scholarly journals Biallelic Mutations in MTPAP Associated with a Lethal Encephalopathy

2019 ◽  
Vol 51 (03) ◽  
pp. 178-184 ◽  
Author(s):  
Lien Van Eyck ◽  
Francesco Bruni ◽  
Anne Ronan ◽  
Tracy A. Briggs ◽  
Tony Roscioli ◽  
...  
Keyword(s):  
De Novo ◽  
Mitochondrial Gene ◽  
Mitochondrial Protein ◽  
Missense Variant ◽  
Mitochondrial Proteins ◽  
Compound Heterozygous ◽  
Altered Expression ◽  
Mitochondrial Transcripts ◽  
Biallelic Mutations ◽  
First Year Of Life

Abstract Background A homozygous founder mutation in MTPAP/TENT6, encoding mitochondrial poly(A) polymerase (MTPAP), was first reported in six individuals of Old Order Amish descent demonstrating an early-onset, progressive spastic ataxia with optic atrophy and learning difficulties. MTPAP contributes to the regulation of mitochondrial gene expression through the polyadenylation of mitochondrially encoded mRNAs. Mitochondrial mRNAs with severely truncated poly(A) tails were observed in affected individuals, and mitochondrial protein expression was altered. Objective To determine the genetic basis of a perinatal encephalopathy associated with stereotyped neuroimaging and infantile death in three patients from two unrelated families. Methods Whole-exome sequencing was performed in two unrelated patients and the unaffected parents of one of these individuals. Variants and familial segregation were confirmed by Sanger sequencing. Polyadenylation of mitochondrial transcripts and de novo synthesis of mitochondrial proteins were assessed in patient's fibroblasts. Results Compound heterozygous p.Ile428Thr and p.Arg523Trp substitutions in MTPAP were recorded in two affected siblings from one family, and a homozygous p.Ile385Phe missense variant identified in a further affected child from a second sibship. Mitochondrial poly(A) tail analysis demonstrated shorter posttranscriptional additions to the mitochondrial transcripts, as well as an altered expression of mitochondrial proteins in the fibroblasts of the two siblings compared with healthy controls. Conclusion Mutations in MTPAP likely cause an autosomal recessive perinatal encephalopathy with lethality in the first year of life.

scholarly journals Profiling subcellular localization of nuclear-encoded mitochondrial gene products in zebrafish

2021 ◽  
Author(s):  
Barbara Uszczynska-Ratajczak ◽  
Sreedevi Sugunan ◽  
Monika Kwiatkowska ◽  
Maciej Migdal ◽  
Silvia Carbonell-Sala ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Protein Import ◽  
Mitochondrial Gene ◽  
Mitochondrial Protein ◽  
Mitochondrial Fraction ◽  
Mitochondrial Proteins ◽  
Gene Products ◽  
Messenger Rnas ◽  
Mitochondrial Transcripts ◽  
Transcriptomic Changes

Most mitochondrial proteins are encoded by nuclear genes, synthetized in the cytosol and targeted into the organelle. The import of some, but not all, nuclear-encoded mitochondrial proteins begins with translation of messenger RNAs (mRNAs) on the surface of mitochondria. To characterize the spatial organization of mitochondrial gene products in zebrafish (Danio rerio), we sequenced RNA from different cellular fractions. Our results confirmed the presence of nuclear-encoded mRNAs in the mitochondrial fraction, which in unperturbed conditions, are mainly transcripts encoding large proteins with specific properties, like transmembrane domains. To further explore the principles of mitochondrial protein compartmentalization in zebrafish, we quantified the transcriptomic changes for each subcellular fraction triggered by the chchd4a-/- mutation, causing the disorders in the mitochondrial protein import. Our results indicate that the proteostatic stress further restricts the population of transcripts on the mitochondrial surface, allowing only the largest and the most evolutionary conserved proteins to be synthetized there. We also show that many nuclear-encoded mitochondrial transcripts translated by the cytosolic ribosomes stay resistant to the global translation shutdown. Thus, vertebrates, in contrast to yeast, are not likely to employ localized translation to facilitate synthesis of mitochondrial proteins under proteostatic stress conditions.

scholarly journals Genetic Study in a Cohort of Children With ROHHAD Syndrome

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A503-A504
Author(s):  
Grazia Iannello ◽  
Cecilia Sena ◽  
Lynn Pais ◽  
Ellie Seaby ◽  
Radha Sathanayagam ◽  
...  
Keyword(s):  
Severe Obesity ◽  
De Novo ◽  
Missense Variant ◽  
Rapid Onset ◽  
Compound Heterozygous ◽  
Extreme Obesity ◽  
Complex Phenotype ◽  
White Girl ◽  
Hypothalamic Dysfunction ◽  
Central Hypoventilation

Abstract Introduction: Rapid-onset obesity, hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) is a rare syndrome beginning at 3-6 years of age with approximately 150 cases described. Additional features include eye abnormalities, neurobehavioral dysfunction and paraneoplastic tumors. The etiology of the complex phenotype remains unknown. Methods: This study aims to investigate the genetic landscape of this complex phenotype by whole exome sequencing (WES) and copy number variation (CNV) analysis. We recruited 33 families (27 trios, 1 duo and 5 singletons) with a proband with ROHHAD syndrome (Ize-Ludlow 2007, Pediatrics). WES of 89 individuals was performed at the Center for Mendelian Genomics, Broad Institute. The Illumina platform with a mean coverage of ~100X (> 90% targets 20x) and Infinium Global Screening Array BeadChip 24v1.0 were used. Results: This report includes 28 probands (female = 18, 64%) with rapid onset obesity (100%), hypoventilation (88%), hypothalamic dysfunction (69%), eye disorders (62%) and neurobehavioral abnormalities (76%). Neuroendocrine tumor, ganglioneuroblastoma, was present in 38% (n=13). No unifying causative single gene or CNV was identified, but a number of sequence variants are prioritized. ARNT2, which encodes for a helix-loop-helix transcription factor, plays a role in the development of the hypothalamic-pituitary axis, postnatal brain growth, and visual and renal function. The de novo monoallelic missense variant was found in a 14-year old white girl (BMIz +3.25) with extreme obesity and a neurobehavioral phenotype. OCRL1, a multi-domain protein involved in cytoskeleton-plasma membrane adhesion, endosomal trafficking and in primary cilium assembly. Mutations in this gene have also been known to cause Lowe syndrome. A hemizygous X-linked frameshift variant in a 5-year old white boy with extreme obesity (BMIz +5.48), central hypoventilation neurobehavioral dysfunction and ganglioneuroblastoma. A monoallelic missense variant in NSD1, a transcriptional intermediary factor acting as a histone methyltransferase, was identified in a 8-year old Hispanic girl with severe obesity (BMIz +2.91), neurobehavioral disorder, pituitary and eye dysfunction and ganglioneuroblastoma. NSD1 is known to cause Sotos and Beckwith-Wiedemann. Compound heterozygous variants in KIF7, a key component of the Hedgehog signaling pathway, were identified in a 14-year old white girl with severe obesity (BMIz +3.00), autistic behavior, pituitary dysfunction and central hypoventilation. This gene is known to cause autosomal recessive hydrolethalis and acroscallosal syndromes with mutations also noted in Bardet-Biedl, Meckel and Joubert syndromes. Conclusion: While no unifying genetic cause has been identified in ROHHAD syndrome, it is possible that the phenotype represents a collection of complex genetic syndromes.

Translational inhibitors as potential therapeutic tool of human neuroblastoma through mitochondrial gene expression

2017 ◽  
Vol 41 (S1) ◽  
pp. S464-S464
Author(s):  
S. Hina
Keyword(s):  
Gene Expression ◽  
Oxidative Phosphorylation ◽  
Neuroendocrine Tumour ◽  
Mitochondrial Gene ◽  
Mitochondrial Protein ◽  
Genetic Material ◽  
Neuronal Cell ◽  
Mitochondrial Proteins ◽  
Mitochondrial Gene Expression ◽  
Human Neuroblastoma

Neuroblastoma is a solid neuroendocrine tumour and most common type of cancer of infancy. It is a complex heterogeneous disease and many factors such as molecular, cellular and genetic features are involved in its development. Mitochondria play a pivotal role in neuronal cell survival or death. Neurons are highly reliant on aerobic oxidative phosphorylation (OXPHOS) for their energy needs. Defective activities of mitochondrial complexes I, II, III and IV have been identified in many neurological and neurodegenerative diseases. Human mitochondria with its own genetic material meet the needs required for the assembly of subunits of the oxidative phosphorylation (OXPHOS) complexes. A number of translational inhibitors are known that could potentially effect translation of mitochondrial protein synthesis. Among these puromycin, homoharringtonine and cyclohexamide were selected for the present study. The effect of these translational inhibitors on mitochondrial gene expression for the treatment of neuroblastoma are not well established. Therefore, in this study, we have investigated the effects of these translational inhibitors on the expression of human mitochondrial gene expression in SH-SY5Y neuroblastoma cells.We observed a significant effect on the level of mitochondrial transcripts upon exposure to these translation inhibitors in SH-SY5Y cells, however, the effects on expression of mitochondrial proteins were minimal. This suggests that translational inhibitors might not directly affect the abundance of mitochondrial proteins. Translational inhibitors induce significant effect on mitochondrial gene expression that can be lead to the new-targeted therapy for treating neuroblastoma.

scholarly journals C6orf203 controls OXPHOS function through modulation of mitochondrial protein biosynthesis

2019 ◽  
Author(s):  
Sara Palacios-Zambrano ◽  
Luis Vázquez-Fonseca ◽  
Cristina González-Páramos ◽  
Laura Mamblona ◽  
Laura Sánchez-Caballero ◽  
...  
Keyword(s):  
De Novo ◽  
Protein Biosynthesis ◽  
Mitochondrial Protein ◽  
Mitochondrial Respiratory Chain ◽  
Culture Conditions ◽  
Mitochondrial Proteins ◽  
Respiratory Chain Complexes ◽  
Central Function ◽  
Mitochondrial Dna Depletion

ABSTRACTMitochondria are essential organelles present in the vast majority of eukaryotic cells. Their central function is to produce cellular energy through the OXPHOS system, and functional alterations provoke so-called mitochondrial OXPHOS diseases. It is estimated that several hundred mitochondrial proteins have unknown functions. Very recently, C6orf203 was described to participate in mitochondrial transcription under induced mitochondrial DNA depletion stress conditions. Here, we describe another role for C6orf203, specifically in OXPHOS biogenesis under regular culture conditions. HEK293T C6orf203-Knockout (KO) cells generated by CRISPR/Cas9 genome editing showed both reduced grow in galactose, as a carbon source, and in their oxygen consumption capability, strongly suggesting an OXPHOS dysfunction. C6orf203-KO also provoked a depletion of OXPHOS proteins and decreased the activity of the mitochondrial respiratory chain complexes. C6orf203 was present in high molecular weight complexes compatible with mitoribosomes, and in vivo labelling of de novo mitochondrial proteins synthesis revealed that C6orf203-KO severely but not completely affected the translation of mitochondrial mRNAs. Taken together, we describe herein a new function for C6orf203, making it a potential OXPHOS disease-related candidate.

scholarly journals Quality control of mitochondrial protein synthesis is required for membrane integrity and cell fitness

2015 ◽  
Vol 211 (2) ◽  
pp. 373-389 ◽  
Author(s):  
Uwe Richter ◽  
Taina Lahtinen ◽  
Paula Marttinen ◽  
Fumi Suomi ◽  
Brendan J. Battersby
Keyword(s):  
Quality Control ◽  
Protein Synthesis ◽  
Oxidative Phosphorylation ◽  
De Novo ◽  
Mitochondrial Protein ◽  
Membrane Integrity ◽  
Mitochondrial Proteins ◽  
Protein Accumulation ◽  
Mitochondrial Protein Synthesis ◽  
Inner Membrane

Mitochondrial ribosomes synthesize a subset of hydrophobic proteins required for assembly of the oxidative phosphorylation complexes. This process requires temporal and spatial coordination and regulation, so quality control of mitochondrial protein synthesis is paramount to maintain proteostasis. We show how impaired turnover of de novo mitochondrial proteins leads to aberrant protein accumulation in the mitochondrial inner membrane. This creates a stress in the inner membrane that progressively dissipates the mitochondrial membrane potential, which in turn stalls mitochondrial protein synthesis and fragments the mitochondrial network. The mitochondrial m-AAA protease subunit AFG3L2 is critical to this surveillance mechanism that we propose acts as a sensor to couple the synthesis of mitochondrial proteins with organelle fitness, thus ensuring coordinated assembly of the oxidative phosphorylation complexes from two sets of ribosomes.

Thyroid Hormone-Induced Changes in Cytoplasmic and Mitochondrial Proteins of a Teleost

1998 ◽  
Vol 53 (1-2) ◽  
pp. 120-124 ◽  
Author(s):  
G. Tripathi
Keyword(s):  
Skeletal Muscle ◽  
Actinomycin D ◽  
De Novo ◽  
Mitochondrial Protein ◽  
Mitochondrial Proteins ◽  
Cytoplasmic Protein ◽  
Freshwater Teleost ◽  
Mitochondrial Fractions ◽  
Induced Changes ◽  
Induced Proteins

AbstractThe effect of triiodothyronine (T3) on the cytoplasmic and mitochondrial protein contents were studied in the liver and skeletal muscle of a freshwater teleost. The fish exposed to thiouracil for 28 days showed 1.5-2 times reduction in the total protein contents of cytoplasmic and mitochondrial fractions. A single injection of T3 to thiouracil exposed fish caused the earliest induction in the liver and skeletal muscle mitochondrial protein and the skeletal muscle cytoplasmic protein at 12 hr of lapses. However, the initial induction in the cytoplasmic protein of the liver was observed at 3 hr after T3 treatment. The maximum inductions (1.5-3.2 fold) in the cytoplasmic and mitochondrial proteins of the liver and skeletal muscle were obtained at 1 8 -2 4 hr following hormonal administration. Thereafter, the cytoplasmic and mitochondrial protein contents of both the tissues declined to their control levels within 3 6 - 4 8 hr of T3 injection which reflected the half-life and turnover period of the induced proteins. These T3 dependent inductions in the cytoplasmic and mitochondrial proteins of the liver (1 .4 -3 .2 fold) and skeletal muscle (1.8 -2.7 fold) were inhibited by actinomycin D and cycloheximide indicating T3-induced de novo synthesis of the proteins. The induction in the cytoplasmic protein (3 fold) was almost double to that of the mitochondrial protein (1.6 fold) suggesting more synthesis of protein molecules in the cytoplasm for cellular and subcellular activities.

scholarly journals Gitelman syndrome caused by a novel hemiallelic missense mutation in SLC12A3 revealed by 16q12.2q21 microdeletion

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Yuki Abe ◽  
Toshiyuki Yamamoto ◽  
Yukie Izumita ◽  
Shinya Tsukano
Keyword(s):  
Missense Mutation ◽  
Clinical Features ◽  
Autosomal Recessive ◽  
De Novo ◽  
Missense Variant ◽  
Gitelman Syndrome ◽  
Recessive Trait ◽  
Autosomal Recessive Trait ◽  
Biallelic Mutations

AbstractGitelman syndrome (GS) is caused by biallelic mutations in SLC12A3 as an autosomal recessive trait. A patient with a de novo 16q12.2q21 microdeletion showed clinical features of GS. SLC12A3 included in the deletion was analyzed, and a rare missense variant (c.1222A>C [p.N406H]) was identified as hemizygous. Consequently, GS was caused by the revealed SLC12A3 variant owing to chromosomal microdeletion.

scholarly journals Functional polypeptides can be synthesized from human mitochondrial transcripts lacking termination codons

2004 ◽  
Vol 377 (3) ◽  
pp. 725-731 ◽  
Author(s):  
Zofia M. A. CHRZANOWSKA-LIGHTOWLERS ◽  
Richard J. TEMPERLEY ◽  
Paul M. SMITH ◽  
Sara H. SENECA ◽  
Robert N. LIGHTOWLERS
Keyword(s):  
Steady State ◽  
Cell Lines ◽  
Atp Synthase ◽  
De Novo ◽  
Mitochondrial Protein ◽  
State Level ◽  
Termination Codon ◽  
Significant Difference ◽  
Mitochondrial Transcripts ◽  
A Minor

The human mitochondrial genome (mtDNA) is a small, circular DNA duplex found in multi-copy in the mitochondrial matrix. It is almost fully transcribed from both strands to produce large polycistronic RNA units that are processed and matured. The 13 mtDNA-encoded polypeptides are translated from mt-mRNAs that have been matured by polyadenylation of their free 3´-termini. A patient with clinical features consistent with an mtDNA disorder was recently shown to carry a microdeletion, resulting in the loss of the termination codon for MTATP6 and in its juxtaposition with MTCO3. Cell lines from this patient exhibited low steady-state levels of RNA14, the bi-cistronic transcript encoding subunits 6 and 8 of the FoF1-ATP synthase, complex V, consistent with a decreased stability. Recent reports of ‘non-stop’ mRNA decay systems in the cytosol have failed to determine the fate of gene products derived from transcripts lacking termination codons, although enhanced decay clearly required the ‘non-stop’ transcripts to be translated. We wished to determine whether functional translation products could still be expressed from non-stop transcripts in the human mitochondrion. Although a minor defect in complex V assembly was noted in the patient-derived cell lines, the steady-state level of ATPase 6 was similar to controls, consistent with the pattern of de novo mitochondrial protein synthesis. Moreover, no significant difference in ATP synthase activity could be detected. We conclude that, in the absence of a functional termination codon, although mitochondrial transcripts are more rapidly degraded, they are also translated to generate stable polypeptides that are successfully integrated into functional enzyme complexes.

Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia

2021 ◽  
Author(s):  
Yamato Ishida ◽  
Takuya Kobayashi ◽  
Shuhei Chiba ◽  
Yohei Katoh ◽  
Kazuhisa Nakayama
Keyword(s):  
Protein Trafficking ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Missense Variant ◽  
Cellular Level ◽  
Compound Heterozygous ◽  
Hypomorphic Allele ◽  
Genes Encoding ◽  
Specific Proteins ◽  
Compound Heterozygous Mutations

Abstract Primary cilia contain specific proteins to achieve their functions as cellular antennae. Ciliary protein trafficking is mediated by the intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes. Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140, and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED). We here characterized the molecular and cellular defects of CED caused by compound heterozygous mutations in IFT144 [the missense variant IFT144(L710S) and the nonsense variant IFT144(R1103*)]. These two variants were distinct with regard to their interactions with other IFT-A subunits and with the IFT-B complex. When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as well as IFT144(WT) rescued both moderately compromised ciliogenesis and the abnormal localization of ciliary proteins. As the homozygous IFT144(L710S) mutation was found to cause autosomal recessive retinitis pigmentosa, IFT144(L710S) is likely to be hypomorphic at the cellular level. In striking contrast, the exogenous expression of IFT144(R1103*) in IFT144-KO cells exacerbated the ciliogenesis defects. The expression of IFT144(R1103*) together with IFT144(WT) restored the abnormal phenotypes of IFT144-KO cells. However, the coexpression of IFT144(R1103*) with the hypomorphic IFT144(L710S) variant in IFT144-KO cells, which mimics the genotype of compound heterozygous CED patients, resulted in severe ciliogenesis defects. Taken together, these observations demonstrate that compound heterozygous mutations in IFT144 cause severe ciliary defects via a complicated mechanism, where one allele can cause severe ciliary defects when combined with a hypomorphic allele.

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