EEFSEC deficiency: A selenopathy with early-onset neurodegeneration.

Inborn errors of selenoprotein expression arise from deleterious variants in genes encoding selenoproteins or selenoprotein biosynthetic factors, some of which are associated with neurodegenerative disorders. This study shows that bi-allelic selenocysteine tRNA-specific eukaryotic elongation factor (EEFSEC) variants cause selenoprotein deficiency, leading to progressive neurodegeneration. EEFSEC deficiency, an autosomal recessive disorder, manifests with global developmental delay, progressive spasticity, ataxia, and seizures.

Clinical and genetic investigation of 14 families with various forms of short stature syndromes.

Skeletal dysplasias are a heterogeneous group of disorders presenting mild to lethal defects. Several factors, such as genetic, prenatal, and postnatal environmental may contribute to reduced growth. Fourteen families of Pakistani origin, presenting the syndromic form of short stature either in the autosomal recessive or autosomal dominant manner were clinically and genetically investigated to uncover the underlying genetic etiology.

Sequence Variants in the Underlying Non-Syndromic Split-Hand/Foot Malformation.

Introduction: Split hand and foot malformation (SHFM) or ectrodactyly is a rare limb deformity characterized by median cleft of the hand and foot with impaired or missing central rays. It can occur as an isolated anomaly or in association with abnormalities of other body parts.

Methods: After delineating the clinical features of two families (A-B), with non-syndromic SHFM, exome and Sanger sequencing were employed to search for the disease-causing variants.

Sequence Variants in and Underlying Syndactyly.

Introduction: Syndactyly is a common congenital limb malformation. It occurs due to embryological failure of digit separation during limb development. Syndactyly often runs in families with an incidence of about one out of every 2,500-3,000 live births.

The virus that devastated tourism: The impact of covid-19 on the housing market.

We study the causal impact of the negative shock on short-term rentals caused by covid-19 in the tourist-intensive city centre of Lisbon. Our difference-in-differences strategy uses a parish-level treatment relying on the pre-pandemic intensity of short-term rentals, using data between Q3 2018 and Q3 2020. The results suggest that landlords relocated properties into the long-term rental market, in which prices de-crease 4.

ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly.

The ATPase Family AAA Domain Containing 3A (ATAD3A), is a mitochondrial inner membrane protein conserved in metazoans. ATAD3A has been associated with several mitochondrial functions, including nucleoid organization, cholesterol metabolism, and mitochondrial translation. To address its primary role, we generated a neuronal-specific conditional knockout (Atad3 nKO) mouse model, which developed a severe encephalopathy by 5 months of age.

Regional and sectorial impacts of the Covid-19 crisis: Evidence from electronic payments.

We use novel and comprehensive monthly data on electronic payments, by municipality and sector, together with cash withdrawals, to study the impact of Covid-19 in Portugal. Our difference-in-differences event study identifies a causal decrease of 17 and 40 percentage points on the year-on-year growth rate of overall purchases in March and April 2020. We document a stronger impact of the crisis in more central and more urban municipalities, due to a combination of the sectorial of the local economy and the sharper confinement in these locations.

Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency.

Complex I (also known as NADH-ubiquinone oxidoreductase) deficiency is the most frequent mitochondrial disorder present in childhood. NADH-ubiquinone oxidoreductase iron-sulfur protein 3 (NDUFS3) is a catalytic subunit of the mitochondrial complex I; NDUFS3 is conserved from bacteria and essential for complex I function. Mutations affecting complex I, including in the Ndufs3 gene, cause fatal neurodegenerative diseases, such as Leigh syndrome.

Myopathy reversion in mice after restauration of mitochondrial complex I.

Myopathies are common manifestations of mitochondrial diseases. To investigate whether gene replacement can be used as an effective strategy to treat or cure mitochondrial myopathies, we have generated a complex I conditional knockout mouse model lacking NDUFS3 subunit in skeletal muscle. NDUFS3 protein levels were undetectable in muscle of 15-day-old smKO mice, and myopathy symptoms could be detected by 2 months of age, worsening over time.

Novel ATAD3A recessive mutation associated to fatal cerebellar hypoplasia with multiorgan involvement and mitochondrial structural abnormalities.

Lethal neonatal encephalopathies are heterogeneous congenital disorders that can be caused by mitochondrial dysfunction. Biallelic large deletions in the contiguous ATAD3B and ATAD3A genes, encoding mitochondrial inner membrane ATPases of unknown function, as well as compound heterozygous nonsense and missense mutations in the ATAD3A gene have been recently associated with fatal neonatal cerebellar hypoplasia. In this work, whole exome sequencing (WES) identified the novel homozygous variant c.

Ablation of Cytochrome c in Adult Forebrain Neurons Impairs Oxidative Phosphorylation Without Detectable Apoptosis.

Cytochrome c (Cyt c), a heme-containing mitochondrial protein, has a critical function in both respiration and apoptosis. Consistent with these vital functions, somatic Cyt c mouse knockout is embryonic lethal. In order to investigate the sensitivity of postnatal neurons to Cyt c depletion, we developed a neuron-specific conditional knockout model.

ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels.

Mutations in the mitochondrial inner membrane ATPase result in neurological syndromes in humans. In mice, the ubiquitous disruption of (also known as ) was embryonic lethal, but a skeletal muscle-specific conditional knockout (KO) was viable. At birth, ATAD3 muscle KO mice had normal weight, but from 2 months onwards they showed progressive motor-impaired coordination and weakness.

Overexpression of PGC-1α in aging muscle enhances a subset of young-like molecular patterns.

PGC-1α is a transcriptional co-activator known as the master regulator of mitochondrial biogenesis. Its control of metabolism has been suggested to exert critical influence in the aging process. We have aged mice overexpressing PGC-1α in skeletal muscle to determine whether the transcriptional changes reflected a pattern of expression observed in younger muscle.

Human COA3 Is an Oligomeric Highly Flexible Protein in Solution.

The assembly of the protein complex of cytochrome c oxidase (COX), which participates in the mitochondrial respiratory chain, requires a large number of accessory proteins (the so-called assembly factors). Human COX assembly factor 3 (hCOA3), also known as MITRAC12 or coiled-coil domain-containing protein 56 (CCDC56), interacts with the first subunit protein of COX to form its catalytic core and promotes its assemblage with the other units. Therefore, hCOA3 is involved in COX biogenesis in humans and can be exploited as a drug target in patients with mitochondrial dysfunctions.

Sustained AMPK activation improves muscle function in a mitochondrial myopathy mouse model by promoting muscle fiber regeneration.

Acute pharmacological activation of adenosine monophosphate (AMP)-kinase using 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICAR) has been shown to improve muscle mitochondrial function by increasing mitochondrial biogenesis. We asked whether prolonged AICAR treatment is beneficial in a mouse model of slowly progressing mitochondrial myopathy (Cox10-Mef2c-Cre), and whether the compensatory mechanism is indeed an increase in mitochondrial biogenesis. We treated the animals for 3 months and found that sustained AMP-dependent kinase activation improved cytochrome c oxidase activity, rescued the motor phenotype and delayed the onset of the myopathy.

Pioglitazone ameliorates the phenotype of a novel Parkinson's disease mouse model by reducing neuroinflammation.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The cause of the motor symptoms is the loss of dopaminergic neurons in the substantia nigra with consequent depletion of dopamine in the striatum. Although the etiology of PD is unknown, mitochondrial dysfunctions, including cytochrome c oxidase (Complex IV) impairment in dopaminergic neurons, have been associated with the disease's pathophysiology.

MitoTALEN: A General Approach to Reduce Mutant mtDNA Loads and Restore Oxidative Phosphorylation Function in Mitochondrial Diseases.

We have designed mitochondrially targeted transcription activator-like effector nucleases or mitoTALENs to cleave specific sequences in the mitochondrial DNA (mtDNA) with the goal of eliminating mtDNA carrying pathogenic point mutations. To test the generality of the approach, we designed mitoTALENs to target two relatively common pathogenic mtDNA point mutations associated with mitochondrial diseases: the m.8344A>G tRNA(Lys) gene mutation associated with myoclonic epilepsy with ragged red fibers (MERRF) and the m.

Mitochondrial Diseases Part I: mouse models of OXPHOS deficiencies caused by defects in respiratory complex subunits or assembly factors.

Mitochondrial disorders are the most common inborn errors of metabolism affecting the oxidative phosphorylation system (OXPHOS). Because of the poor knowledge of the pathogenic mechanisms, a cure for these disorders is still unavailable and all the treatments currently in use are supportive more than curative. Therefore, in the past decade a great variety of mouse models have been developed to assess the in vivo function of several mitochondrial proteins involved in human diseases.

Mitochondrial Diseases Part II: Mouse models of OXPHOS deficiencies caused by defects in regulatory factors and other components required for mitochondrial function.

Mitochondrial disorders are defined as defects that affect the oxidative phosphorylation system (OXPHOS). They are characterized by a heterogeneous array of clinical presentations due in part to a wide variety of factors required for proper function of the components of the OXPHOS system. There is no cure for these disorders owing to our poor knowledge of the pathogenic mechanisms of disease.

Mitochondrial Diseases Part III: Therapeutic interventions in mouse models of OXPHOS deficiencies.

Mitochondrial defects are the cause of numerous disorders affecting the oxidative phosphorylation system (OXPHOS) in humans leading predominantly to neurological and muscular degeneration. The molecular origin, manifestations, and progression of mitochondrial diseases have a broad spectrum, which makes very challenging to find a globally effective therapy. The study of the molecular mechanisms underlying the mitochondrial dysfunction indicates that there is a wide range of pathways, enzymes and molecules that can be potentially targeted for therapeutic purposes.

Partial complex I deficiency due to the CNS conditional ablation of Ndufa5 results in a mild chronic encephalopathy but no increase in oxidative damage.

Deficiencies in the complex I (CI; NADH-ubiquinone oxidoreductase) of the respiratory chain are frequent causes of mitochondrial diseases and have been associated with other neurodegenerative disorders, such as Parkinson's disease. The NADH-ubiquinone oxidoreductase 1 alpha subcomplex subunit 5 (NDUFA5) is a nuclear-encoded structural subunit of CI, located in the peripheral arm. We inactivated Ndufa5 in mice by the gene-trap methodology and found that this protein is required for embryonic survival.