Modeling Lysosomal Storage Disorders in an Innovative Way: Establishment and Characterization of Stem Cell Lines from Human Exfoliated Deciduous Teeth of Mucopolysaccharidosis Type II Patients.

Among the many lysosomal storage disorders (LSDs) that would benefit from the establishment of novel cell models, either patient-derived or genetically engineered, is mucopolysaccharidosis type II (MPS II). Here, we present our results on the establishment and characterization of two MPS II patient-derived stem cell line(s) from deciduous baby teeth. To the best of our knowledge, this is the first time a stem cell population has been isolated from LSD patient samples obtained from the dental pulp.

Help Comes from Unexpected Places: How a Tiny Fairy and a Tropical Fish may help us Model Mucopolysaccharidoses.

Introduction: When it comes to disease modeling, countless models are available for Lysosomal Storage Diseases (LSD). Historically, two major approaches are well-established: in vitro assessments are performed in patient fibroblasts, while in vivo pre-clinical studies are performed in mouse models. Still, both platforms have a series of drawbacks.

A partial duplication of an X-linked gene exclusive of a primate lineage (Macaca).

Gene duplication plays a significant role in evolution. Paralogous gene copies may be lost due to the successive accumulation of deleterious mutations or remain active in the genome. In this work, a partial duplication of an X-linked region in the Macaca genus is identified and explored.

Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (Na 1.5).

Common genetic polymorphisms may modify the phenotypic outcome when co-occurring with a disease-causing variant, and therefore understanding their modulating role in health and disease is of great importance. The polymorphic p.His558Arg variant of the sodium voltage-gated channel alpha subunit 5 (Na 1.

Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example.

Over recent decades, the many functions of RNA have become more evident. This molecule has been recognized not only as a carrier of genetic information, but also as a specific and essential regulator of gene expression. Different RNA species have been identified and novel and exciting roles have been unveiled.

Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity.

Understanding the role of common polymorphisms in modulating the clinical phenotype when they co-occur with a disease-causing lesion is of critical importance in medical genetics. We explored the impact of apparently neutral common polymorphisms, using the gene encoding the urea cycle enzyme, ornithine transcarbamylase (OTC), as a model system. Distinct combinations of genetic backgrounds embracing two missense polymorphisms were created in cis with the pathogenic p.

Evolutionary dynamics of the human pseudoautosomal regions.

Recombination between the X and Y human sex chromosomes is limited to the two pseudoautosomal regions (PARs) that present quite distinct evolutionary origins. Despite the crucial importance for male meiosis, genetic diversity patterns and evolutionary dynamics of these regions are poorly understood. In the present study, we analyzed and compared the genetic diversity of the PAR regions using publicly available genomic sequences encompassing both PAR1 and PAR2.

Lysosomal Storage Disease-Associated Neuropathy: Targeting Stable Nucleic Acid Lipid Particle (SNALP)-Formulated siRNAs to the Brain as a Therapeutic Approach.

More than two thirds of Lysosomal Storage Diseases (LSDs) present central nervous system involvement. Nevertheless, only one of the currently approved therapies has an impact on neuropathology. Therefore, alternative approaches are under development, either addressing the underlying enzymatic defect or its downstream consequences.

Development of an Antisense Oligonucleotide-Mediated Exon Skipping Therapeutic Strategy for Mucolipidosis II: Validation at RNA Level.

Lysosomal storage disorders (LSDs) are a group of rare inherited metabolic diseases caused by the malfunction of the lysosomal system, which results in the accumulation of undergraded substrates inside the lysosomes and leads to severe and progressive pathology. Despite there currently being a broad understanding of the molecular defects behind LSDs, curative therapies have been approved for only few of these diseases, whereas existing treatments are still mostly symptomatic with several limitations. Mucolipidosis type II alpha/beta (ML II) is one of most severe LSDs, which is caused by the total deficiency of the GlcNAc-1-phosphotransferase, a key enzyme for the formation of specific targeting signals on lysosomal hydrolases to lysosomes.

Molecular Characterization of a Novel Splicing Mutation underlying Mucopolysaccharidosis (MPS) type VI-Indirect Proof of Principle on Its Pathogenicity.

Here, we present the molecular diagnosis of a patient with a general clinical suspicion of Mucopolysaccharidosis, highlighting the different tools used to perform its molecular characterization. In order to decrease the turnaround time for the final report and contribute to reduce the "diagnostic odyssey", which frequently afflicts affected families, the proband's sample was simultaneously screened for mutations in a number of lysosomal function-related genes with targeted next-generation sequencing (NGS) protocol. After variant calling, the most probable cause for disease was a novel intronic variant, c.

Unusual β-Globin Haplotype Distribution in Newborns from Bengo, Angola.

Mutations on the gene are a common cause of hemoglobinopathies, including sickle cell anemia, a severe genetic condition that constitutes a major public health concern. The aim of this study was to determine the prevalence of sickle cell anemia and β-globin haplotype distribution in newborns from the Bengo region. The first two exons of β-globin gene were sequenced, and the variability at the single nucleotide polymorphism (SNP) defining the Hb S (: c.

Genes from the TAS1R and TAS2R Families of Taste Receptors: Looking for Signatures of Their Adaptive Role in Human Evolution.

Taste perception is crucial in monitoring food intake and, hence, is thought to play a significant role in human evolution. To gain insights into possible adaptive signatures in genes encoding bitter, sweet, and umami taste receptors, we surveyed the available sequence variation data from the 1000 Genomes Project Phase 3 for TAS1R (TAS1R1-3) and TAS2R (TAS2R16 and TAS2R38) families. Our study demonstrated that genes from these two families have experienced contrasting evolutionary histories: While TAS1R1 and TAS1R3 showed worldwide evidence of positive selection, probably correlated with improved umami and sweet perception, the patterns of variation displayed by TAS2R16 and TAS2R38 were more consistent with scenarios of balancing selection that possibly conferred a heterozygous advantage associated with better capacity to perceive a wide range of bitter compounds.

The Eastern side of the Westernmost Europeans: Insights from subclades within Y-chromosome haplogroup J-M304.

Objectives: We examined internal lineages and haplotype diversity in Portuguese samples belonging to J-M304 to improve the spatial and temporal understanding of the introduction of this haplogroup in Iberia, using the available knowledge about the phylogeography of its main branches, J1-M267 and J2-M172.

Methods: A total of 110 males of Portuguese descent were analyzed for 17 Y-chromosome bi-allelic markers and seven Y-chromosome short tandem repeats (Y-STR) loci.

Results: Among J1-M267 individuals (n = 36), five different sub-haplogroups were identified, with the most common being J1a2b2-L147.

Solving a case of allelic dropout in the GNPTAB gene: implications in the molecular diagnosis of mucolipidosis type III alpha/beta.

While being well known that the diagnosis of many genetic disorders relies on a combination of clinical suspicion and confirmatory genetic testing, not rarely, however, genetic testing needs much perseverance and cunning strategies to identify the causative mutation(s). Here we present a case of a thorny molecular diagnosis of mucolipidosis type III alpha/beta, which is an autosomal recessive lysosomal storage disorder, caused by a defect in the GNPTAB gene that codes for the α/β-subunits of the GlcNAc-1-phosphotransferase. We used both cDNA and gDNA analyses to characterize a mucolipidosis type III alpha/beta patient whose clinical diagnosis was already confirmed biochemically.

Y chromosome diversity in a linguistic isolate (Mirandese, NE Portugal).

Objectives: The purpose of this study was to genetically characterize the male lineages of people who speak Mirandese, an interesting case of a linguistic relict that can still be found in the municipality of Miranda do Douro, NE Portugal. This region lies within the area of the Leonese dialects, which are remnants of the Romance dialects spoken in the Kingdom of Leon currently grouped in the Astur-Leonese linguistic continuum. We intended to disclose affinities with surrounding populations, namely from Spain where the Astur-Leonese is also spoken.

Data in support of a functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II.

This data article contains insights into the methodology used for the analysis of three exonic mutations altering the splicing of the IDS gene: c.241C>T, c.257C>T and c.

Mosaic maternal ancestry in the Great Lakes region of East Africa.

The Great Lakes lie within a region of East Africa with very high human genetic diversity, home of many ethno-linguistic groups usually assumed to be the product of a small number of major dispersals. However, our knowledge of these dispersals relies primarily on the inferences of historical, linguistics and oral traditions, with attempts to match up the archaeological evidence where possible. This is an obvious area to which archaeogenetics can contribute, yet Uganda, at the heart of these developments, has not been studied for mitochondrial DNA (mtDNA) variation.

Therapeutic strategies based on modified U1 snRNAs and chaperones for Sanfilippo C splicing mutations.

Background: Mutations affecting RNA splicing represent more than 20% of the mutant alleles in Sanfilippo syndrome type C, a rare lysosomal storage disorder that causes severe neurodegeneration. Many of these mutations are localized in the conserved donor or acceptor splice sites, while few are found in the nearby nucleotides.

Methods: In this study we tested several therapeutic approaches specifically designed for different splicing mutations depending on how the mutations affect mRNA processing.

Portuguese mitochondrial DNA genetic diversity-An update and a phylogenetic revision.

In recent years a large amount of mitochondrial population data for forensic purposes has been produced. Current efforts are focused at increasing the number of studied populations while generating updated genetic information of forensic quality. However, complete mitochondrial control region sequences are still scarce for most populations and even more so for complete mitochondrial genomes.

The peopling of Greenland: further insights from the analysis of genetic diversity using autosomal and X-chromosomal markers.

The peopling of Greenland has a complex history shaped by population migrations, isolation and genetic drift. The Greenlanders present a genetic heritage with components of European and Inuit groups; previous studies using uniparentally inherited markers in Greenlanders have reported evidence of a sex-biased, admixed genetic background. This work further explores the genetics of the Greenlanders by analysing autosomal and X-chromosomal data to obtain deeper insights into the factors that shaped the genetic diversity in Greenlanders.

Prenatal skeletal dysplasia phenotype in severe MLII alpha/beta with novel GNPTAB mutation.

We report a neonate who was diagnosed as a case of skeletal dysplasia during pregnancy, and was subsequently diagnosed as a case of MLII alpha/beta on the basis of clinical and radiological findings and molecular testing of the parents. A novel GNPTAB mutation c.1701delC [p.

Mucolipidosis II-related mutations inhibit the exit from the endoplasmic reticulum and proteolytic cleavage of GlcNAc-1-phosphotransferase precursor protein (GNPTAB).

Mucolipidosis (ML) II and MLIII alpha/beta are two pediatric lysosomal storage disorders caused by mutations in the GNPTAB gene, which encodes an α/β-subunit precursor protein of GlcNAc-1-phosphotransferase. Considerable variations in the onset and severity of the clinical phenotype in these diseases are observed. We report here on expression studies of two missense mutations c.

Linguistic isolates in Portugal: insights from the mitochondrial DNA pattern.

Miranda do Douro, located in the northeastern region of Portugal, has notable characteristics not only from a geographic or naturalistic point of view, but also from a cultural perspective. A remarkable one is the coexistence of two different languages: Portuguese and Mirandese, the second being an Astur-Leonese dialect. The current persistence of the Astur-Leonese dialect in this population falls on the singularity of the region: relative isolation, implying difficulties to communicate with other Portuguese regions, while the same location facilitated the establishment of social and commercial relationships with adjacent Spanish territories, origin of the Astur-Leonese language.