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Frontiers in Medicine 2019Pierson syndrome (OMIM 609049) is a rare autosomal recessive disorder characterized by congenital nephrotic syndrome and complex ocular abnormalities. Severe renal...
Pierson syndrome (OMIM 609049) is a rare autosomal recessive disorder characterized by congenital nephrotic syndrome and complex ocular abnormalities. Severe renal symptoms had be associated with truncating mutations. Few Chinese patients from diverse ethnic background had been evaluated and reported with this syndrome. Here we report the first Uyghur patient with typical Pierson syndrome phenotypes and a novel pathogenic homozygous variant in gene. A thirty-nine-day old Uyghur girl was born to consanguineous parents, the girl presented with general edema, severe hypotonia and bilateral microcoria. Laboratory tests revealed severe proteinuria, microscopic haematuria, hypoalbuminaemia. By the age of 74 days, she died of renal failure and respiratory infection. We detected on mutations of gene by the sanger sequencing. Sanger sequencing detected a homozygous 2-bp deletion (c.2044_2045insTT/p.Cys682Phefs13) in the exon 16 of gene. Both parents are heterozygous carriers. We reported the first Uyghur case of gene homozygous mutation leading to severe phenotype Pierson syndrome. The clinical presentation of the patient and the novel pathogenic variant detected in this patient added to the overall knowledge of this rare condition.
PubMed: 30778388
DOI: 10.3389/fmed.2019.00012 -
Journal of AAPOS : the Official... Oct 2018Pierson syndrome, an autosomal recessive disorder caused by a mutation in laminin ß2 (LAMB2) gene, is characterized by congenital nephrotic syndrome and various ocular...
Pierson syndrome, an autosomal recessive disorder caused by a mutation in laminin ß2 (LAMB2) gene, is characterized by congenital nephrotic syndrome and various ocular abnormalities. The ocular findings in Pierson syndrome are not well understood, because the incidence of this syndrome is very rare. We report ocular findings in a 5-month-old boy with Pierson syndrome with a novel mutation in LAMB2. We performed a pupilloplasty for his microcoria. Ophthalmic examinations after surgery revealed that he had cataract, severe retinal degeneration, and high myopia. Optical coherence tomography showed the collapse of retinal layer structures and a marked decrease of choroidal thickness. Immunohistochemistry and electron microscopy examinations revealed abnormal iris differentiation and thinning or defect of basal membranes. These results suggest that the development of the iris, lens, retina, and choroid are affected in this type of mutation.
Topics: Abnormalities, Multiple; Cataract; Eye Abnormalities; Humans; Infant; Laminin; Male; Mutation; Myasthenic Syndromes, Congenital; Myopia, Degenerative; Nephrotic Syndrome; Pupil Disorders; Retinal Degeneration
PubMed: 30120985
DOI: 10.1016/j.jaapos.2018.03.016 -
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 -
Journal of the American Society of... May 2018
Topics: Abnormalities, Multiple; Eye Abnormalities; Glomerular Basement Membrane; Humans; Laminin; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Podocytes; Pupil Disorders
PubMed: 29650536
DOI: 10.1681/ASN.2018030294 -
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 -
Journal of the American Society of... May 2018Laminin 521 (LM-521) is a major component of the GBM. Mutations in that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic...
Laminin 521 (LM-521) is a major component of the GBM. Mutations in that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic syndrome with diffuse mesangial sclerosis and ocular and neurologic defects. Because the GBM is uniquely accessible to plasma, which permeates endothelial cell fenestrae, we hypothesized that intravenous delivery of LM-521 could replace the missing LM-521 in the GBM of mutant mice and restore glomerular permselectivity. We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of -/- pups daily. Deposition of hLM-521 into the GBM was investigated by fluorescence microscopy. We assayed the effects of hLM-521 on glomerular permselectivity by urinalysis and the effects on podocytes by desmin immunostaining and ultrastructural analysis of podocyte architecture. Injected hLM-521 rapidly and stably accumulated in the GBM of all glomeruli. Super-resolution imaging showed that hLM-521 accumulated in the correct orientation in the GBM, primarily on the endothelial aspect. Treatment with hLM-521 greatly reduced the expression of the podocyte injury marker desmin and attenuated the foot process effacement observed in untreated pups. Moreover, treatment with hLM-521 delayed the onset of proteinuria but did not prevent nephrotic syndrome, perhaps due to its absence from the podocyte aspect of the GBM. These studies show that GBM composition and function can be altered vascular delivery of even very large proteins, which may advance therapeutic options for patients with abnormal GBM composition, whether genetic or acquired.
Topics: Abnormalities, Multiple; Animals; Desmin; Disease Models, Animal; Eye Abnormalities; Glomerular Basement Membrane; Injections, Intravenous; Laminin; Mice; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Permeability; Podocytes; Proteinuria; Pupil Disorders; Recombinant Proteins
PubMed: 29472414
DOI: 10.1681/ASN.2017060690 -
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 -
Matrix Biology : Journal of the... Apr 2018Laminin polymerization is a key step of basement membrane self-assembly that depends on the binding of the three different N-terminal globular LN domains. Several...
Laminin polymerization is a key step of basement membrane self-assembly that depends on the binding of the three different N-terminal globular LN domains. Several mutations in the LN domains cause LAMA2-deficient muscular dystrophy and LAMB2-deficient Pierson syndrome. These mutations may affect polymerization. A novel approach to identify the amino acid residues required for polymerization has been applied to an analysis of these and other laminin LN mutations. The approach utilizes laminin-nidogen chimeric fusion proteins that bind to recombinant non-polymerizing laminins to provide a missing functional LN domain. Single amino acid substitutions introduced into these chimeras were tested to determine if polymerization activity and the ability to assemble on cell surfaces were lost. Several laminin-deficient muscular dystrophy mutations, renal Pierson syndrome mutations, and Drosophila mutations causing defects of heart development were identified as ones causing loss of laminin polymerization. In addition, two novel residues required for polymerization were identified in the laminin γ1 LN domain.
Topics: Abnormalities, Multiple; Amino Acid Motifs; Animals; Basement Membrane; Drosophila; Drosophila Proteins; Eye Abnormalities; HEK293 Cells; Humans; Laminin; Membrane Glycoproteins; Models, Molecular; Muscular Dystrophies; Mutation; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Protein Binding; Protein Multimerization; Pupil Disorders; Recombinant Fusion Proteins
PubMed: 29408412
DOI: 10.1016/j.matbio.2018.01.012 -
Journal of the American Society of... Mar 2018Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin 2 (), a major component of the glomerular basement...
Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin 2 (), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient's nephrotic syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a mouse model of autosomal recessive Alport syndrome and increased proteinuria in females that exhibit a mild form of X-linked Alport syndrome due to mosaic deposition of collagen 345(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport syndrome onset and severity observed in patients with Alport syndrome, even for family members who share the same mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans.
Topics: Abnormalities, Multiple; Animals; Autoantigens; Collagen Type IV; Disease Models, Animal; Disease Progression; Eye Abnormalities; Female; Glomerular Basement Membrane; Humans; Kidney Failure, Chronic; Laminin; Mice; Mice, Transgenic; Mutation, Missense; Myasthenic Syndromes, Congenital; Nephritis, Hereditary; Nephrotic Syndrome; Phenotype; Polymerization; Proteinuria; Pupil Disorders
PubMed: 29263159
DOI: 10.1681/ASN.2017090997 -
Pediatric Transplantation Dec 2017Congenital nephrotic syndrome is commonly associated with mutations in genes that encode podocyte and slit diaphragm proteins or the structural and regulatory proteins...
Congenital nephrotic syndrome is commonly associated with mutations in genes that encode podocyte and slit diaphragm proteins or the structural and regulatory proteins of the GBM. These mutations lead to the formation of dysfunctional proteins, which account for the resistance of the renal manifestations to conventional treatment methods. Consequently, patients become renal replacement therapy dependent. Mutation of the LAMB2 gene is associated with Pierson syndrome, which is an autosomal recessive disorder characterized by congenital nephrotic syndrome and ocular abnormalities. In this report, a 2-year-old male patient who was diagnosed with Pierson syndrome is presented. He had bilateral microcoria and developmental delay in addition to nephrotic syndrome. His renal function deteriorated rapidly, and he underwent a deceased donor kidney transplantation. He showed dramatic improvement after kidney transplantation; in addition to having good renal function, he started to catch up to his peers in terms of growth. Pierson syndrome should be considered during the diagnostic investigations of children with renal manifestations and ocular abnormalities. Children with Pierson syndrome must be evaluated in terms of kidney transplantation as soon as they are diagnosed.
Topics: Abnormalities, Multiple; Child, Preschool; Eye Abnormalities; Humans; Kidney Transplantation; Male; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders
PubMed: 29094445
DOI: 10.1111/petr.13076