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Nature Reviews. Nephrology Feb 2021The glomerular basement membrane (GBM) is a key component of the glomerular capillary wall and is essential for kidney filtration. The major components of the GBM... (Review)
Review
The glomerular basement membrane (GBM) is a key component of the glomerular capillary wall and is essential for kidney filtration. The major components of the GBM include laminins, type IV collagen, nidogens and heparan sulfate proteoglycans. In addition, the GBM harbours a number of other structural and regulatory components and provides a reservoir for growth factors. New technologies have improved our ability to study the composition and assembly of basement membranes. We now know that the GBM is a complex macromolecular structure that undergoes key transitions during glomerular development. Defects in GBM components are associated with a range of hereditary human diseases such as Alport syndrome, which is caused by defects in the genes COL4A3, COL4A4 and COL4A5, and Pierson syndrome, which is caused by variants in LAMB2. In addition, the GBM is affected by acquired autoimmune disorders and metabolic diseases such as diabetes mellitus. Current treatments for diseases associated with GBM involvement aim to reduce intraglomerular pressure and to treat the underlying cause where possible. As our understanding about the maintenance and turnover of the GBM improves, therapies to replace GBM components or to stimulate GBM repair could translate into new therapies for patients with GBM-associated disease.
Topics: Anti-Glomerular Basement Membrane Disease; Diabetic Nephropathies; Glomerular Basement Membrane; Humans; Myasthenic Syndromes, Congenital; Nephritis, Hereditary; Nephrotic Syndrome; Pupil Disorders
PubMed: 32839582
DOI: 10.1038/s41581-020-0329-y -
Matrix Biology : Journal of the... Oct 2018The glomerular basement membrane (GBM) is an important component of the kidney's glomerular filtration barrier. Like all basement membranes, the GBM contains type IV... (Review)
Review
The glomerular basement membrane (GBM) is an important component of the kidney's glomerular filtration barrier. Like all basement membranes, the GBM contains type IV collagen, laminin, nidogen, and heparan sulfate proteoglycan. It is flanked by the podocytes and glomerular endothelial cells that both synthesize it and adhere to it. Mutations that affect the GBM's collagen α3α4α5(IV) components cause Alport syndrome (kidney disease with variable ear and eye defects) and its variants, including thin basement membrane nephropathy. Mutations in LAMB2 that impact the synthesis or function of laminin α5β2γ1 (LM-521) cause Pierson syndrome (congenital nephrotic syndrome with eye and neurological defects) and its less severe variants, including isolated congenital nephrotic syndrome. The very different types of kidney diseases that result from mutations in collagen IV vs. laminin are likely due to very different pathogenic mechanisms. A better understanding of these mechanisms should lead to targeted therapeutic approaches that can help people with these rare but important diseases.
Topics: Abnormalities, Multiple; Collagen Type IV; Eye Abnormalities; Glomerular Basement Membrane; Humans; Laminin; Mutation; Myasthenic Syndromes, Congenital; Nephritis, Hereditary; Nephrotic Syndrome; Pupil Disorders
PubMed: 29673759
DOI: 10.1016/j.matbio.2018.04.008 -
Kidney360 Dec 2021
Topics: Collagen Type IV; Female; Humans; Laminin; Male; Nephritis, Hereditary
PubMed: 35419542
DOI: 10.34067/KID.0007312021 -
Pediatric Nephrology (Berlin, Germany) Nov 2021Genetic studies of hereditary nephrotic syndrome (NS) have identified more than 50 genes that, if mutated, are responsible for monogenic forms of steroid-resistant NS... (Review)
Review
Genetic studies of hereditary nephrotic syndrome (NS) have identified more than 50 genes that, if mutated, are responsible for monogenic forms of steroid-resistant NS (SRNS), either isolated or syndromic. Most of these genes encode proteins expressed in the podocyte with various functions such as transcription factors, mitochondrial proteins, or enzymes, but mainly structural proteins of the slit diaphragm (SD) as well as cytoskeletal binding and regulator proteins. Syndromic NS is sometimes associated with neurological features. Over recent decades, various studies have established links between the physiology of podocytes and neurons, both morphologically (slit diaphragm and synapse) and functionally (signaling platforms). Variants in genes expressed in different compartments of the podocyte and neurons are responsible for phenotypes associating kidney lesions with proteinuria (mainly Focal and Segmental Glomerulosclerosis (FSGS) or Diffuse Mesangial Sclerosis (DMS)) and central and/or peripheral neurological disorders. The Galloway-Mowat syndrome (GAMOS, OMIM#251300) associates neurological defects, microcephaly, and proteinuria and is caused by variants in genes encoding proteins of various functions (microtubule cytoskeleton regulation (WDR73), regulation of protein synthesis via transfer RNAs (KEOPS and WDR4 complexes)). Pierson syndrome (OMIM#609049) associating congenital nephrotic syndrome and central neurological and ophthalmological anomalies is secondary to variants in LAMB2, involved in glomerular and ocular basement membranes. Finally, Charcot-Marie-Tooth-FSGS (OMIM#614455) combines peripheral sensory-motor neuropathy and proteinuria and arises from INF2 variants, resulting in cytoskeletal polymerization defects. This review focuses on genetic syndromes associating nephrotic range proteinuria and neurological involvement and provides the latest advances in the description of these neuro-renal disorders.
Topics: Humans; Nephrotic Syndrome; Proteinuria
PubMed: 33791874
DOI: 10.1007/s00467-020-04903-x -
The Journal of Biological Chemistry Jun 2024Polymerizing laminins are multi-domain basement membrane (BM) glycoproteins that self-assemble into cell-anchored planar lattices to establish the initial BM scaffold.... (Review)
Review
Polymerizing laminins are multi-domain basement membrane (BM) glycoproteins that self-assemble into cell-anchored planar lattices to establish the initial BM scaffold. Nidogens, collagen-IV and proteoglycans then bind to the scaffold at different domain loci to create a mature BM. The LN domains of adjacent laminins bind to each other to form a polymer node, while the LG domains attach to cytoskeletal-anchoring integrins and dystroglycan, as well as to sulfatides and heparan sulfates. The polymer node, the repeating unit of the polymer scaffold, is organized into a near-symmetrical triskelion. The structure, recently solved by cryo-electron microscopy in combination with AlphaFold2 modeling and biochemical studies, reveals how the LN surface residues interact with each other and how mutations cause failures of self-assembly in an emerging group of diseases, the LN-lamininopathies, that include LAMA2-related dystrophy and Pierson syndrome.
PubMed: 38825010
DOI: 10.1016/j.jbc.2024.107429 -
American Journal of Kidney Diseases :... Apr 2018
Review
Topics: Abnormalities, Multiple; Diagnosis, Differential; Eye Abnormalities; Humans; Kidney; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Periodicals as Topic; Pupil Disorders
PubMed: 29579420
DOI: 10.1053/j.ajkd.2018.02.001 -
BMC Ophthalmology Feb 2023Pierson syndrome is a rare autosomal recessive disorder that causes congenital nephrotic syndrome, neurodevelopmental abnormalities, and several ocular signs. The...
BACKGROUND
Pierson syndrome is a rare autosomal recessive disorder that causes congenital nephrotic syndrome, neurodevelopmental abnormalities, and several ocular signs. The Pierson syndrome is caused by a mutation of the LAMB2 gene, that encodes laminin beta 2, which is expressed in the glomerular basement membrane, in neuromuscular junctions, and within ocular structures. First described by Pierson et al., the ocular signs of Pierson syndrome include microcoria, which is most characteristic sign, as well as iris abnormalities, cataract, glaucoma, and retinal detachment.
CASE PRESENTATION
Herein, we report the case of a young female who, at 16 months, was diagnosed with congenital nephrotic syndrome, subsequently underwent a kidney transplant at age 4,did cataract surgery with IOL implantation in both eyes at age of 2 years and presented with ocular signs including high myopia, band keratopathy, t, nystagmus, retina, and optic nerve atrophy, she did not show nor did the family report any neurodevelopmental abnormalities. her genetic studies this missense variant c.970T< C p. (Cys324Arg) of LAMB2, later she developed spontaneous hyphema along with vitreous haemorrhage and increased intra ocular pressure in her left eye, she underwent cyclophotocouagulation to treat her high IOP.
CONCLUSION
LAMB 2 mutations can be associated with multiple ocular signs that varies from mild to severe form, we are her to report our case who did not present with the typical ocular sign of microcoria for PS, did not have any neurodevelopmental abnormality and presented with hyphaemia 2ndry to iris neovascularisation with vitreous haemorrhage with neovascular glaucoma.
Topics: Female; Humans; Nephrotic Syndrome; Hyphema; Glaucoma, Neovascular; Vitreous Hemorrhage; Hemorrhage; Cataract
PubMed: 36829142
DOI: 10.1186/s12886-023-02826-3 -
Sultan Qaboos University Medical Journal Nov 2020Pierson syndrome is caused by mutations in the gene causing absent β2 laminin, which is a normal component of the basement membranes of the mature glomerulus,...
Pierson syndrome is caused by mutations in the gene causing absent β2 laminin, which is a normal component of the basement membranes of the mature glomerulus, structures in the anterior eye and neuromuscular junctions. The mutations manifest as congenital nephrotic syndrome and microcoria which are characteristic ocular features of this disease. These mutations may also result in neurological abnormalities such as hypotonia and psychomotor retardation. We report a two-month old boy who presented to the Pediatrics Department of Dr. Ruth K. M. Pfau Civil Hospital, Karachi, Pakistan, in 2015, with the typical features of microcoria and congenital nephrotic syndrome. The hypocalcaemia, hypoproteinaemia and probable immunocompromised state consequent to nephrotic syndrome resulted in seizures, hypothyroidism and urosepsis. Despite being treated aggressively with high dose antibiotics, ionotropic support, angiotensin-converting enzyme inhibitors, thyroxine replacement and nutritional support, the infant died due to significant multiorgan disease including renal failure and septic shock.
Topics: Child; Humans; Hypothyroidism; Infant; Male; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders; Shock, Septic
PubMed: 33414946
DOI: 10.18295/squmj.2020.20.04.017 -
Frontiers in Pediatrics 2018The glomerular basement membrane (GBM) is a specialized structure with a significant role in maintaining the glomerular filtration barrier. This GBM is formed from the... (Review)
Review
The glomerular basement membrane (GBM) is a specialized structure with a significant role in maintaining the glomerular filtration barrier. This GBM is formed from the fusion of two basement membranes during development and its function in the filtration barrier is achieved by key extracellular matrix components including type IV collagen, laminins, nidogens, and heparan sulfate proteoglycans. The characteristics of specific matrix isoforms such as laminin-521 (α5β2γ1) and the α3α4α5 chain of type IV collagen are essential for the formation of a mature GBM and the restricted tissue distribution of these isoforms makes the GBM a unique structure. Detailed investigation of the GBM has been driven by the identification of inherited abnormalities in matrix proteins and the need to understand pathogenic mechanisms causing severe glomerular disease. A well-described hereditary GBM disease is Alport syndrome, associated with a progressive glomerular disease, hearing loss, and lens defects due to mutations in the genes , or . Other proteins associated with inherited diseases of the GBM include laminin β2 in Pierson syndrome and in nail patella syndrome. The knowledge of these genetic mutations associated with GBM defects has enhanced our understanding of cell-matrix signaling pathways affected in glomerular disease. This review will address current knowledge of GBM-associated abnormalities and related signaling pathways, as well as discussing the advances toward disease-targeted therapies for patients with glomerular disease.
PubMed: 29435440
DOI: 10.3389/fped.2018.00011 -
CEN Case Reports Dec 2023Pierson syndrome (PS) is a rare autosomal recessive disease, characterized by congenital nephrotic syndrome (CNS), and ocular and neurologic abnormalities. In affected...
Pierson syndrome (PS) is a rare autosomal recessive disease, characterized by congenital nephrotic syndrome (CNS), and ocular and neurologic abnormalities. In affected cases, there is abnormal b-2 laminin which is compound of the several basement membranes caused by inherited mutations in the LAMB2 gene. Although patients have mutations in the same gene, the phenotype is highly variable. In this case series, the relationship between genotype and phenotype is emphasized, and information about the clinical follow-up of the patients is presented. Hereby, we report four pediatric cases with PS as a result of mutation in the LAMB2 gene. Clinical spectrum of LAMB2-associated disorders varies from mild-to-severe ocular, kidney, and neurologic involvement. Since genotype-phenotype correlation in PS has not been clearly demonstrated, we recommend that all patients with ophthalmic anomalies and glomerular proteinuria should be tested for LAMB2 mutations.
PubMed: 38038886
DOI: 10.1007/s13730-023-00838-y