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PloS One 2012The heterotrimeric laminins are a defining component of basement membranes and essential for tissue formation and function in all animals. The three short arms of the...
The heterotrimeric laminins are a defining component of basement membranes and essential for tissue formation and function in all animals. The three short arms of the cross-shaped laminin molecule are composed of one chain each and their tips mediate the formation of a polymeric network. The structural basis for laminin polymerisation is unknown. We have determined crystal structures of the short-arm tips of the mouse laminin β1 and γ1 chains, which are grossly similar to the previously determined structure of the corresponding α5 chain region. The short-arm tips consist of a laminin N-terminal (LN) domain that is attached like the head of a flower to a rod-like stem formed by tandem laminin-type epidermal growth factor-like (LE) domains. The LN domain is a β-sandwich with elaborate loop regions that differ between chains. The γ1 LN domain uniquely contains a calcium binding site. The LE domains have little regular structure and are stabilised by cysteines that are disulphide-linked 1-3, 2-4, 5-6 and 7-8 in all chains. The LN surface is not conserved across the α, β and γ chains, but within each chain subfamily there is a striking concentration of conserved residues on one face of the β-sandwich, while the opposite face invariably is shielded by glycans. We propose that the extensive conserved patches on the β and γ LN domains mediate the binding of these two chains to each other, and that the α chain LN domain subsequently binds to the composite β-γ surface. Mutations in the laminin β2 LN domain causing Pierson syndrome are likely to impair the folding of the β2 chain or its ability to form network interactions.
Topics: Amino Acid Sequence; Animals; Biopolymers; Laminin; Mice; Models, Molecular; Molecular Sequence Data; Protein Conformation; Sequence Homology, Amino Acid
PubMed: 22860131
DOI: 10.1371/journal.pone.0042473 -
Pediatric Nephrology (Berlin, Germany) May 2012Pierson syndrome, caused by mutations in the LAMB2 gene, was originally described as a combination of microcoria and congenital nephrotic syndrome, rapidly progressing...
BACKGROUND
Pierson syndrome, caused by mutations in the LAMB2 gene, was originally described as a combination of microcoria and congenital nephrotic syndrome, rapidly progressing to end-stage renal failure.
CASE-DIAGNOSIS/TREATMENT
We report a minor variant of Pierson syndrome in a teenage girl with severe myopia since early infancy and proteinuria first detected at age 6. At the age of 11 she was found to carry a unique homozygous non-truncating LAMB2 mutation in exon 2: c.T240G (p.S80R). Renal biopsy revealed mild diffuse mesangial sclerosis and residual expression of laminin β2. Today at age 14, on treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, she continues to have nephrotic range proteinuria, but a normal glomerular filtration rate.
CONCLUSIONS
LAMB2 mutations should be considered in all patients with glomerular proteinuria and abnormal ocular phenotype, irrespective of age and disease severity.
Topics: Abnormalities, Multiple; Adolescent; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biopsy; Eye Abnormalities; Female; Glomerular Filtration Rate; Humans; Kidney; Laminin; Losartan; Mutation; Mutation, Missense; Myasthenic Syndromes, Congenital; Myopia; Nephrotic Syndrome; Phenotype; Proteinuria; Pupil Disorders; Ramipril; Retinal Detachment; Vision Disorders
PubMed: 22228401
DOI: 10.1007/s00467-011-2088-2 -
American Journal of Medical Genetics.... Oct 2011
Paternal isodisomy of chromosome 3 unmasked by autosomal recessive microcoria-congenital nephrosis syndrome (Pierson syndrome) in a child with no other phenotypic abnormalities.
Topics: Abnormalities, Multiple; Base Sequence; Biopsy; Chromosomes, Human, Pair 3; Eye Abnormalities; Fatal Outcome; Germany; Haplotypes; Humans; Kidney; Laminin; Male; Molecular Sequence Data; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Phenotype; Pupil Disorders; Sequence Analysis, DNA; Uniparental Disomy
PubMed: 21910237
DOI: 10.1002/ajmg.a.34214 -
Archives de Pediatrie : Organe Officiel... Nov 2011
Topics: Abnormalities, Multiple; Eponyms; Eye Abnormalities; Humans; Molecular Diagnostic Techniques; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders
PubMed: 21903364
DOI: 10.1016/j.arcped.2011.08.002 -
Proceedings of the National Academy of... Sep 2011Pierson syndrome is a congenital nephrotic syndrome with ocular and neurological defects caused by mutations in LAMB2, the gene encoding the basement membrane protein...
Pierson syndrome is a congenital nephrotic syndrome with ocular and neurological defects caused by mutations in LAMB2, the gene encoding the basement membrane protein laminin β2 (Lamβ2). It is the kidney glomerular basement membrane (GBM) that is defective in Pierson syndrome, as Lamβ2 is a component of laminin-521 (LM-521; α5β2γ1), the major laminin in the mature GBM. In both Pierson syndrome and the Lamb2(-/-) mouse model for this disease, laminin β1 (Lamβ1), a structurally similar homolog of Lamβ2, is marginally increased in the GBM, but it fails to fully compensate for the loss of Lamβ2, leading to the filtration barrier defects and nephrotic syndrome. Here we generated several lines of Lamβ1 transgenic mice and used them to show that podocyte-specific Lamβ1 expression in Lamb2(-/-) mice abrogates the development of nephrotic syndrome, correlating with a greatly extended lifespan. In addition, the more Lamβ1 was expressed, the less urinary albumin was excreted. Transgenic Lamβ1 expression increased the level of Lamα5 in the GBM of rescued mice, consistent with the desired increased deposition of laminin-511 (α5β1γ1) trimers. Ultrastructural analysis revealed occasional knob-like subepithelial GBM thickening but intact podocyte foot processes in aged rescued mice. These results suggest the possibility that up-regulation of LAMB1 in podocytes, should it become achievable, would likely lessen the severity of nephrotic syndrome in patients carrying LAMB2 mutations.
Topics: Abnormalities, Multiple; Animals; Capillaries; Disease Models, Animal; Eye Abnormalities; Glomerular Basement Membrane; Glomerular Filtration Rate; Humans; Infant; Laminin; Mice; Mice, Transgenic; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Podocytes; Pupil Disorders; Survival Analysis; Time Factors
PubMed: 21876163
DOI: 10.1073/pnas.1108269108 -
Journal of the American Society of... May 2011Laminin β2 is a component of laminin-521, which is an important constituent of the glomerular basement membrane (GBM). Null mutations in laminin β2 (LAMB2) cause...
Laminin β2 is a component of laminin-521, which is an important constituent of the glomerular basement membrane (GBM). Null mutations in laminin β2 (LAMB2) cause Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects. In contrast, patients with LAMB2 missense mutations, such as R246Q, can have less severe extrarenal defects but still exhibit congenital nephrotic syndrome. To investigate how such missense mutations in LAMB2 cause proteinuria, we generated three transgenic lines of mice in which R246Q-mutant rat laminin β2 replaced the wild-type mouse laminin β2 in the GBM. These transgenic mice developed much less severe proteinuria than their nontransgenic Lamb2-deficient littermates; the level of proteinuria correlated inversely with R246Q-LAMB2 expression. At the onset of proteinuria, expression and localization of proteins associated with the slit diaphragm and foot processes were normal, and there were no obvious ultrastructural abnormalities. Low transgene expressors developed heavy proteinuria, foot process effacement, GBM thickening, and renal failure by 3 months, but high expressors developed only mild proteinuria by 9 months. In vitro studies demonstrated that the R246Q mutation results in impaired secretion of laminin. Taken together, these results suggest that the R246Q mutation causes nephrotic syndrome by impairing secretion of laminin-521 from podocytes into the GBM; however, increased expression of the mutant protein is able to overcome this secretion defect and improve glomerular permselectivity.
Topics: Animals; Glomerular Basement Membrane; Humans; Kidney Glomerulus; Laminin; Mice; Mice, Transgenic; Mutation, Missense; Nephrotic Syndrome; Podocytes; Proteinuria; Rats
PubMed: 21511833
DOI: 10.1681/ASN.2010060632 -
Contributions To Nephrology 2011Animal models have provided important insights into human renal diseases that arise from mutations in genes that encode or regulate the synthesis of glomerular basement...
Animal models have provided important insights into human renal diseases that arise from mutations in genes that encode or regulate the synthesis of glomerular basement membrane proteins. This chapter describes several well-characterized animal models of type IV collagen disorders (Alport syndrome, HANAC syndrome), a laminin disorder (Pierson syndrome), nail-patella syndrome and HERNS syndrome. These models can be exploited in studies of the pathogenesis and treatment of such disorders.
Topics: Abnormalities, Multiple; Animals; Collagen Type IV; Disease Models, Animal; Dogs; Eye Abnormalities; Glomerular Basement Membrane; Humans; Kidney Diseases; Laminin; Mice; Mutation; Myasthenic Syndromes, Congenital; Nail-Patella Syndrome; Nephritis, Hereditary; Nephrotic Syndrome; Pupil Disorders
PubMed: 21252518
DOI: 10.1159/000313956 -
Ophthalmology Jun 2011To describe a novel laminin β-2 (LAMB2) mutation associated with nephrotic syndrome and severe retinal disease without microcoria in a large, multigenerational family... (Comparative Study)
Comparative Study
PURPOSE
To describe a novel laminin β-2 (LAMB2) mutation associated with nephrotic syndrome and severe retinal disease without microcoria in a large, multigenerational family with Pierson syndrome.
DESIGN
Retrospective chart review and prospective family examination.
PARTICIPANTS
An extended consanguineous family of 52 members.
METHODS
The eyes, urine, and serum DNA were evaluated in all family members after discovering 2 patients, both younger than 10 years, with bilateral retinal detachments and concurrent renal dysfunction. Linkage analysis was performed in the 9 living affected individuals, 7 using the Illumina Human Hap370 Duo Bead Array (Illumina, San Diego, CA) and 2 using GeneChip 10K (Affymetrix, Santa Clara, CA) mapping arrays.
MAIN OUTCOME MEASURES
The prevalence and severity of ocular and kidney involvement and genetic findings.
RESULTS
Eleven affected family members were identified (9 living), all manifesting chronic kidney disease and bilateral chorioretinal pigmentary changes, with or without retinal detachments, but without microcoria or neurodevelopmental deficits, segregating in an autosomal recessive pattern. The causative gene was localized to a 9-Mb region on chromosome 3. Comprehensive gene sequencing revealed a novel LAMB2 variant (c.440A → G; His147R) that was homozygous in the 9 living, affected family members, observed at a frequency of 2.1% in the Old Order Mennonite population, and absent in 91 non-Mennonite controls. The mutation is located in a highly conserved site in the N-terminal domain VI of LAMB2.
CONCLUSIONS
This study describes a novel mutation of LAMB2 and further expands the spectrum of eye and renal manifestations associated with defects in the laminin β-2 chain.
FINANCIAL DISCLOSURE(S)
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Topics: Abnormalities, Multiple; Adolescent; Adult; Aged; Child; Child, Preschool; Chromosomes, Human, Pair 3; DNA; DNA Mutational Analysis; Eye Abnormalities; Female; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Infant; Laminin; Male; Middle Aged; Mutation, Missense; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pedigree; Phenotype; Pupil Disorders; Retrospective Studies; Young Adult
PubMed: 21236492
DOI: 10.1016/j.ophtha.2010.10.009 -
Nephron. Clinical Practice 2011This review provides current information about glomerular disorders that arise directly from inherited abnormalities in extracellular matrix proteins intrinsic to the... (Review)
Review
This review provides current information about glomerular disorders that arise directly from inherited abnormalities in extracellular matrix proteins intrinsic to the glomerular basement membrane (Alport syndrome, thin basement membrane nephropathy, HANAC syndrome and Pierson syndrome). The authors also discuss disorders involving genetic defects in cellular proteins that result in structural defects in glomerular basement membranes (MYH9-related disorders, nail-patella syndrome).
Topics: Animals; Genetic Predisposition to Disease; Glomerular Basement Membrane; Humans; Kidney; Kidney Diseases
PubMed: 21071975
DOI: 10.1159/000320876 -
Nature Reviews. Nephrology Dec 2010Patients with some hereditary nephropathies-including autosomal dominant polycystic kidney disease (ADPKD), Fabry disease and Alport syndrome-can progress to end-stage... (Review)
Review
Patients with some hereditary nephropathies-including autosomal dominant polycystic kidney disease (ADPKD), Fabry disease and Alport syndrome-can progress to end-stage renal disease (ESRD) and are candidates for kidney transplantation. When considering whether a potential living donor is appropriate for a particular patient, clinicians should be aware of the increased risk of adverse outcomes for the donor and the recipient. Renal transplantation from a living related donor is not contraindicated in most nephropathies that have an autosomal recessive mode of inheritance (for example, autosomal recessive polycystic kidney disease and cystinosis). Renal transplant recipients with ADPKD, however, should only receive a kidney from a related donor if the disease has been excluded in the donor by imaging and/or genetic testing. Potential living related donors for patients with Alport syndrome should be evaluated carefully for the presence of microhematuria and microalbuminuria before a decision is made to perform transplantation, and mothers or heterozygous sisters of affected male recipients with X-linked Alport syndrome should be informed about the possible long-term increased risk of renal dysfunction associated with donation. Most patients with atypical hemolytic uremic syndrome should not receive a kidney transplant from a living donor because there is a high risk of disease recurrence and graft loss.
Topics: Abnormalities, Multiple; Arteriosclerosis; Cystinosis; Eye Abnormalities; Fabry Disease; Hemolytic-Uremic Syndrome; Humans; Hyperoxaluria; Immunologic Deficiency Syndromes; Kidney Diseases; Kidney Diseases, Cystic; Kidney Transplantation; Living Donors; Myasthenic Syndromes, Congenital; Nephritis, Hereditary; Nephrotic Syndrome; Osteochondrodysplasias; Patient Selection; Polycystic Kidney, Autosomal Dominant; Primary Immunodeficiency Diseases; Pulmonary Embolism; Pupil Disorders; Risk Factors
PubMed: 20877305
DOI: 10.1038/nrneph.2010.122