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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 -
Clinical Nephrology Jan 2017Mutations of the LAMB2 gene mainly cause Pierson syndrome (OMIM) #609049), characterized by congenital nephrotic syndrome (CNS) and complex ocular involvements with...
BACKGROUND
Mutations of the LAMB2 gene mainly cause Pierson syndrome (OMIM) #609049), characterized by congenital nephrotic syndrome (CNS) and complex ocular involvements with microcoria as the most prominent clinical feature. However, the phenotypic spectrum of LAMB2-associated disorders is broader, isolated congenital or infantile nephrotic syndrome can also be seen. The aim of this study was to explore the phenotypes of different LAMB2 mutations in China.
METHODS
LAMB2 mutations were analyzed in three Chinese childhood steroid-resistant nephrotic syndrome cases, two of them with ocular abnormalities.
RESULTS
LAMB2 mutations were confirmed in all the three cases, two presented with Pierson syndrome, while one presented with isolated infantile steroid-resistant nephrotic syndrome.
CONCLUSIONS
The phenotypes caused by LAMB2 mutation were variable, mainly Pierson syndrome, as well as isolated nephrotic syndrome without ocular involvement. Mutational analysis of LAMB2 should be considered in all steroid-resistant nephrotic syndrome patients, with or without any ocular abnormalities. .
Topics: Abnormalities, Multiple; Child, Preschool; China; Eye Abnormalities; Female; Humans; Infant; Laminin; Mutation; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Phenotype; Pupil Disorders
PubMed: 27925579
DOI: 10.5414/CN108979 -
Kidney International Reports Sep 2023Laminin subunit beta-2 -associated disease, termed Pierson syndrome, presents with congenital nephrotic syndrome, ocular symptoms, and neuromuscular symptoms. In recent...
INTRODUCTION
Laminin subunit beta-2 -associated disease, termed Pierson syndrome, presents with congenital nephrotic syndrome, ocular symptoms, and neuromuscular symptoms. In recent years, however, the widespread use of next-generation sequencing (NGS) has helped to discover a variety of phenotypes associated with this disease. Therefore, we conducted this systematic review.
METHODS
A literature search of patients with variants was conducted, and 110 patients were investigated, including 12 of our patients. For genotype-phenotype correlation analyses, the extracted data were investigated for pathogenic variant types, the severity of nephropathy, and extrarenal symptoms. Survival analyses were also performed for the onset age of end-stage kidney disease (ESKD).
RESULTS
Among all patients, 81 (78%) presented with congenital nephrotic syndrome, and 52 (55%) developed ESKD within 12 months. The median age at ESKD onset was 6.0 months. Kidney survival analysis showed that patients with biallelic truncating variants had a significantly earlier progression to ESKD than those with other variants (median age 1.2 months vs. 60.0 months, < 0.05). Although the laminin N-terminal domain is functionally important in laminin proteins, and variants in the laminin N-terminal domain are said to result in a severe kidney phenotype such as earlier onset age and worse prognosis, there were no significant differences in onset age of nephropathy and progression to ESKD between patients with nontruncating variants located in the laminin N-terminal domain and those with variants located outside this domain.
CONCLUSION
This study revealed a diversity of -associated diseases, characteristics of nephropathy, and genotype-phenotype correlations.
PubMed: 37705905
DOI: 10.1016/j.ekir.2023.06.019 -
Kidney International Jul 2020The importance of the glomerular basement membrane (GBM) in glomerular filtration is underscored by the manifestations of Alport and Pierson syndromes, caused by defects...
The importance of the glomerular basement membrane (GBM) in glomerular filtration is underscored by the manifestations of Alport and Pierson syndromes, caused by defects in type IV collagen α3α4α5 and the laminin β2 chain, respectively. Lamb2 null mice, which model the most severe form of Pierson syndrome, exhibit proteinuria prior to podocyte foot process effacement and are therefore useful for studying GBM permselectivity. We hypothesize that some LAMB2 missense mutations that cause mild forms of Pierson syndrome induce GBM destabilization with delayed effects on podocytes. While generating a CRISPR/Cas9-mediated analogue of a human LAMB2 missense mutation in mice, we identified a 44-amino acid deletion (LAMB2-Del44) within the laminin N-terminal domain, a domain mediating laminin polymerization. Laminin heterotrimers containing LAMB2-Del44 exhibited a 90% reduction in polymerization in vitro that was partially rescued by type IV collagen and nidogen. Del44 mice showed albuminuria at 1.8-6.0 g/g creatinine (ACR) at one to two months, plateauing at an average 200 g/g ACR at 3.7 months, when GBM thickening and hallmarks of nephrotic syndrome were first observed. Despite the massive albuminuria, some Del44 mice survived for up to 15 months. Blood urea nitrogen was modestly elevated at seven-nine months. Eight to nine-month-old Del44 mice exhibited glomerulosclerosis and interstitial fibrosis. Similar to Lamb2 mice, proteinuria preceded foot process effacement. Foot processes were widened but not effaced at one-two months despite the high ACRs. At three months some individual foot processes were still observed amid widespread effacement. Thus, our chronic model of nephrotic syndrome may prove useful to study filtration mechanisms, long-term proteinuria with preserved kidney function, and to test therapeutics.
Topics: Animals; Laminin; Mice; Mice, Knockout; Nephrotic Syndrome; Pupil Disorders
PubMed: 32456966
DOI: 10.1016/j.kint.2020.01.033 -
American Journal of Medical Genetics.... Oct 2004We observed the occurrence of congenital nephrotic syndrome (CNS) and distinct ocular anomalies in two unrelated families. Eleven children from both families presented... (Review)
Review
We observed the occurrence of congenital nephrotic syndrome (CNS) and distinct ocular anomalies in two unrelated families. Eleven children from both families presented with a similar course of renal disease starting with nephrotic syndrome and renal failure prenatally or immediately after birth that resulted in death before the age of 2 months. Kidney histopathology showed diffuse mesangial sclerosis (DMS). Clinically obvious eye abnormalities were recognized in six of the eight patients in whom sufficient clinical data were available. Ocular anomalies included enlarged or large appearing corneae in some cases suggesting buphthalmos, and extremely narrow, nonreactive pupils (microcoria). Pathological examination of the eyes of two aborted fetuses revealed a more complex ocular maldevelopment including posterior lenticonus as well as anomalies of cornea and retina. On the basis of these observations and other cases in the literature, we delineate a previously unrecognized distinct entity characterized by congenital nephrotic syndrome, DMS, and eye abnormalities with microcoria as the leading clinical feature. Pedigrees of affected families with parental consanguinity support autosomal recessive inheritance. We propose that this syndrome should be designated microcoria-congenital nephrosis syndrome or Pierson syndrome. Possible overlap with Galloway-Mowat syndrome and relations to other oculo-renal syndromes are discussed.
Topics: Abnormalities, Multiple; Consanguinity; Eye Abnormalities; Family Health; Fatal Outcome; Female; Genes, Recessive; Glomerular Mesangium; Humans; Infant; Infant, Newborn; Male; Necrosis; Nephrosis; Pedigree; Pupil Disorders; Syndrome; Turkey
PubMed: 15372515
DOI: 10.1002/ajmg.a.30310 -
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 -
JCI Insight Mar 2021Mutations in LAMB2, encoding laminin β2, cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense...
Mutations in LAMB2, encoding laminin β2, cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin β2. On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β2 LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin β2 secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the β2 variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin β2 to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the β2 variants to other laminins appears to lead to their increased deposition in the GBM. Laminin β2 also serves as a potentially novel cell-adhesive ligand for integrin α4β1. Our findings define biochemical functions of laminin β2 variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.
Topics: Animals; Extracellular Matrix; HEK293 Cells; Humans; Kidney Diseases; Laminin; Mice; Mice, Knockout; Mutation, Missense; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders
PubMed: 33749661
DOI: 10.1172/jci.insight.145908 -
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 -
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 -
Nephrology, Dialysis, Transplantation :... Nov 2006Pierson syndrome (OMIM 609049) is a severe congenital oculorenal disorder with early lethality. The condition is caused by mutations in the LAMB2 gene leading to...
BACKGROUND
Pierson syndrome (OMIM 609049) is a severe congenital oculorenal disorder with early lethality. The condition is caused by mutations in the LAMB2 gene leading to complete loss of function of the gene product laminin beta2, an essential component of the glomerular and other basement membranes.
METHODS
We present a non-consanguineous family with seven offspring affected by childhood-onset nephrotic syndrome progressing to end-stage renal failure and ocular abnormalities including cataracts, anterior chamber and iris abnormalities, and progressive blindness due to retinal detachment. The LAMB2 gene was analysed in this family by direct sequencing.
RESULTS
The disorder turned out to segregate with compound heterozygosity for two novel LAMB2 mutations, triangle upV79 and Q1728X. Whereas the mutation Q1728X is predicted to confer complete loss of function, triangle upV79 probably represents a hypomorphic allele, thus explaining the substantially milder phenotype in this family.
CONCLUSION
This observation demonstrates that the phenotypic spectrum of LAMB2-associated disorders is broader than previously anticipated, and suggests that milder, non-lethal phenotypes may be associated with mutations retaining some residual function.
Topics: Adolescent; Adult; Age of Onset; Amino Acid Sequence; Amino Acid Substitution; Child; Child, Preschool; Disease Progression; Eye Abnormalities; Female; Humans; Laminin; Male; Molecular Sequence Data; Nephrotic Syndrome; Pedigree; Phenotype; Vision Disorders
PubMed: 16921188
DOI: 10.1093/ndt/gfl463