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Indian Journal of Pediatrics Dec 2014
Topics: Abnormalities, Multiple; Diagnosis, Differential; Eye Abnormalities; Humans; Infant, Newborn; Male; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders
PubMed: 24944146
DOI: 10.1007/s12098-014-1507-3 -
The Journal of Pathology May 2014The study of mutations causing the steroid-resistant nephrotic syndrome in children has greatly advanced our understanding of the kidney filtration barrier. In...
The study of mutations causing the steroid-resistant nephrotic syndrome in children has greatly advanced our understanding of the kidney filtration barrier. In particular, these genetic variants have illuminated the roles of the podocyte, glomerular basement membrane and endothelial cell in glomerular filtration. However, in a significant number of familial and early onset cases, an underlying mutation cannot be identified, indicating that there are likely to be multiple unknown genes with roles in glomerular permeability. We now show how the combination of N-ethyl-N-nitrosourea mutagenesis and next-generation sequencing could be used to identify the range of mutations affecting these pathways. Using this approach, we isolated a novel mouse strain with a viable nephrotic phenotype and used whole-genome sequencing to isolate a causative hypomorphic mutation in Lamb2. This discovery generated a model for one part of the spectrum of human Pierson's syndrome and provides a powerful proof of principle for accelerating gene discovery and improving our understanding of inherited forms of renal disease.
Topics: Abnormalities, Multiple; Animals; DNA Mutational Analysis; Disease Models, Animal; Ethylnitrosourea; Eye Abnormalities; Genetic Association Studies; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Kidney Tubules; Laminin; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pedigree; Phenotype; Proteinuria; Pupil Disorders
PubMed: 24293254
DOI: 10.1002/path.4308 -
Genetic Counseling (Geneva, Switzerland) 2013Pierson syndrome is a rare autosomal recessive disorder which is mainly characterized by congenital nephrotic syndrome (CNS), diffuse mesangial sclerosis (DMS) and...
Pierson syndrome is a rare autosomal recessive disorder which is mainly characterized by congenital nephrotic syndrome (CNS), diffuse mesangial sclerosis (DMS) and distinct ocular abnormalities, including microcoria. Most affected children exhibit early onset of chronic renal failure, neurodevelopmental deficits, and blindness. It is caused by a homozygous or compound heterozygous mutation in the gene encoding laminin beta2 (LAMB2) on chromosome 3p21. In this article, we report on a patient with CNS, bilateral megalocornea and microcoria. The patient had developed renal failure at very early postnatal period and died of septic shock. A novel homozygous donor splice mutation (IVS4 + 2T > C) in LAMB2 gene was identified in the patient.
Topics: Abnormalities, Multiple; Eye Abnormalities; Fatal Outcome; Female; Gestational Age; Humans; Infant, Newborn; Laminin; Mutation; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders; RNA Splicing
PubMed: 24032283
DOI: No ID Found -
Nature Reviews. Nephrology Aug 2013The glomerular basement membrane (GBM) is the central, non-cellular layer of the glomerular filtration barrier that is situated between the two cellular... (Review)
Review
The glomerular basement membrane (GBM) is the central, non-cellular layer of the glomerular filtration barrier that is situated between the two cellular components--fenestrated endothelial cells and interdigitated podocyte foot processes. The GBM is composed primarily of four types of extracellular matrix macromolecule--laminin-521, type IV collagen α3α4α5, the heparan sulphate proteoglycan agrin, and nidogen--which produce an interwoven meshwork thought to impart both size-selective and charge-selective properties. Although the composition and biochemical nature of the GBM have been known for a long time, the functional importance of the GBM versus that of podocytes and endothelial cells for establishing the glomerular filtration barrier to albumin is still debated. Together with findings from genetic studies in mice, the discoveries of four human mutations affecting GBM components in two inherited kidney disorders, Alport syndrome and Pierson syndrome, support essential roles for the GBM in glomerular permselectivity. Here, we explain in detail the proposed mechanisms whereby the GBM can serve as the major albumin barrier and discuss possible approaches to circumvent GBM defects associated with loss of permselectivity.
Topics: Abnormalities, Multiple; Albumins; Animals; Collagen Type IV; Eye Abnormalities; Glomerular Basement Membrane; Humans; Laminin; Membrane Glycoproteins; Mutation; Myasthenic Syndromes, Congenital; Nephritis, Hereditary; Nephrotic Syndrome; Pupil Disorders
PubMed: 23774818
DOI: 10.1038/nrneph.2013.109 -
Journal of the American Society of... Jul 2013Mutations in the laminin β2 gene (LAMB2) cause Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects. LAMB2 is a component of the...
Mutations in the laminin β2 gene (LAMB2) cause Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects. LAMB2 is a component of the laminin-521 (α5β2γ1) trimer, an important constituent of the glomerular basement membrane (GBM). The C321R-LAMB2 missense mutation leads to congenital nephrotic syndrome but only mild extrarenal symptoms; the mechanisms underlying the development of proteinuria with this mutation are unclear. We generated three transgenic mouse lines, in which rat C321R-LAMB2 replaced mouse LAMB2 in the GBM. During the first postnatal month, expression of C321R-LAMB2 attenuated the severe proteinuria exhibited by Lamb2(-/-) mice in a dose-dependent fashion; proteinuria eventually increased, however, leading to renal failure. The C321R mutation caused defective secretion of laminin-521 from podocytes to the GBM accompanied by podocyte endoplasmic reticulum (ER) stress, likely resulting from protein misfolding. Moreover, ER stress preceded the onset of significant proteinuria and was manifested by induction of the ER-initiated apoptotic signal C/EBP homologous protein (CHOP), ER distention, and podocyte injury. Treatment of cells expressing C321R-LAMB2 with the chemical chaperone taurodeoxycholic acid (TUDCA), which can facilitate protein folding and trafficking, greatly increased the secretion of the mutant LAMB2. Taken together, these results suggest that the mild variant of Pierson syndrome caused by the C321R-LAMB2 mutation may be a prototypical ER storage disease, which may benefit from treatment approaches that target the handling of misfolded proteins.
Topics: Abnormalities, Multiple; Animals; Endoplasmic Reticulum Stress; Eye Abnormalities; Glomerular Basement Membrane; Laminin; Mice; Mice, Transgenic; Mutation; Mutation, Missense; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Podocytes; Pupil Disorders; Rats
PubMed: 23723427
DOI: 10.1681/ASN.2012121149 -
Pediatrics International : Official... Apr 2013Pierson syndrome (OMIM 609049) is typically characterized by congenital nephritic syndrome and peculiar ocular anomalies with microcoria. It is caused by mutations in...
Pierson syndrome (OMIM 609049) is typically characterized by congenital nephritic syndrome and peculiar ocular anomalies with microcoria. It is caused by mutations in LAMB2, which encodes laminin β2. Approximately 50 mutations of LAMB2 from approximately 40 unrelated families have been identified; however, most of them were from Western countries. Although three patients in Asia with mutations of LAMB2 have been reported, they were not typical cases. We report the first Japanese case of Pierson syndrome with proven causative LAMB2 mutations. She presented with congenital nephrotic syndrome and bilateral microcoria at birth, and developed end-stage renal disease at 2 months of age. This is the first report of a typical case from Asia. LAMB2 analysis by direct sequencing revealed the compound heterozygous mutations c.3974_3975insA (p.N1325KfsX1331, maternal, novel) in exon 25 and c.4519C>T (p.Q1507X, paternal) in exon 27. The phenotype due to LAMB2 mutations appears to be similar between different ethnic groups.
Topics: Abnormalities, Multiple; DNA; DNA Mutational Analysis; Eye Abnormalities; Female; Humans; Infant, Newborn; Japan; Laminin; Mutation; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Phenotype; Pupil Disorders
PubMed: 23679161
DOI: 10.1111/j.1442-200X.2012.03629.x -
Annals of the New York Academy of... Dec 2012Presynaptic active zones are synaptic vesicle release sites that play essential roles in the function and pathology of mammalian neuromuscular junctions (NMJs). The... (Review)
Review
Presynaptic active zones are synaptic vesicle release sites that play essential roles in the function and pathology of mammalian neuromuscular junctions (NMJs). The molecular mechanisms of active zone organization use presynaptic voltage-dependent calcium channels (VDCCs) in NMJs as scaffolding proteins. VDCCs interact extracellularly with the muscle-derived synapse organizer, laminin β2 and interact intracellularly with active zone-specific proteins, such as Bassoon, CAST/Erc2/ELKS2alpha, ELKS, Piccolo, and RIMs. These molecular mechanisms are supported by studies in P/Q- and N-type VDCCs double-knockout mice, and they are consistent with the pathological conditions of Lambert-Eaton myasthenic syndrome and Pierson syndrome, which are caused by autoantibodies against VDCCs or by a laminin β2 mutation. During normal postnatal maturation, NMJs maintain the density of active zones, while NMJs triple their size. However, active zones become impaired during aging. Propitiously, muscle exercise ameliorates the active zone impairment in aged NMJs, which suggests the potential for therapeutic strategies.
Topics: Abnormalities, Multiple; Aging; Animals; Autoantibodies; Calcium Channels; Eye Abnormalities; Humans; Lambert-Eaton Myasthenic Syndrome; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Nerve Tissue Proteins; Neuromuscular Junction; Presynaptic Terminals; Pupil Disorders
PubMed: 23252894
DOI: 10.1111/j.1749-6632.2012.06836.x -
The Journal of Biological Chemistry Dec 2012The polymerization of laminins into a cell-associated network is a key process in basement membrane assembly. Network formation is mediated by the homologous short arm...
The polymerization of laminins into a cell-associated network is a key process in basement membrane assembly. Network formation is mediated by the homologous short arm tips of the laminin heterotrimer, each consisting of a globular laminin N-terminal (LN) domain followed by a tandem of laminin-type epidermal growth factor-like (LEa) domains. How the short arms interact in the laminin network is unclear. Here, we have addressed this question by reconstituting laminin network nodes in solution and analyzing them by size exclusion chromatography and light scattering. Recombinant LN-LEa1-4 fragments of the laminin α1, α2, α5, β1, and γ1 chains were monomeric in solution. The β1 and γ1 fragments formed the only detectable binary complex and ternary complexes of 1:1:1 stoichiometry with all α chain fragments. Ternary complex formation required calcium and did not occur at 4 °C, like the polymerization of full-length laminins. Experiments with chimeric short arm fragments demonstrated that the LEa2-4 regions of the β1 and γ1 fragments are dispensable for ternary complex formation, and an engineered glycan in the β1 LEa1 domain was also tolerated. In contrast, mutation of Ser-68 in the β1 LN domain (corresponding to a Pierson syndrome mutation in the closely related β2 chain) abolished ternary complex formation. We conclude that authentic ternary nodes of the laminin network can be reconstituted for structure-function studies.
Topics: Animals; Basement Membrane; HEK293 Cells; Humans; Kinetics; Laminin; Mice; Protein Binding; Protein Conformation; Protein Multimerization; Protein Structure, Tertiary
PubMed: 23166322
DOI: 10.1074/jbc.M112.418426 -
Indian Journal of Nephrology May 2012Diffuse mesangial sclerosis (DMS) is a rare cause of nephrotic syndrome in the infantile and childhood period. DMS is a phenotypic expression of syndromic entities such...
Diffuse mesangial sclerosis (DMS) is a rare cause of nephrotic syndrome in the infantile and childhood period. DMS is a phenotypic expression of syndromic entities such as WAGR syndrome (Wilms' tumor, aniridia, genitourinary anomalies and mental retardation), Denys Drash syndrome, Pierson syndrome, Frasier syndrome, or Galloway-Mowat syndrome. We report two cases of DMS, one presenting in first year of life and another in second decade of life. Both of them had fatal outcome. Recognition of the disease is very important in modifying the management of patient and active surveillance of family members.
PubMed: 23087559
DOI: 10.4103/0971-4065.98764 -
Seminars in Nephrology Jul 2012This article summarizes the basic cellular and extracellular events in the development of the glomerulus and assembly of the glomerular basement membrane (GBM), paying... (Review)
Review
This article summarizes the basic cellular and extracellular events in the development of the glomerulus and assembly of the glomerular basement membrane (GBM), paying special attention to laminin (LM) and type IV collagen. Cellular receptors for GBM proteins, including the integrins, dystroglycan, and discoidin domain receptor 1 also are discussed. Evidence is reviewed showing that the laminin isoform present in the earliest GBM, LM-111, and final isoform found in the mature GBM, LM-521, are each derived from both endothelial cells and podocytes. Although the early collagen α1α2α1(IV) similarly derives from endothelial cells and podocytes, collagen α3α4α5(IV) found in fully mature GBM is a product solely of podocytes. Genetic diseases affecting laminin and type IV collagen synthesis also are presented, with an emphasis on mutations to LAMB2 (Pierson syndrome) and COL4A3, COL4A4, and COL4A5 (Alport syndrome), and their experimental mouse models. Stress is placed on the assembly of a compositionally correct GBM for the acquisition and maintenance of glomerular barrier properties.
Topics: Animals; Collagen Type IV; Endothelium; Glomerular Basement Membrane; Heparan Sulfate Proteoglycans; Humans; Kidney Diseases; Laminin; Podocytes
PubMed: 22958488
DOI: 10.1016/j.semnephrol.2012.06.005