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The central hallmark of Parkinson's disease pathology is the aggregation of the α-synuclein protein, which, in its healthy form, is associated with lipid membranes. Purified monomeric α-synuclein is relatively stable in vitro, but its aggregation can be triggered by the presence of lipid vesicles. Despite this central importance of lipids in the context of α-synuclein aggregation, their detailed mechanistic role in this process has not been established to date. Here, we use chemical kinetics to develop a mechanistic model that is able to globally describe the aggregation behaviour of α-synuclein in the presence of DMPS lipid vesicles, across a range of lipid and protein concentrations. Through the application of our kinetic model to experimental data, we find that the reaction is a co-aggregation process involving both protein and lipids and that lipids promote aggregation as much by enabling fibril elongation as by enabling their initial formation. Moreover, we find that the primary nucleation of lipid-protein co-aggregates takes place not on the surface of lipid vesicles in bulk solution but at the air-water and/or plate interfaces, where lipids and proteins are likely adsorbed. Our model forms the basis for mechanistic insights, also in other lipid-protein co-aggregation systems, which will be crucial in the rational design of drugs that inhibit aggregate formation and act at the key points in the α-synuclein aggregation cascade.
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Junctional epidermolysis bullosa (JEB) is a rare autosomal recessive genodermatosis with a broad spectrum of phenotypes. Current genotype-phenotype paradigms are insufficient to accurately predict JEB subtype and characteristics from genotype, particularly for splice site variants, which account for over a fifth of disease-causing variants in JEB. This study evaluated the genetic and clinical findings from a JEB cohort, investigating genotype-phenotype correlations through bioinformatic analyses and comparison with previously reported variants. Eighteen unique variants in LAMB3, LAMA3, LAMC2, or COL17A1 were identified from 17 individuals. Seven had severe JEB, 9 had intermediate JEB, and 1 had laryngo-onycho-cutaneous syndrome. Seven variants were previously unreported. Deep phenotyping was completed for all intermediate JEB cases and demonstrated substantial variation between individuals. Splice site variants underwent analysis with SpliceAI, a state-of-the-art artificial intelligence tool, to predict resultant transcripts. Predicted functional effects included exon skipping and cryptic splice site activation, which provided potential explanations for disease severity and in most cases correlated with laminin-332 immunofluorescence. RT-PCR was performed for 1 case to investigate resultant transcripts produced from the splice site variant. This study expands the JEB genomic and phenotypic landscape. Artificial intelligence tools show potential for predicting the functional effects of splice site variants and may identify candidates for confirmatory laboratory investigation. Investigation of RNA transcripts will help to further elucidate genotype-phenotype correlations for novel variants.
Assuntos
Colágeno Tipo XVII , Epidermólise Bolhosa Juncional , Estudos de Associação Genética , Calinina , Laminina , Colágenos não Fibrilares , Índice de Gravidade de Doença , Humanos , Epidermólise Bolhosa Juncional/genética , Epidermólise Bolhosa Juncional/patologia , Laminina/genética , Masculino , Feminino , Colágenos não Fibrilares/genética , Criança , Fenótipo , Moléculas de Adesão Celular/genética , Pré-Escolar , Autoantígenos/genética , Sítios de Splice de RNA/genética , Lactente , Adolescente , Adulto , Mutação , Adulto Jovem , GenótipoRESUMO
Epidermolysis bullosa (EB) is a devastating genetic condition caused by mutations in genes that give rise to aberrant proteins. There are 16 different such proteins implicated in EB that are important in maintaining the integrity of the dermoepidermal junction. It is classified into four major subtypes: (i) EB simplex; (ii) junctional EB (JEB); (iii) dystrophic EB (DEB); and (iv) Kindler EB. Renal disease is a recognized complication of EB and the aetiology is complex. We describe our experience of managing five patients with EB and IgA nephropathy. We recommend that patients with recessive DEB and JEB routinely have the following monitored: renal function, urinary albumin/creatinine ratio, urine analysis, serum albumin levels and immunoglobulins; specifically serum IgA. Management of IgA nephropathy in the context of EB should be tailored to the individual and be carried out within a specialist multidisciplinary team. Our case series provides important insights into the treatment of IgA nephropathy in patients with EB and will help inform treatment in this rare genetic disease. Case series and reports like ours are key in gaining real-life data to quantify the actual risk of morbidity and mortality from each of the treatment modalities discussed.
Assuntos
Epidermólise Bolhosa , Glomerulonefrite por IGA , Adulto , Humanos , Epidermólise Bolhosa/sangue , Epidermólise Bolhosa/complicações , Epidermólise Bolhosa/genética , Epidermólise Bolhosa/terapia , Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa Simples , Epidermólise Bolhosa Juncional , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/etiologia , Glomerulonefrite por IGA/genética , Glomerulonefrite por IGA/terapiaRESUMO
We describe the successful use of rituximab for the treatment of IgA nephropathy in a patient with recessive dystrophic epidermolysis bullosa. To our knowledge, this is the first reported case in the literature.
Assuntos
Antineoplásicos , Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Glomerulonefrite por IGA , Anticorpos Monoclonais , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/tratamento farmacológico , Humanos , Rituximab/uso terapêuticoRESUMO
BACKGROUND: The National Health Service (NHS) epidermolysis bullosa (EB) service, established in 2002, offers comprehensive, free care to all patients in England and Wales. OBJECTIVES: To quantify prevalence, incidence and mortality of EB in England and Wales. METHODS: Demographic data for patients in England and Wales were collected on a secure electronic database, prospectively from January 2002 to April 2021 and retrospectively for cases prior to 2002. Vital status was verified using central NHS data. RESULTS: By March 2021, 2594 individuals were registered, of whom 2361 were living, which yielded a prevalence of 34·8 per million of the population for all EB types [EB simplex (EBS) 17 per million, dystrophic EB (DEB) 10·7 per million, junctional EB (JEB) 1 per million and Kindler EB 0·3 per million]. We recorded 1200 babies with EB born since 2002. The average incidence per million live births for EBS, DEB, JEB and Kindler EB was 32·5, 26·1, 8·9 and 0·9, respectively (total incidence for all types of EB was 67·8 per million). Birth rates fell progressively over the 19-year period for JEB-severe (JEB-S) (r = -0·56) and recessive DEB-severe (r = -0·44) and also for milder types of EB. We observed longer survival in JEB-S over the 19-year period (r2 = 0·18) with a median survival of 12·7 months over the past 5 years. CONCLUSIONS: In this study, we provide the first accurate epidemiological data for EB in England and Wales. We believe the observed reduction in birth incidence of severe types of EB reflects an uptake of genetic counselling advice, whereas the reduction in milder types may be due to delayed presentation. A potential small trend towards longer survival of babies with JEB-S may reflect improved multidisciplinary care.
Assuntos
Epidermólise Bolhosa Juncional , Epidermólise Bolhosa , Epidermólise Bolhosa/epidemiologia , Epidermólise Bolhosa/genética , Humanos , Lactente , Estudos Retrospectivos , Medicina Estatal , País de Gales/epidemiologiaRESUMO
Background Cutaneous malignancies are on the rise, associated with an increased number in scalp cancers that require wide local excision (WLE) to ensure clearance; the inelastic nature of the scalp poses a particular challenge when dealing with such large defects. Case presentation A series of 68 cases with large scalp defects following WLE for the clearance of squamous cell carcinoma, atypical fibroxanthoma, dermatofibrosarcoma protuberans, and melanoma skin cancers are presented. These cases were treated in one center under local anesthesia and underwent extended scalp flaps to close the resulting defect primarily without the use of skin grafts for the flap donor site on the scalp. Conclusion Extended scalp flap is a safe and reproducible solution for extensive scalp defects, which results in quicker wound healing with cosmetically superior results, and can be performed safely and comfortably under local anesthesia in the day case setting.
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Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma. A broad phenotypic spectrum has been described, with potentially severe extracutaneous manifestations, morbidity and mortality. Over 30 subtypes are recognized, grouped into four major categories, based predominantly on the plane of cleavage within the skin and reflecting the underlying molecular abnormality: EB simplex, junctional EB, dystrophic EB and Kindler EB. The study of EB has led to seminal advances in our understanding of cutaneous biology. To date, pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion. Precise diagnosis is reliant on correlating clinical, electron microscopic and immunohistological features with mutational analyses. In the absence of curative treatment, multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications, the most feared of which - and also the leading cause of mortality - is squamous cell carcinoma. Preclinical advances in cell-based, protein replacement and gene therapies are paving the way for clinical successes with gene correction, raising hopes amongst patients and clinicians worldwide.