Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations.

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76).

Beyond Val30Met transthyretin (TTR): variants associated with age-at-onset in hereditary ATTRv amyloidosis.

Objectives: V30M in transthyretin () gene is causative for hereditary ATTRv amyloidosis (familial amyloid polyneuropathy). ATTRv amyloidosis shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We aim at identifying genetic modifiers of disease onset that may contribute to this variability in Portuguese patients by identifying other variants in , beyond the ATTRv amyloidosis causing variant that could play a regulatory role in its expression level.

Antisense Transcription across Nucleotide Repeat Expansions in Neurodegenerative and Neuromuscular Diseases: Progress and Mysteries.

Unstable repeat expansions and insertions cause more than 30 neurodegenerative and neuromuscular diseases. Remarkably, bidirectional transcription of repeat expansions has been identified in at least 14 of these diseases. More remarkably, a growing number of studies has been showing that both sense and antisense repeat RNAs are able to dysregulate important cellular pathways, contributing together to the observed clinical phenotype.

Opportunistic genomic screening. Recommendations of the European Society of Human Genetics.

If genome sequencing is performed in health care, in theory the opportunity arises to take a further look at the data: opportunistic genomic screening (OGS). The European Society of Human Genetics (ESHG) in 2013 recommended that genome analysis should be restricted to the original health problem at least for the time being. Other organizations have argued that 'actionable' genetic variants should or could be reported (including American College of Medical Genetics and Genomics, French Society of Predictive and Personalized Medicine, Genomics England).

APOEɛ4-TOMM40L Haplotype Increases the Risk of Mild Cognitive Impairment Conversion to Alzheimer's Disease.

Background: Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer's disease (AD) conversion remain controversial.

Objective: Evaluate whether TOMM40 poly-T (TOMM40' 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype.

Methods: 147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism.

Going Deep into Synaptic Vesicle Machinery Genes and Migraine Susceptibility - A Case-Control Association Study.

Objective: A number of observations, including among our study population, have implicated variants in the syntaxin-1A, a component of the synaptic vesicles, in migraine susceptibility. Therefore, we hypothesize that variants in other components of the vesicle machinery are involved in migraine.

Background: Migraine is a common and complex neurologic disorder that affects approximately 15-18% of the general population.

Global Public Perceptions of Genomic Data Sharing: What Shapes the Willingness to Donate DNA and Health Data?

Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do not enable comparison.

VvERD6l13 is a grapevine sucrose transporter highly up-regulated in response to infection by Botrytis cinerea and Erysiphe necator.

The Early-Response to Dehydration six-like (ERD6l) is one of the largest families of sugar transporters in plants, however, is also one of the less studied with very few members characterized. In this work, we identified 18 members of the grapevine ERD6l family, analyzed their promoters and putative topology and additionally functionally characterized the member VvERD6l13. VvERD6l13 was strongly up-regulated in grape berries infected with Botrytis cinerea and Erysiphe necator in cv.

Shift of µ-opioid Receptor Signaling in the Dorsal Reticular Nucleus Is Implicated in Morphine-induced Hyperalgesia in Male Rats.

Background: Increased descending pain facilitation accounts for opioid-induced hyperalgesia, but the underlying mechanisms remain elusive. Given the role of µ-opioid receptors in opioid-induced hyperalgesia in animals, the authors hypothesized that the dorsal reticular nucleus, a medullary pain facilitatory area, is involved in opioid-induced hyperalgesia through altered µ-opioid receptor signaling.

Methods: The authors used male Wistar rats (n = 5 to 8 per group), chronically infused with morphine, to evaluate in the dorsal reticular nucleus the expressions of the µ-opioid receptor and phosphorylated cAMP response element-binding, a downstream marker of excitatory µ-opioid receptor signaling.

Web-based return of BRCA2 research results: one-year genetic counselling experience in Iceland.

There is an increased pressure to return results from research studies. In Iceland, deCODE Genetics has emphasised the importance of returning results to research participants, particularly the founder pathogenic BRCA2 variant; NM_000059.3:c.

A late-onset congenital myasthenic syndrome due to a heterozygous DOK7 mutation.

Congenital myasthenic syndromes are disorders of the neuromuscular junction resulting from genetic defects in its components. Clinical presentations are diverse and virtually always of early onset. We report a 67-year-old female patient first presenting with episodes of sudden respiratory failure.

Management of information within Portuguese families with Huntington disease: a transgenerational process for putting the puzzle together.

Huntington disease (HD) is a rare progressive neurological disease, with no cure, inherited in an autosomal dominant fashion, significantly impacting family relations, health and well-being. So far, no studies have reported how Portuguese families deal with information about HD, from a transgenerational perspective. This qualitative study aims to fill in that gap, and focuses on how families acquire knowledge about HD and management of information within the family and in their social relationships.

Novel Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype.

Homozygous variants in , encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in (c.

HOX genes function in Breast Cancer development.

Breast cancer develops in the mammary glands during mammalian adulthood and is considered the second most common type of human carcinoma and the most incident and mortal in the female population. In contrast to other human structures, the female mammary glands continue to develop after birth, undergoing various modifications during pregnancy, lactation and involution under the regulation of hormones and transcription factors, including those encoded by the HOX clusters (A, B, C, and D). Interestingly, HOX gene deregulation is often associated to breast cancer development.

VvSWEET7 Is a Mono- and Disaccharide Transporter Up-Regulated in Response to Infection in Grape Berries.

The newly-identified SWEETs are high-capacity, low-affinity sugar transporters with important roles in numerous physiological mechanisms where sugar efflux is critical. SWEETs are desirable targets for manipulation by pathogens and their expression may be transcriptionally reprogrammed during infection. So far, few plant SWEET transporters have been functionally characterized, especially in grapevine.

Conversion of DNA Sequences: From a Transposable Element to a Tandem Repeat or to a Gene.

Eukaryotic genomes are rich in repetitive DNA sequences grouped in two classes regarding their genomic organization: tandem repeats and dispersed repeats. In tandem repeats, copies of a short DNA sequence are positioned one after another within the genome, while in dispersed repeats, these copies are randomly distributed. In this review we provide evidence that both tandem and dispersed repeats can have a similar organization, which leads us to suggest an update to their classification based on the sequence features, concretely regarding the presence or absence of retrotransposons/transposon specific domains.

Parkin truncating variants result in a loss-of-function phenotype.

Parkinson disease (PD) is the second most common neurodegenerative disorder. Most cases of PD are sporadic, while 5-10% have a known genetic basis. Variants in the PARK2 gene are the most frequent cause of autosomal recessive juvenile-onset PD.

European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death.

Sudden cardiac death (SCD) accounts for 10-20% of total mortality, i.e., one in five individuals will eventually die suddenly.

Yemenite-Jewish families with Machado-Joseph disease (MJD/SCA3) share a recent common ancestor.

In 1994, a kindred from Yemen was described as the first Jewish family with Machado-Joseph disease (MJD/SCA3), a dominant ataxia caused by the expansion of a (CAG) above 61 repeats, in ATXN3. MJD is spread worldwide due to an ancient variant of Asian origin (the Joseph lineage). A second, more recent, independent expansion arose in a distinct haplotype (Machado lineage); other possible origins are still under study.

Developing a national certification pathway for genetic counselors in Sweden-a short report.

There is no Master's level education for genetic counseling in Sweden, meaning that genetic counselor professionals have very different backgrounds. Hence, there is a need to harmonize the quality of genetic counseling and introduce standards for practice. The Swedish Society for Genetic Counselors and the Swedish Society of Medical Genetics and Genomics collaborated to determine professional requirements and a career pathway, defining three vocational levels within the genetic counselor profession.

Twenty Years of a Pre-Symptomatic Testing Protocol for Late-Onset Neurological Diseases in Portugal.

Introduction: The national protocol of genetic counselling and pre-symptomatic testing for late-onset neurological diseases began in Portugal in 1995. Initially, it was accessible only to adults at-risk for Machado-Joseph disease, but was later extended to other hereditary ataxias, to Huntington's disease and to familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene. The aim of this study was to describe the profile of the population seeking pre-symptomatic testing, while also reflecting on the experience of conducting the protocol of multidisciplinary sessions since 1996.

Structural Insights into the Development of Cycloguanil Derivatives as Pteridine-Reductase-1 Inhibitors.

Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of PTR1 (PTR1). A small library of cycloguanil derivatives was developed, resulting in and having IC values of 692 and 186 nM, respectively, toward PTR1.

Is the High Frequency of Machado-Joseph Disease in China Due to New Mutational Origins?

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia 3 or SCA3) is the most common dominant ataxia worldwide, with an overall average prevalence of 1-5/100,000. To this date, two major ancestral lineages have been found throughout the world. In China, the relative frequency of MJD among the SCAs reaches as high as 63%, however, little is known about its mutational origin in this country.

Inhalation of Bacterial Cellulose Nanofibrils Triggers an Inflammatory Response and Changes Lung Tissue Morphology of Mice.

In view of the growing industrial use of Bacterial cellulose (BC), and taking into account that it might become airborne and be inhaled after industrial processing, assessing its potential pulmonary toxic effects assumes high relevance. In this work, the murine model was used to assess the effects of exposure to respirable BC nanofibrils (nBC), obtained by disintegration of BC produced by . Murine bone marrow-derived macrophages (BMMΦ) were treated with different doses of nBC (0.