Dominant Gα mutations in human disease: unifying mechanisms and treatment strategies.

Sixteen Gα-subunits transduce hundreds of G protein-coupled receptors and control countless cellular activities. Mutations in respective GNA genes underlie developmental, oncological, metabolic, neurological, and other pathologies. In addition to classical loss-of-function (LOF) and gain-of-function (GOF) mutations (the former represented by gene deletions/truncations, the latter by specific GTP hydrolysis-deficient mutations), multiple pathogenic dominant missense variants have been discovered in GNA genes, and their numbers constantly increase through advanced genetic diagnostics.

Novel Mutation at Cys225 in -Associated Developmental and Epileptic Encephalopathies: Clinical, Molecular, and Pharmacological Profiling of Case Studies.

-associated disorders have a large spectrum of neurological symptoms, from early-onset developmental and epileptic encephalopathies (DEE) to late-onset movement disorders. First reported in 2013 and now identified in around 400 cases worldwide, this disease is caused by dominant, mostly de novo missense mutations in , the gene encoding the major neuronal G protein Gαo. Being the immediate transducer of a number of neuronal G protein-coupled receptors, Gαo plays crucial functions in brain development and physiology.

A Personalized 14-3-3 Disease-Targeting Workflow Yields Repositioning Drug Candidates.

Rare diseases typically evade the application of the standard drug discovery and development pipelines due to their understudied molecular etiology and the small market size. Herein, we report a rare disease-directed workflow that rapidly studies the molecular features of the disorder, establishes a high-throughput screening (HTS) platform, and conducts an HTS of thousands of approved drugs to identify and validate repositioning drug candidates. This study examines the pediatric neurological disorder caused by de novo mutations in , the gene encoding the scaffolding protein 14-3-3γ, and the workflow discovers nuclear relocalization and a severe drop in 14-3-3γ binding to its phosphorylated protein partners as the key molecular features of the pathogenic hotspot mutations.

Impacts of Different Perinatal Factors on Faecal Immune Compounds in Infants: Determination of Normal Values.

The gut microbiota is a key and primary stimulus for the development of a host's immune system. The early establishment of the gut microbiota is affected by several perinatal factors but little is known about their influence on shaping normal immune development and, consequently, on the programming of future health. The analysis of different immune compounds is well-documented in serum samples; however, their presence in faecal samples has not been studied, and this information could be valuable in early life.

Personalized Nutrition with Banked Human Milk for Early Gut Microbiota Development: In Pursuit of the Perfect Match.

The correct initial colonization and establishment of the gut microbiota during the early stages of life is a key step, with long-lasting consequences throughout the entire lifespan of the individual. This process is affected by several perinatal factors; among them, feeding mode is known to have a critical role. Breastfeeding is the optimal nutrition for neonates; however, it is not always possible, especially in cases of prematurity or early pathology.

Clinical and Molecular Profiling in GNAO1 Permits Phenotype-Genotype Correlation.

Background: Defects in GNAO1, the gene encoding the major neuronal G-protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain the different phenotypes.

Objectives: We aimed to analyze the clinical phenotype and the molecular characterization of GNAO1-related disorders.

Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies.

GNAO1 mutated in pediatric encephalopathies encodes the major neuronal G protein Gαo. Of the more than 80 pathogenic mutations, most are single amino acid substitutions spreading across the Gαo sequence. We performed extensive characterization of Gαo mutants, showing abnormal GTP uptake and hydrolysis and deficiencies in binding Gβγ and RGS19.

GNAO1 Mutations Affecting the N-Terminal α-Helix of Gαo Lead to Parkinsonism.

Background: Patients carrying pathogenic variants in GNAO1 present a phenotypic spectrum ranging from severe early-onset epileptic encephalopathy and developmental delay to mild adolescent/adult-onset dystonia. Genotype-phenotype correlation and molecular mechanisms underlying the disease remain understudied.

Methods: We analyzed the clinical course of a child carrying the novel GNAO1 mutation c.

In-depth molecular profiling of an intronic GNAO1 mutant as the basis for personalized high-throughput drug screening.

Background: The GNAO1 gene, encoding the major neuronal G protein Gαo, is mutated in a subset of pediatric encephalopathies. Most such mutations consist of missense variants.

Methods: In this study, we present a precision medicine workflow combining next-generation sequencing (NGS) diagnostics, molecular etiology analysis, and personalized drug discovery.

The Gut Microbiota in Infants: Focus on .

A long time has passed since the initial pioneering works were carried out on the composition of infant microbiota by Thedore Escherich (1857-1911) and Ernst Moro (1874-1951), and since the observations of Henry Tissier (1866-1916) which linked "Bacillus bifidus" to the health of babies [...

Restoration of the GTPase activity and cellular interactions of Gα mutants by Zn in encephalopathy models.

De novo point mutations in , gene encoding the major neuronal G protein Gα, have recently emerged in patients with pediatric encephalopathy having motor, developmental, and epileptic dysfunctions. Half of clinical cases affect codons Gly, Arg, or Glu; we show that these mutations accelerate GTP uptake and inactivate GTP hydrolysis through displacement Gln critical for GTP hydrolysis, resulting in constitutive GTP binding by Gα. However, the mutants fail to adopt the activated conformation and display aberrant interactions with signaling partners.

Psychomotor development in very and extremely low-birth-weight preterm children: Could it be predicted by early motor milestones and perinatal complications?

Preterm-born children are at risk of slower psychomotor development. This risk may be associated with low birth weight and other perinatal factors and morbidities. We aimed to assess psychomotor development in school-aged preterm children, and to determine whether some early motor and perinatal variables could be related to and/or predict the later motor achievements.

Symptomatic ACL mucoid degeneration in middle-age athletes.

Background: Mucoid degeneration of the anterior cruciate ligament (ACL) is an uncommon non-traumatic cause of knee pain and motion restriction, typically seen in a middle-aged population. Primarily, the management consists of partial arthroscopic debridement and notchplasty, which has proven satisfactory clinical and functional outcomes.

Study Objectives: This review aims to highlight key clinical, radiological and arthroscopic findings of mucoid ACL degeneration, and also to provide an approach to manage a symptomatic middle-aged athlete.

Local and substrate-specific S-palmitoylation determines subcellular localization of Gαo.

Peripheral membrane proteins (PMPs) associate with cellular membranes through post-translational modifications like S-palmitoylation. The Golgi apparatus is generally viewed as the transitory station where palmitoyl acyltransferases (PATs) modify PMPs, which are then transported to their ultimate destinations such as the plasma membrane (PM). However, little substrate specificity among the many PATs has been determined.

In Vitro Probiotic Modulation of the Intestinal Microbiota and 2'Fucosyllactose Consumption in Fecal Cultures from Infants at Two Months of Age.

2'-fucosyllactose (2'FL) is one of the most abundant oligosaccharides in human milk, with benefits on neonatal health. Previous results point to the inability of the fecal microbiota from some infants to ferment 2'FL. We evaluated a probiotic formulation, including the strains Rosell-52 (R0052), subsp.

Gαi2-induced conductin/axin2 condensates inhibit Wnt/β-catenin signaling and suppress cancer growth.

Conductin/axin2 is a scaffold protein negatively regulating the pro-proliferative Wnt/β-catenin signaling pathway. Accumulation of scaffold proteins in condensates frequently increases their activity, but whether condensation contributes to Wnt pathway inhibition by conductin remains unclear. Here, we show that the Gαi2 subunit of trimeric G-proteins induces conductin condensation by targeting a polymerization-inhibiting aggregon in its RGS domain, thereby promoting conductin-mediated β-catenin degradation.

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of and for the Dominant Disease.

Heterotrimeric G proteins are immediate transducers of G protein-coupled receptors-the biggest receptor family in metazoans-and play innumerate functions in health and disease. A set of de novo point mutations in and , the genes encoding the α-subunits (Gαo and Gαi1, respectively) of the heterotrimeric G proteins, have been described to cause pediatric encephalopathies represented by epileptic seizures, movement disorders, developmental delay, intellectual disability, and signs of neurodegeneration. Among such mutations, the Gln52Pro substitutions have been previously identified in and .

Effect of Intrapartum Antibiotics Prophylaxis on the Bifidobacterial Establishment within the Neonatal Gut.

Antibiotics are important disruptors of the intestinal microbiota establishment, linked to immune and metabolic alterations. The intrapartum antibiotics prophylaxis (IAP) is a common clinical practice that is present in more than 30% of labours, and is known to negatively affect the gut microbiota composition. However, little is known about how it affects to (sub)species level, which is one of the most important intestinal microbial genera early in life.

Levels of Predominant Intestinal Microorganisms in 1 Month-Old Full-Term Babies and Weight Gain during the First Year of Life.

The early life gut microbiota has been reported to be involved in neonatal weight gain and later infant growth. Therefore, this early microbiota may constitute a target for the promotion of healthy neonatal growth and development with potential consequences for later life. Unfortunately, we are still far from understanding the association between neonatal microbiota and weight gain and growth.

Influence of 2'-Fucosyllactose on the Microbiota Composition and Metabolic Activity of Fecal Cultures from Breastfed and Formula-Fed Infants at Two Months of Age.

Although breast milk is considered the gold standard of nutrition for infant feeding, some circumstances may make breastfeeding difficult. Several commercial milk preparations include synthetic human milk oligosaccharides (HMOs) in their composition. However, the effect of HMOs on the establishment of the intestinal microbiota remains incompletely understood.