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CEN Case Reports Dec 2023Pierson syndrome (PS) is a rare autosomal recessive disease, characterized by congenital nephrotic syndrome (CNS), and ocular and neurologic abnormalities. In affected...
Pierson syndrome (PS) is a rare autosomal recessive disease, characterized by congenital nephrotic syndrome (CNS), and ocular and neurologic abnormalities. In affected cases, there is abnormal b-2 laminin which is compound of the several basement membranes caused by inherited mutations in the LAMB2 gene. Although patients have mutations in the same gene, the phenotype is highly variable. In this case series, the relationship between genotype and phenotype is emphasized, and information about the clinical follow-up of the patients is presented. Hereby, we report four pediatric cases with PS as a result of mutation in the LAMB2 gene. Clinical spectrum of LAMB2-associated disorders varies from mild-to-severe ocular, kidney, and neurologic involvement. Since genotype-phenotype correlation in PS has not been clearly demonstrated, we recommend that all patients with ophthalmic anomalies and glomerular proteinuria should be tested for LAMB2 mutations.
PubMed: 38038886
DOI: 10.1007/s13730-023-00838-y -
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 -
BMC Ophthalmology Feb 2023Pierson syndrome is a rare autosomal recessive disorder that causes congenital nephrotic syndrome, neurodevelopmental abnormalities, and several ocular signs. The...
BACKGROUND
Pierson syndrome is a rare autosomal recessive disorder that causes congenital nephrotic syndrome, neurodevelopmental abnormalities, and several ocular signs. The Pierson syndrome is caused by a mutation of the LAMB2 gene, that encodes laminin beta 2, which is expressed in the glomerular basement membrane, in neuromuscular junctions, and within ocular structures. First described by Pierson et al., the ocular signs of Pierson syndrome include microcoria, which is most characteristic sign, as well as iris abnormalities, cataract, glaucoma, and retinal detachment.
CASE PRESENTATION
Herein, we report the case of a young female who, at 16 months, was diagnosed with congenital nephrotic syndrome, subsequently underwent a kidney transplant at age 4,did cataract surgery with IOL implantation in both eyes at age of 2 years and presented with ocular signs including high myopia, band keratopathy, t, nystagmus, retina, and optic nerve atrophy, she did not show nor did the family report any neurodevelopmental abnormalities. her genetic studies this missense variant c.970T< C p. (Cys324Arg) of LAMB2, later she developed spontaneous hyphema along with vitreous haemorrhage and increased intra ocular pressure in her left eye, she underwent cyclophotocouagulation to treat her high IOP.
CONCLUSION
LAMB 2 mutations can be associated with multiple ocular signs that varies from mild to severe form, we are her to report our case who did not present with the typical ocular sign of microcoria for PS, did not have any neurodevelopmental abnormality and presented with hyphaemia 2ndry to iris neovascularisation with vitreous haemorrhage with neovascular glaucoma.
Topics: Female; Humans; Nephrotic Syndrome; Hyphema; Glaucoma, Neovascular; Vitreous Hemorrhage; Hemorrhage; Cataract
PubMed: 36829142
DOI: 10.1186/s12886-023-02826-3 -
Nature Communications Jan 2023Laminin polymerization is the major step in basement membranes assembly. Its failures cause laminin N-terminal domain lamininopathies including Pierson syndrome. We have...
Laminin polymerization is the major step in basement membranes assembly. Its failures cause laminin N-terminal domain lamininopathies including Pierson syndrome. We have employed cryo-electron microscopy to determine a 3.7 Å structure of the trimeric laminin polymer node containing α1, β1 and γ1 subunits. The structure reveals the molecular basis of calcium-dependent formation of laminin lattice, and provides insights into polymerization defects manifesting in human disease.
Topics: Humans; Laminin; Cryoelectron Microscopy; Polymerization; Nephrotic Syndrome; Pupil Disorders; Basement Membrane
PubMed: 36658135
DOI: 10.1038/s41467-023-36077-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 -
Kidney360 Dec 2021
Topics: Collagen Type IV; Female; Humans; Laminin; Male; Nephritis, Hereditary
PubMed: 35419542
DOI: 10.34067/KID.0007312021 -
Frontiers in Genetics 2021The laminins (LM) are a family of basement membranes glycoproteins with essential structural roles in supporting epithelia, endothelia, nerves and muscle adhesion, and... (Review)
Review
The laminins (LM) are a family of basement membranes glycoproteins with essential structural roles in supporting epithelia, endothelia, nerves and muscle adhesion, and signaling roles in regulating cell migration, proliferation, stem cell maintenance and differentiation. Laminins are obligate heterotrimers comprised of α, β and γ chains that assemble intracellularly. However, extracellularly these heterotrimers then assemble into higher-order networks interaction between their laminin N-terminal (LN) domains. protein studies have identified assembly kinetics and the structural motifs involved in binding of adjacent LN domains. The physiological importance of these interactions has been identified through the study of pathogenic point mutations in LN domains that lead to syndromic disorders presenting with phenotypes dependent on which laminin gene is mutated. Genotype-phenotype comparison between knockout and LN domain missense mutations of the same laminin allows inferences to be drawn about the roles of laminin network assembly in terms of tissue function. In this review, we will discuss these comparisons in terms of laminin disorders, and the therapeutic options that understanding these processes have allowed. We will also discuss recent findings of non-laminin mediators of laminin network assembly and their implications in terms of basement membrane structure and function.
PubMed: 34456976
DOI: 10.3389/fgene.2021.707087 -
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 -
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 -
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