Extreme Phenotypic Variability of -Related Disorders in Hearing Loss.

Hearing loss is the most common sensory defect in humans, affecting normal communication. In most cases, hearing loss is a multifactorial disorder caused by both genetic and environmental factors, but single-gene mutations can lead to syndromic or non-syndromic hearing loss. Monoallelic variants in , coding for gamma (γ)-actin, are associated with classical Baraitser-Winter Syndrome type 2 (BRWS2, nonsyndromic deafness, and a variety of clinical presentations not fitting the original BRWS2 description or nonsyndromic deafness.

Study of the impact of ClinGen Revisions on ACMG/AMP variant semi-automatic classification for Rare Diseases diagnosis.

With the rapid development of massive sequencing technologies, the analysis of genetic variants for clinical diagnosis has exponentially escalated, particularly in the context of Rare Diseases (RDs). Diagnosing them involves identifying the genetic variants responsible for the underlying pathology development. In 2015, the American College of Medical Genetics (ACMG) established a set of recommendations to assess the evidence associated with each variant, aiming to achieve a standardized five tier classification.

Phosphorylation Mechanism Switching in Histidine Kinases Is a Tool for Fast Protein Evolution: Insights From AlphaFold Models.

Histidine kinases (HKs) are a central part of bacterial environmental-sensing two-component systems. They provide their hosts with the ability to respond to a wide range of physical and chemical signals. HKs are multidomain proteins consisting of at least a sensor domain, dimerization and phosphorylation domain (DHp), and a catalytic domain.

Knockout mice with pituitary malformations help identify human cases of hypopituitarism.

Background: Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS).

Exome Sequencing Has a High Diagnostic Rate in Sporadic Congenital Hypopituitarism and Reveals Novel Candidate Genes.

Context: The pituitary gland is key for childhood growth, puberty, and metabolism. Pituitary dysfunction is associated with a spectrum of phenotypes, from mild to severe. Congenital hypopituitarism (CH) is the most commonly reported pediatric endocrine dysfunction, with an incidence of 1:4000, yet low rates of genetic diagnosis have been reported.

Bacterial cytochrome P450s: a bioinformatics odyssey of substrate discovery.

Bacterial P450 cytochromes (BacCYPs) are versatile heme-containing proteins responsible for oxidation reactions on a wide range of substrates, contributing to the production of valuable natural products with limitless biotechnological potential. While the sequencing of microbial genomes has provided a wealth of BacCYP sequences, functional characterization lags behind, hindering our understanding of their roles. This study employs a comprehensive approach to predict BacCYP substrate specificity, bridging the gap between sequence and function.

Local energetic frustration conservation in protein families and superfamilies.

Energetic local frustration offers a biophysical perspective to interpret the effects of sequence variability on protein families. Here we present a methodology to analyze local frustration patterns within protein families and superfamilies that allows us to uncover constraints related to stability and function, and identify differential frustration patterns in families with a common ancestry. We analyze these signals in very well studied protein families such as PDZ, SH3, ɑ and β globins and RAS families.

Best Practices on QM/MM Simulations of Biological Systems.

During the second half of the 20th century, following structural biology hallmark works on DNA and proteins, biochemists shifted their questions from "what does this molecule look like?" to "how does this process work?". Prompted by the theoretical and practical developments in computational chemistry, this led to the emergence of biomolecular simulations and, along with the 2013 Nobel Prize in Chemistry, to the development of hybrid QM/MM methods. QM/MM methods are necessary whenever the problem we want to address involves chemical reactivity and/or a change in the system's electronic structure, with archetypal examples being the studies of an enzyme's reaction mechanism and a metalloprotein's active site.

An allosteric switch ensures efficient unidirectional information transmission by the histidine kinase DesK from .

Phosphorylation carries chemical information in biological systems. In two-component systems (TCSs), the sensor histidine kinase and the response regulator are connected through phosphoryl transfer reactions that may be uni- or bidirectional. Directionality enables the construction of complex regulatory networks that optimize signal propagation and ensure the forward flow of information.

The interplay between serine proteases and caspase-1 regulates the autophagy-mediated secretion of Interleukin-1 beta in human neutrophils.

Neutrophils play major roles against bacteria and fungi infections not only due to their microbicide properties but also because they release mediators like Interleukin-1 beta (IL-1β) that contribute to orchestrate the inflammatory response. This cytokine is a leaderless protein synthesized in the cytoplasm as a precursor (pro-IL-1β) that is proteolytically processed to its active isoform and released from human neutrophils by secretory autophagy. In most myeloid cells, pro-IL-1β is processed by caspase-1 upon inflammasome activation.

Solvent Sites Improve Docking Performance of Protein-Protein Complexes and Protein-Protein Interface-Targeted Drugs.

Protein-protein interactions (PPIs) are essential, and modulating their function through PPI-targeted drugs is an important research field. PPI sites are shallow protein surfaces readily accessible to the solvent, thus lacking a proper pocket to fit a drug, while their lack of endogenous ligands prevents drug design by chemical similarity. The development of PPI-blocking compounds is, therefore, a tough challenge.

Cosolvent Sites-Based Discovery of Protein Kinase G Inhibitors.

Computer-aided drug discovery methods play a major role in the development of therapeutically important small molecules, but their performance needs to be improved. Molecular dynamics simulations in mixed solvents are useful in understanding protein-ligand recognition and improving molecular docking predictions. In this work, we used ethanol as a cosolvent to find relevant interactions for ligands toward protein kinase G, an essential protein of ().

Delayed Puberty Due to a WDR11 Truncation at Its N-Terminal Domain Leading to a Mild Form of Ciliopathy Presenting With Dissociated Central Hypogonadism: Case Report.

Pubertal delay in males is frequently due to constitutional delay of growth and puberty, but pathologic hypogonadism should be considered. After general illnesses and primary testicular failure are ruled out, the main differential diagnosis is central (or hypogonadotropic) hypogonadism, resulting from a defective function of the gonadotropin-releasing hormone (GnRH)/gonadotropin axis. Ciliopathies arising from defects in non-motile cilia are responsible for developmental disorders affecting the sense organs and the reproductive system.

Type 1 Insulin-Like Growth Factor Receptor Nuclear Localization in High-Grade Glioma Cells Enhances Motility, Metabolism, and Tumorigenesis.

Gliomas are the most frequent solid tumors in children. Among these, high-grade gliomas are less common in children than in adults, though they are similar in their aggressive clinical behavior. In adults, glioblastoma is the most lethal tumor of the central nervous system.

Mycobacterium tuberculosis DosS binds HS through its Fe heme iron to regulate the DosR dormancy regulon.

Mycobacterium tuberculosis (Mtb) senses and responds to host-derived gasotransmitters NO and CO via heme-containing sensor kinases DosS and DosT and the response regulator DosR. Hydrogen sulfide (HS) is an important signaling molecule in mammals, but its role in Mtb physiology is unclear. We have previously shown that exogenous HS can modulate expression of genes in the Dos dormancy regulon via an unknown mechanism(s).

Specificity and Reactivity of Serine/Threonine Kinases PknG and PknB.

(Mtb), the causative agent of Tuberculosis, has 11 eukaryotic-like serine/threonine protein kinases, which play essential roles in cell growth, signal transduction, and pathogenesis. Protein kinase G (PknG) regulates the carbon and nitrogen metabolism by phosphorylation of the glycogen accumulation regulator (GarA) protein at Thr21. Protein kinase B (PknB) is involved in cell wall synthesis and cell shape, as well as phosphorylates GarA but at Thr22.

MotSASi: Functional short linear motifs (SLiMs) prediction based on genomic single nucleotide variants and structural data.

Short linear motifs (SLiMs) are key to cell physiology mediating reversible protein-protein interactions. Precise identification of SLiMs remains a challenge, being the main drawback of most bioinformatic prediction tools, their low specificity (high number of false positives). An important, usually overlooked, aspect is the relation between SLiMs mutations and disease.

Gp29 LysA of mycobacteriophage TM4 can hydrolyze peptidoglycan through an N-acetyl-muramoyl-L-alanine amidase activity.

Bacteriophage endolysins are crucial for progeny release at the end of the lytic cycle. Mycobacteriophage's genomes carry a lysin A essential gene, whose product cleaves the peptidoglycan (PG) layer and a lysin B, coding for an esterase, that cleaves the linkage between the mycolic acids and the arabinogalactan-PG complex. Lysin A mycobacteriophage proteins are highly modular and in gp29 (LysA) of phage TM4 three distinctive domains were identified.

A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN.

Dendritic cells (DC) are antigen-presenting cells coordinating the interplay of the innate and the adaptive immune response. The endocytic C-type lectin receptors DC-SIGN and Langerin display expression profiles restricted to distinct DC subtypes and have emerged as prime targets for next-generation immunotherapies and anti-infectives. Using heteromultivalent liposomes copresenting mannosides bearing aromatic aglycones with natural glycan ligands, we serendipitously discovered striking cooperativity effects for DC-SIGN but not for Langerin cell lines.

High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency.

Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor.

From Genome to Drugs: New Approaches in Antimicrobial Discovery.

Decades of successful use of antibiotics is currently challenged by the emergence of increasingly resistant bacterial strains. Novel drugs are urgently required but, in a scenario where private investment in the development of new antimicrobials is declining, efforts to combat drug-resistant infections become a worldwide public health problem. Reasons behind unsuccessful new antimicrobial development projects range from inadequate selection of the molecular targets to a lack of innovation.

Structural modeling of a novel membrane-bound globin-coupled sensor in .

Globin-coupled sensors (GCS) usually consist of three domains: a sensor/globin, a linker, and a transmitter domain. The globin domain (GD), activated by ligand binding and/or redox change, induces an intramolecular signal transduction resulting in a response of the transmitter domain. Depending on the nature of the transmitter domain, GCSs can have different activities and functions, including adenylate and di-guanylate cyclase, histidine kinase activity, aerotaxis and/or oxygen sensing function.

A Novel SLC5A5 Variant Reveals the Crucial Role of Kinesin Light Chain 2 in Thyroid Hormonogenesis.

Context: Iodide transport defect (ITD) (Online Mendelian Inheritance in Man No. 274400) is an uncommon cause of dyshormonogenic congenital hypothyroidism due to loss-of-function variants in the SLC5A5 gene, which encodes the sodium/iodide symporter (NIS), causing deficient iodide accumulation in thyroid follicular cells.

Objective: This work aims to determine the molecular basis of a patient's ITD clinical phenotype.