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European Journal of Medical Research Apr 2016Pierson syndrome (PS) is a rare autosomal recessive disorder, caused by mutations in the laminin β2 (LAMB2) gene. It is characterized by congenital nephrotic syndrome,...
BACKGROUND
Pierson syndrome (PS) is a rare autosomal recessive disorder, caused by mutations in the laminin β2 (LAMB2) gene. It is characterized by congenital nephrotic syndrome, microcoria, and neurodevelopmental deficits. Several mutations with genotype-phenotype correlations have been reported, often with great clinical variability. We hereby report a novel homozygous nonsense mutation in the LAMB2 gene, associated with a severe phenotype presentation.
CASE DIAGNOSIS
We describe a term male infant born from consanguineous parents. The mother previously lost three children in the neonatal period, secondary to undefined renal disease, had two spontaneous abortions, and gave birth to one healthy daughter. The index case presented at birth with bilateral microcoria, severe hypotonia, respiratory distress, and congenital nephrotic syndrome associated with anuria and severe renal failure requiring peritoneal dialysis. The patients' clinical follow-up was unfavorable, and the newborn died at 7 days of life, after withdrawal of life support. Genetic analysis revealed a homozygous nonsense mutation at position c.2890C>T causing a premature stop codon (p.R964*) in LAMB2 gene.
CONCLUSION
We here describe a novel nonsense homozygous mutation in LAMB2 gene causing a severe neonatal presentation of Pierson syndrome. This new mutation expands the genotype-phenotype spectrum of this rare disease and confirms that truncating mutations might be associated with severe clinical features.
Topics: Abnormalities, Multiple; Codon, Nonsense; Consanguinity; DNA Mutational Analysis; Eye Abnormalities; Family Health; Fatal Outcome; Female; Humans; Infant, Newborn; Laminin; Male; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pedigree; Phenotype; Pupil Disorders; Severity of Illness Index
PubMed: 27130041
DOI: 10.1186/s40001-016-0215-z -
PloS One 2022Records of anthropogenic marine debris and the threats it poses are increasing worldwide, yet we know relatively little about the distribution of benthic debris. The...
Records of anthropogenic marine debris and the threats it poses are increasing worldwide, yet we know relatively little about the distribution of benthic debris. The seafloor is the final destination for a large proportion of debris due to the degradation and sinking of items. A more detailed understanding of debris distributions in hotspots such as urbanised estuaries can help decision makers target management and remediation activities. We selected sites frequented by fishers and boaters in Sydney Harbour, an urbanised estuary, to investigate the impacts of recreational activities on debris abundance. The aim of this study was to examine variation in macro debris (>5mm in diameter) type and abundance at two habitat types (piers and non-piers). We chose five locations at various distances from the estuary mouth. In each location SCUBA teams performed fixed transects at two sites, one under a pier and one over nearby soft-sediment habitat. Debris was recovered by the divers and brought to the surface for classification and disposal. Surveys were repeated multiple times at each location between November 2019 and February 2020, recording a total of 2803 debris items over 36 survey events. Overall, piers had more than ten times the debris abundance of soft-sediment sites, and much higher proportion of debris types related to recreational fishing. Over half of the debris items in this study were plastic (65%), and approximately 70% of the total debris was classified as related to recreational fishing. This trait was most prominent in debris at sites closest to the estuary mouth, likely reflecting increased fishing activity in this area. This study indicates that policy makers and community groups in urbanised estuaries should focus monitoring, reduction, and remediation efforts near artificial structures such as piers, and that public awareness campaigns should target the behaviour of recreational users of these structures.
Topics: Estuaries; Plastics; Ecosystem; Environmental Monitoring; Waste Products
PubMed: 36576908
DOI: 10.1371/journal.pone.0274512 -
The Journal of Clinical Endocrinology... Mar 2020Mutations in LAMB2, encoding the basement membrane protein, laminin β2, are associated with an autosomal recessive disorder characterized by congenital nephrotic...
CONTEXT
Mutations in LAMB2, encoding the basement membrane protein, laminin β2, are associated with an autosomal recessive disorder characterized by congenital nephrotic syndrome, ocular abnormalities, and neurodevelopmental delay (Pierson syndrome).
CASE DESCRIPTION
This report describes a 12-year-old boy with short stature, visual impairment, and developmental delay who presented with macroscopic hematuria and albuminuria. He had isolated growth hormone deficiency, optic nerve hypoplasia, and a small anterior pituitary with corpus callosum dysgenesis on his cranial magnetic resonance imaging, thereby supporting a diagnosis of optic nerve hypoplasia syndrome. Renal histopathology revealed focal segmental glomerulosclerosis. Using next-generation sequencing on a targeted gene panel for steroid-resistant nephrotic syndrome, compound heterozygous missense mutations were identified in LAMB2 (c.737G>A p.Arg246Gln, c.3982G>C p.Gly1328Arg). Immunohistochemical analysis revealed reduced glomerular laminin β2 expression compared to control kidney and a thin basement membrane on electron microscopy. Laminin β2 is expressed during pituitary development and Lamb2-/- mice exhibit stunted growth, abnormal neural retinae, and here we show, abnormal parenchyma of the anterior pituitary gland.
CONCLUSION
We propose that patients with genetically undefined optic nerve hypoplasia syndrome should be screened for albuminuria and, if present, screened for mutations in LAMB2.
Topics: Albuminuria; Child; Humans; Hypopituitarism; Laminin; Male; Mutation; Optic Nerve Hypoplasia; Phenotype
PubMed: 31769495
DOI: 10.1210/clinem/dgz216 -
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 -
European Journal of Pediatrics Apr 2017This report describes a novel mutation of LAMB2, the gene associated with Pierson syndrome (microcoria-congenital nephrosis syndrome), in two female siblings. The...
UNLABELLED
This report describes a novel mutation of LAMB2, the gene associated with Pierson syndrome (microcoria-congenital nephrosis syndrome), in two female siblings. The c.970T>C p.(Cys324Arg) mutation in the LAMB2 gene affects one of the eight highly conserved cysteine residues within the first EGF-like module of the laminin β2 protein. These residues form disulfide bonds in order to achieve a correct 3D structure of the protein. The reported phenotype is considered a relatively mild variant of Pierson syndrome and is associated with later-onset (18 months) therapy-resistant nephrotic syndrome leading to renal failure, and ocular abnormalities consisting of high myopia, microcoria, diverse retinal abnormalities, hence a low level of visual acuity. Importantly, the reported LAMB2 mutation was associated with normal neurological development in both siblings.
CONCLUSION
this report presents the variability of the renal, ocular and neurological phenotypes associated with LAMB2 mutations and underscores the importance of ophthalmologic examination in all children with unexplained renal insufficiency or nephrotic syndrome. What is known • LAMB2 mutations are associated with Pierson syndrome • Pierson syndrome is associated with congenital nephrotic syndrome, microcoria and neurological deficits What is new • A novel mutation in the LAMB2 gene in two female siblings • Genotype and clinical phenotype description of a novel LAMB2 mutation.
Topics: Abnormalities, Multiple; Child; Child, Preschool; Eye Abnormalities; Female; Humans; Kidney; Kidney Glomerulus; Laminin; Mutation; Myasthenic Syndromes, Congenital; Nephrectomy; Nephrotic Syndrome; Phenotype; Pupil Disorders; Renal Insufficiency; Retina; Siblings; Tomography, Optical
PubMed: 28188379
DOI: 10.1007/s00431-017-2871-6 -
Kidney International Sep 2006Congenital nephrotic syndrome is clinically and genetically heterogeneous. The majority of cases can be attributed to mutations in the genes NPHS1, NPHS2, and WT1. By...
Congenital nephrotic syndrome is clinically and genetically heterogeneous. The majority of cases can be attributed to mutations in the genes NPHS1, NPHS2, and WT1. By homozygosity mapping in a consanguineous family with isolated congenital nephrotic syndrome, we identified a potential candidate region on chromosome 3p. The LAMB2 gene, which was recently reported as mutated in Pierson syndrome (microcoria-congenital nephrosis syndrome; OMIM #609049), was located in the linkage interval. Sequencing of all coding exons of LAMB2 revealed a novel homozygous missense mutation (R246Q) in both affected children. A different mutation at this codon (R246W), which is highly conserved through evolution, has recently been reported as causing Pierson syndrome. Subsequent LAMB2 mutational screening in six additional families with congenital nephrotic syndrome revealed compound heterozygosity for two novel missense mutations in one family with additional nonspecific ocular anomalies. These findings demonstrate that the spectrum of LAMB2-associated disorders is broader than previously anticipated and includes congenital nephrotic syndrome without eye anomalies or with minor ocular changes different from those observed in Pierson syndrome. This phenotypic variability likely reflects specific genotypes. We conclude that mutational analysis in LAMB2 should be considered in congenital nephrotic syndrome, if no mutations are found in NPHS1, NPHS2, or WT1.
Topics: Child, Preschool; Chromosomes, Human, Pair 3; Consanguinity; Exons; Female; Genes, Recessive; Genetic Markers; Haplotypes; Humans; Introns; Laminin; Male; Microsatellite Repeats; Mutation, Missense; Nephrotic Syndrome; Physical Chromosome Mapping
PubMed: 16912710
DOI: 10.1038/sj.ki.5001679 -
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 -
Molecular Genetics & Genomic Medicine Jul 2021Both Pierson syndrome (PS) and isolated nephrotic syndrome can be caused by LAMB2 biallelic pathogenic variants. Only 15 causative splicing variants in the LAMB2 gene...
BACKGROUND
Both Pierson syndrome (PS) and isolated nephrotic syndrome can be caused by LAMB2 biallelic pathogenic variants. Only 15 causative splicing variants in the LAMB2 gene have been reported. However, the pathogenicity of most of these variants has not been verified, which may lead to incorrect interpretation of the functional consequence of these variants.
METHODS
Using high-throughput DNA sequencing and Sanger sequencing, we detected variants in a female with clinically suspected PS. A minigene splicing assay was performed to assess the effect of LAMB2 intron 20 c.2885-9C>A on RNA splicing. We also performed the immunohistochemical analysis of laminin beta-2 in kidney tissues.
RESULTS
Two novel LAMB2 heteroallelic variants were found: a paternally inherited variant c.2885-9C>A in intron 20 and a maternally inherited variant c. 3658C>T (p. (Gln1220Ter)). In vitro minigene assay showed that the variant c.2885-9C>A caused erroneous integration of a 7 bp sequence into intron 20. Immunohistochemical analysis revealed the absence of glomerular expression of laminin beta-2, the protein encoded by LAMB2.
CONCLUSION
We demonstrated the impact of a novel LAMB2 intronic variant on RNA splicing using the minigene assay firstly. Our results extend the mutational spectrum of LAMB2.
Topics: Diagnosis, Differential; Female; Genetic Testing; HEK293 Cells; Humans; Infant; Laminin; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Point Mutation; Pupil Disorders; RNA Splicing
PubMed: 33982833
DOI: 10.1002/mgg3.1704 -
CEN Case Reports Aug 2021Biallelic pathogenic variants in the laminin β2 (LAMB2) gene, which encodes laminin β2, are associated with Pierson syndrome characterized by a congenital nephrotic...
Biallelic pathogenic variants in the laminin β2 (LAMB2) gene, which encodes laminin β2, are associated with Pierson syndrome characterized by a congenital nephrotic syndrome that rapidly progresses to end-stage renal disease, distinct ocular maldevelopment with bilateral microcoria, and neurodevelopmental deficits. However, the phenotypic spectrum of LAMB2-associated disorder is broader than expected, and cases with milder phenotypes such as isolated congenital or infantile nephrotic syndrome have also been reported. We report a patient with LAMB2-associated renal disorder showing an extremely mild phenotype. A 5-year-old girl presented with asymptomatic proteinuria and hematuria detected by urinalysis screening. She had been previously healthy without any additional renal symptoms. The serum albumin and creatinine levels were normal. Renal biopsy revealed minor glomerular abnormalities with occasional focal mesangial proliferation. Electron microscopy showed no structural changes in the glomerular basement membrane. Targeted sequencing of podocyte-related genes using next-generation sequencing was performed. As a result, previously reported biallelic pathogenic variants of the truncating variant (c.5073_5076dupCCAG) and a splice site variant (c.3797 + 5G > A) in the LAMB2 gene were detected, and the patient was diagnosed with LAMB2-associated renal disorder. Interestingly, a previously reported case with this splicing variant also showed an atypically mild phenotype. We suggest that clinicians should consider LAMB2-associated nephritis as an important differential diagnosis in children with asymptomatic proteinuria and microscopic hematuria if there is no structural change in the glomerular basement membrane. A comprehensive gene-screening system using next-generation sequencing is useful for diagnosing these atypical cases with isolated urine abnormalities.
Topics: Child; Female; High-Throughput Nucleotide Sequencing; Humans; Laminin; Nephritis
PubMed: 33476040
DOI: 10.1007/s13730-021-00574-1 -
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