Congenital focal segmental glomerulosclerosis associated with β4 integrin mutation and epidermolysis bullosa

Kambham, Neeraja; Tanji, Nozomu; Seigle, Robert L.; Markowitz, Glen S.; Pulkkinen, Leena; Uitto, Jouni; D’Agati, Vivette D.

doi:10.1053/ajkd.2000.8293

Cited by 88 publications

(55 citation statements)

References 23 publications

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“…21 Proteinuria and mild hypoalbuminemia (not in the nephrotic range), secondary to focal segmental glomerulosclerosis, have been reported in epidermolysis bullosa with pyloric atresia, an autosomal recessive disease caused by mutations in the genes encoding either 1 of the 2 subunits of ␣6␤4 integrin, which are expressed in the hemidesmosomes of a variety of epithelial tissues, including human skin and the gastrointestinal tract. 22 In the case of epidermolysis bullosa with pyloric atresia, reduced ␤4 integrin expression was demonstrated in glomerular podocytes. 22 The finding that ␣6␤4 integrin functions as a receptor for laminin-5 23 supports the functional importance of laminin-5 in human kidney.…”

Section: Resultsmentioning

confidence: 99%

“…22 In the case of epidermolysis bullosa with pyloric atresia, reduced ␤4 integrin expression was demonstrated in glomerular podocytes. 22 The finding that ␣6␤4 integrin functions as a receptor for laminin-5 23 supports the functional importance of laminin-5 in human kidney. It has been shown that both laminin-5 and laminin-binding integrins play a role in kidney development and ureteric bud branching morphogenesis in embryonic rats.…”

Section: Resultsmentioning

confidence: 99%

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Nephrotic Syndrome and Aberrant Expression of Laminin Isoforms in Glomerular Basement Membranes for an Infant With Herlitz Junctional Epidermolysis Bullosa

Hata

Miyazaki²,

Seto³

et al. 2005

Pediatrics

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ABSTRACT. Herlitz junctional epidermolysis bullosa (H-JEB) is a hereditary bullous disease caused by absent expression of laminin-5, a component of anchoring filaments within the dermal-epidermal basement membrane zone. Affected individuals usually die during the first 1 year of life. We studied an infant with H-JEB who presented with nephrotic syndrome, a previously unreported complication that may contribute to early death in this disease. DNA analysis revealed a compound heterozygote for mutations 2379delG and Q995X in the LAMB3 gene. The patient had massive albuminuria, attributable to failure of the glomerular filtration barrier, and high urinary N-acetylglucosaminidase levels, indicating renal tubular involvement. Electron-microscopic examination of the renal tissue revealed diffuse fusion of the foot processes, irregular swelling of the lamina rara interna, and disappearance of endothelial cell fenestrations. Immunohistopathologic analysis of the patient's renal tissue revealed compositional changes in laminin isoforms of the glomerular basement membrane and no detectable laminin-5 in the renal tubular basement membrane, which suggests that laminin-5 may play an important role in renal function. Our findings strongly suggest that H-JEB should be considered in the spectrum of congenital nephrotic syndromes. Combination therapy with meticulous skin care and treatment strategies established for congenital nephrotic syndromes may rescue patients with this disease. Pediatrics 2005;116:e601-e607. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2005-0160; Herlitz junctional epidermolysis bullosa, laminin-5, nephrotic syndrome, proteinuria, glomerular basement membrane.ABBREVIATIONS. H-JEB, Herlitz junctional epidermolysis bullosa; PTC, premature termination codon; GBM, glomerular basement membrane; TBM, tubular basement membrane; NAG, Nacetylglucosaminidase; mAb, monoclonal antibody; PCR, polymerase chain reaction. J unctional epidermolysis bullosa is a group of autosomal recessive diseases characterized by profound skin fragility, with blister formation resulting from dermal-epidermal disadhesion at the level of the lamina lucida within the basement membrane zone. The most severe form, Herlitz junctional epidermolysis bullosa (H-JEB), manifests with generalized blistering and erosions of the skin, with extracutaneous involvement, and is usually lethal during the first 1 year of life. 1 Immunohistochemical and molecular genetic studies have demonstrated that the underlying cause of H-JEB is absent expression of laminin-5, a component of anchoring filaments traversing the lamina lucida of the dermal-epidermal basement membrane zone. A characteristic genetic lesion is a premature termination codon (PTC)-causing mutation in both alleles of 1 of the 3 genes (LAMA3, LAMB3, and LAMC2) encoding the subunit polypeptides of laminin-5 (ie, the ␣3, ␤3, and ␥2 chains, respectively). Because all 3 chains are necessary for the structural assembly of trimeric laminin-5 macromolecules, defects in any of the 3 genes can result in c...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Nephrotic Syndrome and Aberrant Expression of Laminin Isoforms in Glomerular Basement Membranes for an Infant With Herlitz Junctional Epidermolysis Bullosa

Hata

Miyazaki²,

Seto³

et al. 2005

Pediatrics

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“…Table 2 lists the major extrarenal manifestations associated with gene defects causing syndromic SRNS; if extra-renal manifestations are present, it is highly likely that a causative mutation will be identified. A full description of syndromic SRNS is beyond the scope of this review but readers are directed to several detailed reviews for a thorough discussion [5,20,21,44,45,50,55,84,86,87].…”

Section: Syndromic Srns and Mitochondrial Disordersmentioning

confidence: 99%

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

2017

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Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

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“…In this regard, a patient presenting with FSGS and a mutation in the integrin b4 subunit has been described. 18 Studies in mice null for the integrin a6 and/or b4 subunit in the kidney need to be conducted to define the contribution of integrins a6b1 and a6b4 in kidney repair after injury.…”

Section: The Laminin Receptorsmentioning

confidence: 99%

Integrins in Kidney Disease

Pozzi

Zent²

2013

Journal of the American Society of Nephrology

104

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A major hallmark of chronic kidney injury is fibrosis, which is characterized by increased accumulation of extracellular matrix components that replace the damaged tissue. Normally, the synthesis and degradation of extracellular matrix components are finely regulated; however, when matrix replacement goes unchecked, there is unwanted and irreversible tissue scarring with consequent organ damage, organ failure, and, in certain cases, death. Many factors, including cell-matrix interactions, play a role in the development of renal fibrosis. Cell-matrix interactions are made possible by integrins, a family of transmembrane receptors that, upon binding to the extracellular matrix, activate intracellular signaling. Thus, they control various cell functions, including survival, proliferation, migration, and matrix homeostasis. Genetic mutations in humans and the development of animal models lacking integrins in selective parts of the kidney have improved our understanding of molecular mechanisms and pathways controlling matrix remodeling in kidney disease. Here we outline the major integrins involved in kidney disease and some of the major molecular mechanisms whereby integrins contribute to kidney fibrosis.

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Congenital focal segmental glomerulosclerosis associated with β4 integrin mutation and epidermolysis bullosa

Cited by 88 publications

References 23 publications

Nephrotic Syndrome and Aberrant Expression of Laminin Isoforms in Glomerular Basement Membranes for an Infant With Herlitz Junctional Epidermolysis Bullosa

Nephrotic Syndrome and Aberrant Expression of Laminin Isoforms in Glomerular Basement Membranes for an Infant With Herlitz Junctional Epidermolysis Bullosa

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

Integrins in Kidney Disease

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