gap junctions, and other signaling pathway functions. Immune cell infiltration and immunomodulatory correlation analyses showed that MPV17 and HIF1AN are strongly correlated with the content of immune cells and significantly correlated with HLA expression. Conclusion: The identification of hub genes associated with AF using WGCNA combined with machine learning algorithms and their correlation with immune cells and immune gene expression can elucidate the molecular mechanisms underlying AF occurrence. This may further identify more accurate and effective biomarkers and therapeutic targets for the diagnosis and treatment of AF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tong and Sun.)

Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases, characterized by a reduction of the number of copies of mitochondrial DNA (mtDNA) in affected tissues. In the context of MDS, yeast has proved to be both an excellent model for the study of the mechanisms underlying mitochondrial pathologies and for the discovery of new therapies via high-throughput assays. Among the several genes involved in MDS, it has been shown that recessive mutations in MPV17 cause a hepatocerebral form of MDS and Navajo neurohepatopathy. MPV17 encodes a non selective channel in the inner mitochondrial membrane, but its physiological role and the nature of its cargo remains elusive. In this study we identify ten drugs active against MPV17 disorder, modelled in yeast using the homologous gene SYM1. All ten of the identified molecules cause a concomitant increase of both the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool and mtDNA stability, which suggests that the reduced availability of DNA synthesis precursors is the cause for the mtDNA deletion and depletion associated with Sym1 deficiency. We finally evaluated the effect of these molecules on mtDNA stability in two other MDS yeast models, extending the potential use of these drugs to a wider range of MDS patients.

Background: Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan.Results: We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 18 of 23 patients: MPV17 (n = 13), DGUOK (n = 3), POLG (n = 1), and MICOS13 (n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive (n = 13, 56.5%). The most frequent liver symptom was cholestasis (n = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G > A or c.293C > T.Conclusions: MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboring MPV17 mutations associated with mild phenotypes such as c.149G > A or c.293C > T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT. [ABSTRACT FROM AUTHOR]

Keywords: MPV17; navajo neurohepatopathy; neurologic outcomes; pediatric liver transplant EN MPV17 navajo neurohepatopathy neurologic outcomes pediatric liver transplant 1 2 2 04/20/23 20230501 NES 230501 We respond with respect to our colleagues Holve and Hu[1] and their decades long experience caring for children on the Navajo Nation. I When faced with a child with MPV17 deficiency in liver failure who faces imminent death without transplantation, our approach has been to offer transplant with direct counseling to families: that liver transplantation does not prevent phenotypically variable neurologic manifestations i . The authors primary concern focuses on long-term neurologic outcomes for four children with MPV17 deficiency (MPV17-related mitochondrial DNA maintenance defect) following liver transplantation. [Extracted from the article]

MPV17 encodes a putative channel‐forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations were first reported in patients with Navajo neurohepatopathy, an autosomal recessive mitochondrial DNA depletion syndrome, characterized by early‐onset liver failure, failure to thrive as well as central and peripheral neurological involvement. Recently, two patients with juvenile‐onset peripheral sensorimotor neuropathy associated with an MVP17 c.122G>A (p.Arg41Gln) variant have been reported. Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants. Patients of the first family carried the known c.122G>A variant and affected individuals of the second family had a novel c.376‐9T>G near‐splice variant, which was shown to result in an in‐frame deletion of 11 amino acids. This report provides further evidence that MPV17 mutations should be considered in patients with pure, non‐syndromic axonal neuropathy. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA depletion syndromes (MDS) are often serious autosomal recessively inherited disorders characterized by tissue-specific mtDNA copy number reduction. Many genes, including MPV17, are associated with the hepatocerebral form of MDS. MPV17 encodes for a mitochondrial inner membrane protein with a poorly characterized function. Several MPV17 mutations have been reported in association with a heterogeneous group of early-onset manifestations, including liver disease and neurological problems. Mpv17-deficient mice present renal and hearing defects. We describe here a MPV17 truncation mutation in dogs. We found a 1-bp insertion in exon 4 of the MPV17 gene, resulting in a frameshift and early truncation of the encoded protein. The mutation halves MPV17 expression in the lymphocytes of the homozygous dogs and the truncated protein is not translated in transfected cells. The insertion mutation is recurrent and exists in many unrelated breeds, although is highly enriched in the Boxer breed. Unexpectedly, despite the truncation of MPV17, we could not find any common phenotypes in the genetically affected dogs. The lack of observable phenotype could be due to a late onset, mild symptoms or potential tissue-specific compensatory mechanisms. This study suggests species-specific differences in the manifestation of the MPV17 defects and establishes a novel large animal model to further study MPV17 function and role in mitochondrial biology.

MPV17 is a mitochondrial inner membrane protein, and its deficiency can cause mitochondrial DNA (mtDNA) depletion, increase reactive oxygen species (ROS), and promote apoptosis in several cell types, suggesting that MPV17 plays a protective role in cells although the underlying mechanism remains unknown. To test whether MPV17 is also protective in diabetic kidney disease, we treated Mpv17-deficient mice with streptozotocin (STZ) and surprisingly found that they were resistant to diabetes. Mpv17 deficiency was also found to confer resistance to the diabetes induced by an insulin mutation (Ins2Akita), which represents a mouse model of monogenic diabetes characterized by proinsulin misfolding and β-cell failure. In both STZ and Ins2Akita models, Mpv17 mutants had significantly less severe β-cell loss and apoptosis compared with the wild-type mice. We next showed that MPV17 is expressed in β-cells of mice normally, suggesting that MPV17 acts β-cells autonomously to facilitate apoptosis. Consistently, Mpv17 knockdown improved the viability and ameliorated the apoptosis of cultured MIN6 cells treated with STZ and palmitic acid (PA), respectively, accompanied by prevention of caspase 3 activation. The proapoptotic effect of MPV17 in β-cells is in contrast with its known anti-apoptotic effect in other cell types. Thus, we have identified a novel regulator of β-cell death in diabetes development., (© 2023 The Author(s).)

Mitochondrial DNA depletion consisting of the systemic reduction of mtDNA copy number in cells may have a heterogenous genetic basis, resulting from a pathogenic change in the nuclear genes involved in mtDNA synthesis. The mode of inheritance is autosomal recessive. Severe hepatocerebral disease represents one of many different clinical forms of so-called mitochondrial depletion syndrome (MDS). We present the liver histopathology of 13 children who eventually died in the course of hepatocerebral MDS confirmed molecularly, harbouring mutations of DGUOK, MPV17, and POLG genes. Material comprising eight autopsy and five liver biopsy specimens showed a moderately reproducible pattern of parenchymal damage, which we consider potentially helpful in the differential diagnosis and planning of the diagnostic investigation in families of children who died due to early-onset acute liver failure and encephalopathy. [ABSTRACT FROM AUTHOR]

MPV17‐related mitochondrial neurohepatopathy is a rare genetic disorder worldwide. We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non‐consanguineous Black South African heritage. Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in 2 unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122‐1/38) with an estimated newborn incidence of 1 in 18 496 (95% CI; 1/59 536‐1/5776). Affected infants all presented with infantile onset neurohepatopathy with none surviving beyond infancy. This description of a relatively common pathogenic variant underlying a previously uncharacterized severe neurohepatopathy in South Africa will engender increased awareness, earlier diagnosis and possibly improve outcome if preventative or specific therapeutic options can be found. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile‐onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17‐related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early‐onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late‐onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis. [ABSTRACT FROM AUTHOR]

MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MDS) is a very rare condition, and only a few cases have been reported in East Asian countries. Here, we describe four Korean children affected by hepatocerebral MDS. The DGUOK, POLG1, and MPV17 genes were analyzed, and all patients had MPV17 mutations.

Summary In the skin of adult zebrafish, three pigment cell types arrange into alternating horizontal stripes, melanophores in dark stripes, xanthophores in light interstripes and iridophores in both stripes and interstripes. The analysis of mutants and regeneration studies revealed that this pattern depends on interactions between melanophores and xanthophores; however, the role of iridophores in this process is less understood. We describe the adult viable and fertile mutant transparent (tra), which shows a loss or strong reduction of iridophores throughout larval and adult stages. In addition, in adults only the number of melanophores is strongly reduced, and stripes break up into spots. Stripes in the fins are normal. By cell transplantations we show that tra acts cell-autonomously in iridophores, whereas the reduction in melanophores in the body occurs secondarily as a consequence of iridophore loss. We conclude that differentiated iridophores are required for the accumulation and maintenance of melanophores during pigment pattern formation. The tra mutant phenotype is caused by a small deletion in mpv17, an ubiquituously expressed gene whose protein product, like its mammalian and yeast homologs, localizes to mitochondria. Iridophore death might be the result of mitochondrial dysfunction, consistent with the mitochondrial DNA depletion syndrome observed in mammalian mpv17 mutants. The specificity of the tra phenotype is most likely due to redundancy after gene multiplication, making this mutant a valuable model to understand the molecular function of Mpv17 in mitochondria.

Mitochondrial DNA depletion syndromes (MDSs) are autosomal recessive diseases characterized by a severe decrease in mitochondrial DNA content leading to dysfunction of the affected organ. Autosomal recessive mutations in MPV17 have been identified in the hepatocerebral form of MDS. We describe the clinical features, biochemical and molecular results of a Saudi infant with a new mutation of MPV17 and compared the features to those of previously reported cases. We stress the importance of such rare cases particularly in countries with high consanguineous marriage rate.

Background: Mutations in MPV17 cause the autosomal recessive disorder mitochondrial DNA depletion syndrome 6 (MTDPS6), also called Navajo neurohepatopathy (NNH). Clinical features of MTDPS6 is infantile onset of progressive liver failure with seldom development of progressive neurologic involvement.Methods: Whole exome sequencing (WES) was performed to isolate the causative gene of two unrelated neuropathy patients (9 and 13 years of age) with onset of the syndrome. Clinical assessments and biochemical analysis were performed.Results: A novel homozygous mutation (p.R41Q) in MPV17 was found by WES in both patients. Both showed axonal sensorimotor polyneuropathy without liver and brain involvement, which is neurophysiologically similar to axonal Charcot-Marie-Tooth disease (CMT). A distal sural nerve biopsy showed an almost complete loss of the large and medium-sized myelinated fibers compatible with axonal neuropathy. An in vitro assay using mouse motor neuronal cells demonstrated that the abrogation of MPV17 significantly affected cell integrity. In addition, the expression of the mutant protein affected cell proliferation. These results imply that both the loss of normal function of MPV17 and the gain of detrimental effects of the mutant protein might affect neuronal function.Conclusion: We report a novel homozygous mutation in MPV17 from two unrelated patients harboring axonal sensorimotor polyneuropathy without hepatoencephalopathy. This report expands the clinical spectrum of diseases caused by mutations of MPV17, and we recommend MPV17 gene screening for axonal peripheral neuropathies. [ABSTRACT FROM AUTHOR]

The Mpv17 gene encodes a mitochondrial inner-membrane protein that has been implicated in several cell activities. Almost all studies have previously indicated that loss of function or gene-inactivated in Mpv17 can induce the development of disease. Here, we explored the roles of Mpv17 protein in the pathophysiology of intracerebral hemorrhage (ICH). An ICH rat model was established and assessed by behavioral tests. Using western blot and immunohistochemistry, significant up-regulation of Mpv17 was found in neurons in brain areas surrounding the hematoma following ICH. The increase of Mpv17 expression was found to be accompanied by the enhanced expression of p53, Bax, cytochrome c (Cyt c) and active caspase-3, and decreased expression of Bcl-2 in the pathological process of rat ICH. Furthermore, immunofluorescent staining revealed that Mpv17 co-localized with p53, Bax and active caspase-3 in neurons, suggesting its biological function in the process of neuronal apoptosis. Our in vitro study, using Mpv17 RNA interference in primary cortical neurons, indicated that Mpv17 might exert its anti-apoptotic function in neuronal apoptosis. Thus, Mpv17 may play a role in protecting the brain from secondary damage following ICH. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is increasingly recognized as contributing to glomerular diseases, including those secondary to mitochondrial DNA (mtDNA) mutations and deletions. Mitochondria maintain cellular redox and energy homeostasis and are a major source of intracellular reactive oxygen species (ROS) production. Mitochondrial ROS accumulation may contribute to stress-induced mitochondrial dysfunction and apoptosis and thereby to glomerulosclerosis. In mice, deletion of the gene encoding Mpv17 is associated with glomerulosclerosis, but the underlying mechanism remains poorly defined. Here we report that Mpv17 localizes to mitochondria of podocytes and its expression is reduced in several glomerular injury models and in human focal segmental glomerulosclerosis (FSGS) but not in minimal change disease. Using models of mild or severe nephrotoxic serum nephritis (NTSN) in Mpv17-/- wild-type (WT) and Mpv17+/+ knockout mice, we found that Mpv17 deficiency resulted in increased proteinuria (mild NTSN) and renal insufficiency (severe NTSN) compared with WT. These lesions were associated with increased mitochondrial ROS generation and mitochondrial injury such as oxidative DNA damage. In vitro, podocytes with loss of Mpv17 function were characterized by increased susceptibility to apoptosis and ROS injury including decreased mitochondrial function, loss of mtDNA content, and change in mitochondrial configuration. In summary, the inner mitochondrial membrane protein Mpv17 in podocytes is essential for the maintenance of mitochondrial homeostasis and protects podocytes against oxidative stress-induced injury both in vitro and in vivo. [ABSTRACT FROM AUTHOR]