A5043458784- Hereditary Neurological Disorders
- Neurological diseases and metabolism
- Cellular transport and secretion
- Neurogenetic and Muscular Disorders Research
- Botulinum Toxin and Related Neurological Disorders
- Genetic Neurodegenerative Diseases
- Genomics and Rare Diseases
- Genetics and Neurodevelopmental Disorders
- Nerve injury and regeneration
- Lysosomal Storage Disorders Research
- Mitochondrial Function and Pathology
- Genomic variations and chromosomal abnormalities
- Celiac Disease Research and Management
- Genetic factors in colorectal cancer
- Metabolism and Genetic Disorders
- Endoplasmic Reticulum Stress and Disease
- Microtubule and mitosis dynamics
- Immunodeficiency and Autoimmune Disorders
- Genetic and Kidney Cyst Diseases
- Blood Coagulation and Thrombosis Mechanisms
- Retinal Development and Disorders
- Cancer Genomics and Diagnostics
- Developmental Biology and Gene Regulation
- Autophagy in Disease and Therapy
- Telomeres, Telomerase, and Senescence
University of Cambridge
2016-2025
Cambridge University Hospitals NHS Foundation Trust
2018-2021
Moorfields Eye Hospital NHS Foundation Trust
2021
MRC Mitochondrial Biology Unit
2021
University College London
2021
NIHR Cambridge Biomedical Research Centre
2021
Birmingham Children's Hospital
2019
Addenbrooke's Hospital
1999-2018
University of Manchester
2018
Manchester Academic Health Science Centre
2018
Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilized 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural (SVs), single-nucleotide (SNVs), insertion-deletions (indels), and short tandem repeat (STR) expansions studied families without clear molecular diagnosis. Our cohort includes 293 individuals from 114 genetically selected by European Reference...
The retromer complex is required for the efficient endosome-to-Golgi retrieval of CIMPR, sortilin, SORL1, wntless and other physiologically important membrane proteins. Retromer comprises two protein complexes that act together in retrieval; cargo-selective a trimer VPS35, VPS29 VPS26 sorts cargo into tubules to Golgi. Tubules are produced by oligomerization sorting nexin dimers. Here, we report identification five endosomally-localised proteins modulate tubule formation recruited via...
Mutations in the gene encoding microtubule (MT)-severing protein spastin are most common cause of hereditary spastic paraplegia, a genetic condition which axons corticospinal tracts degenerate. We show that not only does endogenous colocalize with MTs, but it is also located on early secretory pathway, can be recruited to endosomes and present cytokinetic midbody. Spastin has two main isoforms, 68 kD full-length isoform 60 short form. These isoforms preferentially localize different membrane...
Pure hereditary spastic paraplegia is characterized by length-dependent degeneration of the distal ends long axons. Mutations in spastin are most common cause condition. We set out to investigate function using a yeast two-hybrid approach identify interacting proteins. Using full-length as bait, we identified CHMP1B, protein associated with ESCRT (endosomal sorting complex required for transport)–III complex, binding partner. Several different approaches confirmed physiological relevance...
Summary: Purpose: SCN1A is the most clinically relevant epilepsy gene, mutations lead to severe myoclonic of infancy (SMEI) and generalized with febrile seizures plus (GEFS+). We studied 132 patients syndromes precipitated by fever, performed phenotype–genotype correlations alterations. Methods: included SMEI including borderline (SMEB), GEFS+, (FS), or other seizure types fever. a clinical genetic study focusing on , using dHPLC, gene sequencing, MLPA detect genomic deletions/duplications...
Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They characterized by progressive paralysis the legs as result selective, length-dependent degeneration axons corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape ER into sheets and tubules - receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), spastin (SPAST) have been found underlie many cases HSP Northern Europe North America. Applying Sanger...
Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but mechanisms involved consequences of fission failure are incompletely understood. We found that interaction microtubule-severing enzyme spastin ESCRT protein IST1 at ER–endosome contacts drives fission. Failure caused defective sorting mannose 6-phosphate receptor, with consequently disrupted lysosomal trafficking abnormal morphology, including in mouse primary neurons human stem cell–derived...
Mechanisms coordinating endosomal degradation and recycling are poorly understood, as the cellular roles of microtubule (MT) severing. We show that cells lacking MT-severing protein spastin had increased tubulation defective receptor sorting through tubular compartments. Spastin required ability to sever MTs interact with ESCRT-III (a complex controlling cargo degradation) proteins regulate tubulation. Cells IST1 (increased sodium tolerance 1), an for transport (ESCRT) component which binds,...
The hereditary spastic paraplegias (HSPs) are genetic conditions characterized by distal axonopathy of the longest corticospinal tract axons, and so their study provides an important opportunity to understand mechanisms involved in axonal maintenance degeneration.A group HSP genes encode proteins that localize endosomes.One these is NIPA1 (non-imprinted Prader-Willi/Angelman syndrome 1) we have shown recently its Drosophila homologue spichthyin inhibits bone morphogenic protein (BMP)...
Abstract Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilised 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural (SVs), single nucleotide (SNVs), insertion-deletions (InDels), and short tandem repeat (STR) expansions extensively studied families without clear molecular diagnoses. Our cohort includes 293 individuals from 114 genetically selected...
The pure hereditary spastic paraplegias (HSPs) are a group of conditions in which there is progressive length-dependent degeneration the distal ends corticospinal tract axons, resulting paralysis legs. Pure HSPs most frequently inherited an autosomal-dominant pattern and commonly caused by mutations either SPG4 gene spastin or SPG3A atlastin. To identify binding partners for spastin, we carried out yeast two-hybrid screen on brain cDNA library, using as bait. Remarkably, nearly all positive...
Cytokinesis and abscission are complicated events that involve changes in membrane transport cytoskeleton organization. We have used the combination of time-lapse microscopy correlative high-resolution 3D tomography to analyze regulation spatio-temporal remodeling endosomes microtubules during abscission. show is driven by formation a secondary ingression within intracellular bridge connecting two daughter cells. The initiation expansion this requires recycling endosome fusion with furrow...
Abstract Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is increase the supply of growth molecules and organelles. We achieved this by expressing adaptor molecule Protrudin which normally found at low levels in non-regenerative neurons. Elevated expression enabled robust both vitro primary cortical neurons vivo injured adult optic nerve. overexpression facilitated...
The endosomal sorting complexes required for transport (ESCRTs) are essential multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, anemia. In cultured cells, overexpression VPS4A mutants caused enlarged vacuoles...
Abstract Over 130 X-linked genes have been robustly associated with developmental disorders, and causes hypothesised to underlie the higher disorder rates in males. Here, we evaluate burden of coding variation 11,044 patients, find a similar rate males females (6.0% 6.9%, respectively), indicating that such variants do not account for 1.4-fold male bias. We develop an improved strategy detect disorders identify 23 significant genes, all which were previously known, consistent our inference...