Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
JCI Insight ; 6(6)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33749661

RESUMO

Mutations in LAMB2, encoding laminin ß2, cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin ß2. On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the ß2 LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin ß2 secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the ß2 variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin ß2 to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the ß2 variants to other laminins appears to lead to their increased deposition in the GBM. Laminin ß2 also serves as a potentially novel cell-adhesive ligand for integrin α4ß1. Our findings define biochemical functions of laminin ß2 variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.


Assuntos
Matriz Extracelular/metabolismo , Nefropatias/metabolismo , Laminina/metabolismo , Animais , Células HEK293 , Humanos , Laminina/genética , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Síndromes Miastênicas Congênitas/genética , Síndrome Nefrótica/genética , Distúrbios Pupilares/genética
2.
J Cell Sci ; 133(13)2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32482797

RESUMO

Cubilin (CUBN) and amnionless (AMN), expressed in kidney and intestine, form a multiligand receptor complex called CUBAM that plays a crucial role in albumin absorption. To date, the mechanism of albumin endocytosis mediated by CUBAM remains to be elucidated. Here, we describe a quantitative assay to evaluate albumin uptake by CUBAM using cells expressing full-length CUBN and elucidate the crucial roles of the C-terminal part of CUBN and the endocytosis signal motifs of AMN in albumin endocytosis. We also demonstrate that nuclear valosin-containing protein-like 2 (NVL2), an interacting protein of AMN, is involved in this process. Although NVL2 was mainly localized in the nucleolus in cells without AMN expression, it was translocated to the extranuclear compartment when coexpressed with AMN. NVL2 knockdown significantly impaired internalization of the CUBN-albumin complex in cultured cells, demonstrating an involvement of NVL2 in endocytic regulation. These findings uncover a link between membrane and nucleolar proteins that is involved in endocytic processes.


Assuntos
Endocitose , Proteínas Nucleares , Albuminas/genética , Membrana Celular , Rim , Proteínas Nucleares/genética
3.
Eur J Hum Genet ; 28(10): 1414-1421, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32457516

RESUMO

Nail-patella syndrome (NPS) is a multi-system disorder characterized by hypoplastic nails, hypoplastic patella, skeletal deformities, and iliac horns, which is caused by heterozygous variants of LMX1B. Nephropathy ranging from mild urinary abnormality to end-stage renal disease occurs in some individuals with NPS. Because of the low prevalence of NPS and the lack of longitudinal studies of its kidney involvement, the clinical, pathological, and genetic features characterizing severe nephropathy remain unclear. We conducted a Japanese survey of NPS with nephropathy, and analyzed their clinical course, pathological features, and factors associated with severe renal phenotype. LMX1B gene analysis and luciferase reporter assay were also performed. Among 13 NPS nephropathy cases with genetic validation, 5 patients who had moderate-to-massive proteinuria progressed to advanced chronic kidney disease or end-stage renal disease. Pathological findings in the early phase did not necessarily correlate with renal prognosis. Variants associated with deteriorated renal function including a novel variants were confined to the N-terminal region of the LIM domain and a short sequence in the LMX1B homeodomain, which were distinct from reported variants found in isolated nephropathy without extrarenal manifestation (LMX1B-associated nephropathy). Luciferase reporter analysis demonstrated that variants in patients with severe renal phenotype caused haploinsufficiency, but no dominant-negative effects on promoter activation. A distinct proportion of NPS nephropathy patients progressed to end-stage renal disease in adolescence or young adulthood. Patients with moderate or severe proteinuria, especially those with variants in specific regions of LMX1B, should be monitored for potential deterioration of renal function.


Assuntos
Síndrome da Unha-Patela/genética , Nefrite Hereditária/genética , Fenótipo , Proteinúria/genética , Adolescente , Animais , Células COS , Criança , Pré-Escolar , Chlorocebus aethiops , Feminino , Humanos , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Síndrome da Unha-Patela/patologia , Nefrite Hereditária/patologia , Regiões Promotoras Genéticas , Proteinúria/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
4.
Kidney Int Rep ; 4(9): 1312-1322, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517150

RESUMO

INTRODUCTION: Mutations in genes encoding nucleoporins (NUPs; components of nuclear pore complexes [NPCs]), such as NUP93, have been reported to cause steroid-resistant nephrotic syndrome (SRNS) or focal segmental glomerulosclerosis (FSGS), which often progresses to end-stage renal disease (ESRD) in childhood. The expression of NUP93 in renal or extrarenal tissues, and the mechanism by which NUP93 mutations cause this renal phenotype, remain unclear. METHODS: The expression of NUP93 in normal control kidney and in a patient with FSGS carrying NUP93 mutations was examined by immunofluorescence analysis. The expression of NUP93 in blood cells was analyzed by Western blot analysis. RESULTS: Immunofluorescence analysis detected NUP93 expression in nuclei of all glomerular and tubulointerstitial cells in human kidneys. Whole-exome sequencing identified a compound heterozygous NUP93 mutation comprising a novel missense mutation p.Arg525Trp, and a previously reported mutation, p.Tyr629Cys, in a patient with FSGS that developed ESRD at the age of 6 years. In the patient's kidney, the intensity of NUP93 immunofluorescence was significantly decreased in the nuclei of both glomerular and extraglomerular cells. The expression of CD2-associated protein (CD2AP) and nephrin in the patient's podocytes was relatively intact. The amount of NUP93 protein was not significantly altered in the peripheral blood mononuclear cells of the patient. CONCLUSION: NUP93 is expressed in the nuclei of all the cell types of the human kidney. Altered NUP93 expression in glomerular cells as well as extraglomerular cells by NUP93 mutations may underlie the pathogenic mechanism of SRNS or FSGS.

5.
Sci Rep ; 8(1): 2351, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29402915

RESUMO

Mutations in either cubilin (CUBN) or amnionless (AMN) genes cause Imerslund-Gräsbeck syndrome (IGS), a hereditary disease characterised by anaemia attributed to selective intestinal malabsorption of cobalamin and low-molecular weight proteinuria. Although cubilin protein does not have a transmembrane segment, it functions as a multi-ligand receptor by binding to the transmembrane protein, amnionless. We established a system to quantitatively analyse membrane targeting of the protein complex in cultured renal and intestinal cells and analysed the pathogenic mechanisms of mutations found in IGS patients. A novel CUBN mutation, several previously reported CUBN missense mutations and all previously reported AMN missense mutations resulted in endoplasmic reticulum (ER) retention and completely inhibited amnionless-dependent plasma membrane expression of cubilin. The ER retention of cubilin and amnionless was confirmed in renal proximal tubular cells of a patient with IGS. Notably, the interaction between cubilin and amnionless was not sufficient, but amnionless-mediated glycosylation of cubilin was necessary for their surface expression. Quantitative mass spectrometry and mutagenesis demonstrated that N-linked glycosylation of at least 4 residues of cubilin protein was required for its surface targeting. These results delineated the molecular mechanisms of membrane trafficking of cubilin in renal and intestinal cells.


Assuntos
Transporte Proteico , Proteínas/metabolismo , Receptores de Superfície Celular/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Retículo Endoplasmático/metabolismo , Glicosilação , Humanos , Mucosa Intestinal/metabolismo , Rim/metabolismo , Proteínas de Membrana , Mutação de Sentido Incorreto , Proteínas/genética , Receptores de Superfície Celular/genética
6.
Intern Med ; 55(20): 3029-3034, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27746444

RESUMO

Tumor lysis syndrome (TLS) is a metabolic disorder that is generally associated with a malignancy leading to hyperuricemia, hyperphosphatemia, and acute kidney injury. On the other hand, we sometimes encounter these phenomena in nonmalignant disease, which has been referred to as tumor lysis-like syndrome in some studies. We herein experienced a case in which tumor lysis-like syndrome occurred in the course of therapy for eosinophilic disease of the lung, a nonmalignant disease. Even in nonmalignant disease, massive cell lysis induced by therapy can cause phenomena such as TLS or tumor lysis-like syndrome.


Assuntos
Eosinofilia Pulmonar/complicações , Síndrome de Lise Tumoral/diagnóstico , Síndrome de Lise Tumoral/etiologia , Idoso , Glucocorticoides/uso terapêutico , Humanos , Masculino , Metilprednisolona/uso terapêutico , Eosinofilia Pulmonar/tratamento farmacológico , Síndrome de Lise Tumoral/terapia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...