A5071925173- Growth Hormone and Insulin-like Growth Factors
- Bioinformatics and Genomic Networks
- Genetics, Bioinformatics, and Biomedical Research
- Protein Structure and Dynamics
- Hypothalamic control of reproductive hormones
- Genomics and Rare Diseases
- Lipid metabolism and disorders
- RNA and protein synthesis mechanisms
- Genomics and Phylogenetic Studies
- Genetic Syndromes and Imprinting
- Genetic Associations and Epidemiology
- SARS-CoV-2 and COVID-19 Research
- Diabetes and associated disorders
- Microbial Metabolic Engineering and Bioproduction
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Lipoproteins and Cardiovascular Health
- Hormonal Regulation and Hypertension
- COVID-19 Clinical Research Studies
- Glycosylation and Glycoproteins Research
- Digestive system and related health
- Thyroid Disorders and Treatments
- Enzyme Structure and Function
- Receptor Mechanisms and Signaling
- Neurogenetic and Muscular Disorders Research
- Thyroid Cancer Diagnosis and Treatment
Imperial College London
2015-2025
Imperial College Healthcare NHS Trust
2023
William Harvey Research Institute
2005-2011
Queen Mary University of London
2005-2011
St Bartholomew's Hospital
2005
University of Ferrara
2001-2005
Knowledge of protein structure can be used to predict the phenotypic consequence a missense variant. Since structural coverage human proteome roughly tripled over 50% residues if homology-predicted structures are included in addition experimentally determined coordinates, it is important assess reliability using predicted models when analyzing variants. Accordingly, we whether variant structurally damaging by experimental and structures. We considered 606 show that 40% 1965...
Many nonsynonymous single nucleotide polymorphisms (nsSNPs) are disease causing due to effects at protein-protein interfaces. We have integrated a database of the three-dimensional (3D) structures human protein/protein complexes and humsavar nsSNPs. analyzed location nsSNPS in terms their protein core, interfaces, on surface when not an interface. Disease-causing nsSNPs that do occur core preferentially located interfaces rather than noninterface regions compared random segregation. The...
Research Article13 April 2016Open Access Source DataTransparent process IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty Sasha R Howard Centre for Endocrinology, William Harvey Institute, Barts and the London School of Medicine Dentistry, Queen Mary University London, UK Search more papers by this author Leonardo Guasti Gerard Ruiz-Babot Alessandra Mancini Alessia David Integrative Systems Biology Bioinformatics, Department Life...
Missense mutations at protein–protein interaction sites, called interfaces, are important contributors to human disease. Interfaces non-uniform surface areas characterized by two main regions, "core" and "rim", which differ in terms of evolutionary conservation physicochemical properties. Moreover, within only a small subset residues ("hot spots") is crucial for the binding free energy complex. We performed large-scale structural analysis single amino acid variations (SAVs) demonstrated that...
The Protein Data Bank in Europe - Knowledge Base (PDBe-KB, https://pdbe-kb.org) is an open collaboration between world-leading specialist data resources contributing functional and biophysical annotations derived from or relevant to the (PDB). goal of PDBe-KB place macromolecular structure their biological context by developing standardised exchange formats integrating partner into a knowledge graph that can provide valuable insights. Since we described 2019, there have been significant...
The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus' spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 genetic variants affecting structure and function of may modulate severity infection.
Abstract Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations ion channels or transporters. Herein we report discovery, replication and phenotype in neuronal cell adhesion gene CADM1 . Independent whole exome sequencing 40 81 APAs found intramembranous p.Val380Asp p.Gly379Asp variants two patients whose hypertension periodic primary aldosteronism were cured by adrenalectomy. Replication identified more with each...
The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion depends on the development a complex neuroendocrine network during embryonic life. Although delayed (DP) affects up to 2% population, highly heritable, and associated with adverse health outcomes, genes underlying DP remain largely unknown. We aimed discover regulators whole-exome sequencing 160 individuals 67 multigenerational families our large,...
The interpretation of human genetic variation is one the greatest challenges modern genetics. New approaches are urgently needed to prioritize variants, especially those that rare or lack a definitive clinical interpretation. We examined 10,136,597 missense variants from GnomAD, ClinVar and UniProt. were able perform large-scale atom-based mapping phenotype 3,960,015 these onto 18,874 experimental 84,818 in house predicted three-dimensional coordinates proteome. demonstrate 14% amino acid...
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking the GLP-1R influence its signalling properties and therapeutic potential type 2 diabetes. Here, we have evaluated how different factors combine to control post-endocytic recycling versus degradative pathways. Experiments were performed primary islet cells, INS-1 832/3 clonal beta cells HEK293 using biorthogonal labelling determine...
<i>Background/Aims:</i> Growth hormone insensitivity (GHI) is characterized by severe short stature, high serum growth (GH), low IGF-I and IGFBP-3 levels classically associated with genetic defects of the GH receptor (GHR). Recently, mutations <i>STAT5b </i>gene have been identified shown to be GHI IGF deficiency. We investigated 2 sisters from a consanguineous family Kuwait, clinical biochemical features GHI, in whom no molecular GHR were identified....
Abstract Context Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of timing have identified multiple loci for age at menarche females and voice break males, particularly pathways controlling energy balance. Objective/Main Outcome Measures We sought to assess contribution rare variants such genes phenotype familial DP. Design/Patients performed...
The initiation of puberty is orchestrated by an augmentation gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control may be regulated hierarchically organized network transcriptional factors acting upstream GnRH. These include enhanced at 1 (EAP1), which contributes to female through transactivation GnRH promoter. However, no EAP1 mutations been found in humans with disorders pubertal timing. We...
Human genetic defects in the growth hormone (GH) –IGF-I axis affecting IGF system present with failure as their principal clinical feature. This is usually associated GH insensitivity (GHI) presenting childhood severe or mild short stature. Dysmorphic features and metabolic abnormalities may also be present. The field of GHI due to mutations action has evolved radidly since first description extreme phenotype related homozygous receptor (GHR) 1966. A continuum genetic, phenotypic,...
Pleiotropy is the phenomenon by which same gene can result in multiple phenotypes. Pleiotropic proteins are emerging as important contributors to rare and common disorders. Nevertheless, little known on mechanisms underlying pleiotropy characteristic of pleiotropic proteins. We analyzed disease-causing reported UniProt observed that 12% (variants protein cause more than one disease). were enriched deleterious variants, but not variants. likely be involved pathogenesis neoplasms,...
Autosomal-recessive mutations in the growth hormone receptor (GHR) are most common causes for primary insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like factor (IGF)-I deficiency. We report three families dominant-negative heterozygous intracellular domain of GHR causing a nonclassical phenotype.To determine if identified variants exert potential effects cause phenotype our patients.All (c.964dupG,...