RESUMEN

INTRODUCTION: Genetic mutations or inflammatory, degenerative, or neoplastic conditions can trigger amyloidosis. Hereditary gelsolin amyloidosis is a genetic disorder primarily marked by amyloid fibrils composed of misfolded gelsolin fragments. CASE REPORT: We present three sisters with AGel amyloidosis, illustrating its clinical diversity. Patient 1, a 51-year-old, had bilateral ptosis, ocular discomfort, and dry eye syndrome due to cranial nerve involvement. Patient 2, a 53-year-old, experienced progressive bilateral visual impairment. Patient 3, a 50-year-old, exhibited right eye ectropion. Genetic analysis, with the identical mutation, heterozygous c.640G > A (p.Asp214Asn) mutation, confirmed AGel amyloidosis diagnoses, with common findings including lattice corneal amyloidosis, reduced corneal sensitivity, and recurrent corneal erosions. Neurological manifestations included ataxia and peripheral neuropathy, with skin abnormalities observed in patient 1. Ocular involvement severity and distribution varied among patients. DISCUSSION: Common ocular and neurological manifestations validated AGel amyloidosis diagnoses, reinforcing its hereditary basis. Neurological symptoms highlighted the disorder's impact on various organ systems, while skin abnormalities contributed to ocular discomfort. Variable ocular involvement emphasized the disorder's heterogeneity. These patients emphasize hereditary gelsolin amyloidosis's clinical diversity and suggest potential environmental influences on disease expression. Genetic confirmation and confocal microscopy findings reaffirm the genetic basis while raising questions about assessing systemic disease severity, necessitating further investigation in larger cohorts. Ophthalmologists' specialized care is crucial for managing ocular symptoms, given the absence of a universal cure.

Asunto(s)

Amiloidosis Familiar , Gelsolina , Microscopía Confocal , Humanos , Femenino , Persona de Mediana Edad , Gelsolina/genética , Amiloidosis Familiar/genética , Amiloidosis Familiar/diagnóstico , Linaje , Brasil , Mutación , Síndromes de Ojo Seco/diagnóstico , Síndromes de Ojo Seco/genética

RESUMEN

BACKGROUND: Previous studies have shown that the ability of tumor cells to move and migrate is related to the molecular chain pathway mediated by actin. This study focused on the molecular mechanism of gelsolin (GSN) as an important actin-binding protein in promoting HCC invasion and metastasis. METHODS: The relationship between GSN expression and clinical characteristics was observed by immunohistochemistry (IHC). In vitro and in vivo experiments confirmed the role of GSN in HCC metastasis. Dual-immunoprecipitation (IP), immunofluorescence (IF), western blotting, and the gelatinase activity assay were used to investigate the mechanism of GSN-promoting metastasis. PEX fusion proteins were used to intervene in the transfer molecular chain. RESULTS: Our study found that GSN promoted HCC invasion and metastasis through its synergistic effect with actin-related transfer molecular chain (actin-CD44-MMPs). Concretely, as an important binding molecule of actin, GSN activated MMP2 by interacting with MMP14. Furthermore, CD44 might be a key node in the above-mentioned mechanism. The use of MMP14 domain (PEX fusion protein) to competitively bind to CD44 helped to inhibit the activation of downstream MMP2. CONCLUSIONS: GSN played crucial roles in HCC metastatic process. An improved understanding of the multiple effects of GSN in HCC might facilitate a deeper appreciation of GSN as an important HCC regulator. The study identified GSN and its regulated transfer molecular chain as potential therapeutic targets for HCC.

Asunto(s)

Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Gelsolina/genética , Gelsolina/metabolismo , Actinas , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 14 de la Matriz/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Línea Celular Tumoral

RESUMEN

Purpose: Familial amyloidosis of the Finnish type (FAF) is an inherited amyloidosis arising from mutations in the gelsolin protein (GSN). The disease includes facial paralysis, loose skin, and lattice corneal dystrophy. To date, FAF has been invariably associated with substitution of Asp214 in GSN. We describe the clinical, histopathological, and genetic features of a family with FAF due to a novel GSN mutation. Methods: Five affected adult individuals in a three-generation FAF pedigree were included in the study. Histopathological analysis was performed on an eyelid skin biopsy from one patient. Genetic analysis included next-generation sequencing (NGS) and Sanger sequencing for confirmation of the GSN variant. Several tools for in silico analysis of pathogenicity for the novel variant and to predict the effect of the amino acid replacement on protein stability were used. Results: Three older adult affected patients exhibited corneal lattice dystrophy, cutis laxa, and facultative peripheral neuropathy. Two younger adult individuals presented only with corneal amyloid deposits. NGS identified a heterozygous GSN c.1631T>G transversion, predicting a novel p.Met544Arg mutation. All in silico tools indicated that p.Met544Arg is deleterious for GSN functionality or stability. Conclusions: The results expand the molecular spectrum of GSN-linked systemic amyloidosis. The novel p.Met544Arg pathogenic variant is predicted to affect gelsolin function, presumably by impairing a potential calcium-sensitive, actin-binding region.

Asunto(s)

Neuropatías Amiloides Familiares/genética , Gelsolina/genética , Adulto , Amiloide/metabolismo , Neuropatías Amiloides Familiares/sangre , Neuropatías Amiloides Familiares/metabolismo , Neuropatías Amiloides Familiares/patología , Biopsia , Distrofias Hereditarias de la Córnea/genética , Cutis Laxo/genética , Párpados/citología , Párpados/metabolismo , Párpados/patología , Familia , Femenino , Gelsolina/metabolismo , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Malformaciones del Sistema Nervioso/genética , Linaje , Filogenia , Estabilidad Proteica

RESUMEN

Sepsis is a life-threatening disorder characterized by organ dysfunction and a major cause of mortality worldwide. The major challenge in studying sepsis is its diversity in such factors as age, source of infection and etiology. Recently, genomic and proteomic approaches have improved our understanding of its complex pathogenesis. In the present study, we use quantitative proteomics to evaluate the host proteome response in septic patients secondary to community-acquired pneumonia (CAP). Samples obtained at admission and after 7 days of follow-up were analyzed according to the outcomes of septic patients. The patients' proteome profiles were compared with age- and gender-matched healthy volunteers. Bioinformatic analyses of differentially expressed proteins showed alteration in the cytoskeleton, cellular assembly, movement, lipid metabolism and immune responses in septic patients. Actin and gelsolin changes were assessed in mononuclear cells using immunofluorescence, and a higher expression of gelsolin and depletion of actin were observed in survivor patients. Regarding lipid metabolism, changes in cholesterol, HDL and apolipoproteins were confirmed using enzymatic colorimetric methods in plasma. Transcriptomic studies revealed a massive change in gene expression in sepsis. Our proteomic results stressed important changes in cellular structure and metabolism, which are possible targets for future interventions of sepsis.

Asunto(s)

Infecciones Comunitarias Adquiridas/genética , Metabolismo de los Lípidos/genética , Neumonía/genética , Sepsis/genética , Actinas/genética , Anciano , Infecciones Comunitarias Adquiridas/sangre , Infecciones Comunitarias Adquiridas/complicaciones , Infecciones Comunitarias Adquiridas/patología , Femenino , Gelsolina/genética , Regulación de la Expresión Génica/genética , Genoma Humano/genética , Genómica , Interacciones Huésped-Patógeno/genética , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Neumonía/sangre , Neumonía/complicaciones , Neumonía/patología , Proteoma/genética , Sepsis/sangre , Sepsis/complicaciones , Sepsis/patología , Transcriptoma/genética

RESUMEN

A role of gelsolin in opening the way along the microvilli for secretory vesicles during microapocrine secretion is proposed here. Data obtained with different techniques showed that many digestive enzymes are released by microapocrine secretion in insects. Proteins that might be involved in the machinery of microapocrine secretion were selected from our transcriptomes and literature searches. The proteins were annexin, Complex actin-related proteins 2 and 3 (ARP 2/3) cofilin, fimbrin, gelsolin 1, gelsolin 2, moesin, myosin 1, myosin 6, protein disulphide isomerase 1 (PDI 1), PDI 2 and profilin. The cDNAs coding for annexin, fimbrin, gelsolin 1, myosin 1, PDI 1 and PDI 2 were cloned and their sequences deposited in GenBank. Only gelsolin 1 and myosin 1 are expressed exclusively in the midgut (semiquantitative reverse transcriptase PCR). As myosin 1 may have a structural role in microvilli, gelsolin 1 is the best guess to be involved in the secretory machinery. A truncated recombinant gelsolin 1 was used to generate antibodies with which it was shown labelling inside and around midgut cell microvilli shown in an electron microscope, reinforcing a microvillar role for gelsolin 1. Suppression of gelsolin 1 synthesis by RNA interference prevents secretory vesicles from advancing inside the microvilli, in agreement with its putative role in severing the actin filaments to free the way for the vesicles.

Asunto(s)

Gelsolina/genética , Proteínas de Insectos/genética , Spodoptera/genética , Animales , Clonación Molecular , ADN Complementario/genética , ADN Complementario/metabolismo , Gelsolina/metabolismo , Proteínas de Insectos/metabolismo , Análisis de Secuencia de ADN , Spodoptera/metabolismo

RESUMEN

OBJECTIVES: The purpose of our study was to describe the results of molecular screening of TGFBI, CHST6, and GSN genes in a group of Mexican patients with different stromal corneal dystrophies (CD). MATERIAL AND METHODS: A total of 16 CD Mexican patients pertaining to nine different pedigrees were subjected to a complete ophthalmological investigation. A clinical diagnosis of lattice CD was performed in 10 patients from five pedigrees. Three patients from two pedigrees were diagnosed with granular CD type 2, two patients with unrelated probands had Finnish-type corneal amyloidosis, and one patient had macular CD. Genetic analysis included DNA isolation from blood leukocytes and polymerase chain reaction (PCR) amplification and direct nucleotide sequencing of TGFBI, CHST6, and GSN genes. RESULTS: Seven lattice CD patients from four unrelated families had an identical p.H626R mutation in TGFBI, three patients from a single lattice CD family carried a p.R124C substitution in TGFBI, and a granular type 2 CD pedigree was demonstrated to carry a heterozygous TGFBI p.M619K substitution. A patient having Finnish-type corneal amyloidosis had a p.D187N mutation in GSN. Finally, molecular analysis of CHST6 in a patient with macular CD disclosed the presence of a homozygous p.Y110C change. CONCLUSIONS: This study improves the knowledge of the genetic features of Mexican patients with corneal stromal dystrophies by identifying mutations in the TGFBI, CHST6, and GSN genes. Genetic screening of larger samples of patients from distinct ethnic groups would be of great importance for a better understanding of the mutational spectrum of stromal CD.

Asunto(s)

Distrofias Hereditarias de la Córnea/genética , Proteínas de la Matriz Extracelular/genética , Gelsolina/genética , Mutación , Sulfotransferasas/genética , Factor de Crecimiento Transformador beta/genética , Adulto , Distrofias Hereditarias de la Córnea/epidemiología , Femenino , Humanos , Masculino , México/epidemiología , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Adulto Joven , Carbohidrato Sulfotransferasas

RESUMEN

Familial amyloidosis of the Finnish type (FAF) is an autosomal dominant form of systemic amyloidosis showing marked geographic clustering in Finland. The disease is caused by a point mutation, 654G-A, in the gelsolin gene. The Danish-subtype of FAF has been previously described in three families, the patients present clinical findings similar to FAF, and the mutation 654G-T in the gelsolin gene. Three members from two generations of the same family, with familial amyloidosis, were screened for mutations in the GSN gene. Genomic DNA was extracted from peripheral blood lymphocytes and the polymerase chain reaction (PCR) was carried out under standard conditions, using appropriate primers. Sequence analysis showed the presence of a G to T transition at nucleotide 654 of the gelsolin gene. This is the first report of gelsolin-related familial amyloidosis in a Brazilian family, and the result is particularly significant as this pedigree presents an unusual mutation, described previously in three families, with no known Finnish ancestors (Danish type).

Asunto(s)

Amiloidosis Familiar/genética , Distrofias Hereditarias de la Córnea/genética , Gelsolina/genética , Mutación Puntual/genética , Adulto , Amiloidosis Familiar/diagnóstico , Distrofias Hereditarias de la Córnea/diagnóstico , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa

RESUMEN

Familial amyloidosis of the Finnish type (FAF) is an autosomal dominant form of systemic amyloidosis showing marked geographic clustering in Finland. The disease is caused by a point mutation, 654G-A, in the gelsolin gene. The Danish-subtype of FAF has been previously described in three families, the patients present clinical findings similar to FAF, and the mutation 654G-T in the gelsolin gene. Three members from two generations of the same family, with familial amyloidosis, were screened for mutations in the GSN gene. Genomic DNA was extracted from peripheral blood lymphocytes and the polymerase chain reaction (PCR) was carried out under standard conditions, using appropriate primers. Sequence analysis showed the presence of a G to T transition at nucleotide 654 of the gelsolin gene. This is the first report of gelsolin-related familial amyloidosis in a Brazilian family, and the result is particularly significant as this pedigree presents an unusual mutation, described previously in three families, with no known Finnish ancestors (Danish type).

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Amiloidose familiar do tipo finlandes (FAF) é uma forma de amiloidose sistêmica autossômica dominante com grande concentração geográfica na Finlândia. É causada por uma mutação, 654G-A, no gene gelsolin. O subtipo dinamarquês da FAF foi previamente descrito em três famílias, com achados clínicos similares mas com a mutação 654G-T no gene gelsolin. Três membros de duas gerações da mesma família, com diagnóstico de amiloidose familiar, foram submetidos a screening de mutações no gene gelsolin. O DNA genômico foi extraído de linfócitos do sangue periférico, sendo realizada reação em cadeia de polimerase (PCR) em condições padronizadas. A análise do sequenciamento revelou uma transição de G para T no nucleotidio 654 do gene gelsolin. Este é o primeiro relato de uma amiloidose familiar relacionada ao gene gelsolin em uma família brasileira, que apresenta uma forma rara de mutação, descrita previamente em três famílias, sem ancestrais finlandeses (tipo dinamarquês).

Asunto(s)

Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Amiloidosis Familiar/genética , Distrofias Hereditarias de la Córnea/genética , Gelsolina/genética , Mutación Puntual/genética , Amiloidosis Familiar/diagnóstico , Distrofias Hereditarias de la Córnea/diagnóstico , Análisis Mutacional de ADN , Linaje , Reacción en Cadena de la Polimerasa