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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 -
Pediatric Nephrology (Berlin, Germany) Oct 2008Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disorder characterized by early onset nephrotic syndrome and microcephaly with various anomalies of the...
Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disorder characterized by early onset nephrotic syndrome and microcephaly with various anomalies of the central nervous system. GMS likely represents a heterogeneous group of disorders with hitherto unknown genetic etiology. The clinical phenotype to some extent overlaps that of Pierson syndrome (PS), which comprises congenital nephrotic syndrome and distinct ocular abnormalities but which may also include neurodevelopmental deficits and microcephaly. PS is caused by mutations of LAMB2, the gene encoding laminin beta2. We hypothesized that GMS might be allelic to PS or be caused by defects in proteins that interact with laminin beta2. In a cohort of 18 patients with GMS or a GMS-like phenotype we therefore analyzed the genes encoding laminin beta2 (LAMB2), laminin alpha5 (LAMA5), alpha3-integrin (ITGA3), beta1-integrin (ITGB1) and alpha-actinin-4 (ACTN4), but we failed to find causative mutations in these genes. We inferred that LAMA5, ITGA3, ITGB1, and ACTN4 are not directly involved in the pathogenesis of GMS. We excluded LAMB2 as a candidate gene for GMS. Further studies are required, including linkage analysis in families with GMS to identify genes underlying this disease.
Topics: Actinin; Adolescent; Child; Child, Preschool; Female; Humans; Infant; Intellectual Disability; Laminin; Male; Microcephaly; Mutation; Nephrotic Syndrome; Syndrome
PubMed: 18594871
DOI: 10.1007/s00467-008-0880-4 -
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 -
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 -
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 -
BMC Pediatrics Mar 2016LAMB2 mutations cause Pierson syndrome (OMIM 609049), an autosomal recessive genetic disease typically characterized by congenital nephrotic syndrome (CNS) and early...
BACKGROUND
LAMB2 mutations cause Pierson syndrome (OMIM 609049), an autosomal recessive genetic disease typically characterized by congenital nephrotic syndrome (CNS) and early onset renal failure, as well as bilateral microcoria. NPHP1 mutations cause familial juvenile nephronophthisis type 1 (NPHP1, OMIM 256100), another autosomal recessive renal disease that usually occurs years after birth. Both Pierson syndrome and nephronophthisis cause end-stage renal disease and rare kidney diseases in children. We report an extremely rare case of concurrent mutations of LAMB2 and NPHP1 in a Chinese girl with isolated CNS and the association of the phenotype with novel non-truncating mutations of LAMB2.
CASE PRESENTATION
A-34-day-old girl presented with CNS but no eye abnormalities, and mild hyperechogenicity of kidneys. A novel c.1176_1178delTCT mutation caused deletion of a glycine in exon 9 of LAMB2, and another mutation c.4923 + 2 T > G led to a splicing error. In addition, compound heterozygous mutations of NPHP1 were identified in this child using next generation sequencing, and confirmed by Sanger sequencing.
CONCLUSION
Mutations of the LAMB2 and NPHP1 are present in infants with isolated CNS. Next generation sequencing enabled high-throughput screening for mutant genes promptly, with clinically significant outcomes. In addition, our results expand the phenotype spectrum of LAMB2 mutations as the only renal manifestation.
Topics: Adaptor Proteins, Signal Transducing; China; Cytoskeletal Proteins; Female; Genetic Markers; Heterozygote; Humans; Infant; Laminin; Membrane Proteins; Mutation; Nephrotic Syndrome; Phenotype
PubMed: 27004562
DOI: 10.1186/s12887-016-0583-0 -
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 -
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 -
Pediatric Nephrology (Berlin, Germany) Mar 2008Distinct eye abnormalities have been described in children with nephrotic syndrome, particularly in diffuse mesangial sclerosis (i.e. Pierson syndrome). The aim of the...
Distinct eye abnormalities have been described in children with nephrotic syndrome, particularly in diffuse mesangial sclerosis (i.e. Pierson syndrome). The aim of the study was to investigate whether there were any associated ocular anomalies in children with steroid-resistant nephrotic syndrome (SRNS), all of whom had revealed primary focal segmental glomerulosclerosis in biopsy. Thirty-three SRNS patients (16 male, 17 female) with a median age of 10.5 years (range 3-25 years) were enrolled in the study. Twenty steroid-sensitive nephrotic syndrome (SSNS) patients (ten male, ten female) with a median age of 8 years (range 3-15 years) served as controls. All SRNS patients were examined by mutational analysis for mutations in the NPHS2, WT1, and LAMB2 genes. Nine out of 33 SRNS patients (27.2%) showed various eye abnormalities. However, no abnormal ocular findings were detected in any of the SSNS patients. Abnormal eye findings detected in SRNS patients were anisometropic amblyopia (n = 4), Mittendorf's dots (n = 4), myopic astigmatism (n = 3) and exotropia (n = 1). Macular pigment changes (n = 1), posterior subcapsular opacities (n = 1) and cataract (n = 1) were considered as steroid-induced side effects. In four patients, more than one eye abnormality was found. Mutational analysis for the NPHS2, WT1 and LAMB2 genes revealed disease-causing mutations in 24.2% of patients. Homozygous NPHS2 mutations were detected in five patients (15.1%), all of whom had parental consanguinity. In three patients (9%) from non-consanguineous parents, heterozygous de novo WT1 mutations were detected as disease-causing mutations. No LAMB2 mutation was detected in any patient. While four out of five (80%) patients with homozygous NPHS2 mutations showed at least one abnormal ocular finding (i.e. Mittendorf's dot or anisometric amblyopia), none of the patients with a WT1 mutation had ocular involvement. In conclusion, ocular involvement may accompany SRNS caused by primary focal segmental glomerulosclerosis (FSGS). Ophthalmologic evaluation at the time of diagnosis might be beneficial to characterize further the spectrum of this possible association.
Topics: Adolescent; Adult; Child; Child, Preschool; Drug Resistance; Eye Diseases; Female; Genes, Wilms Tumor; Glomerulosclerosis, Focal Segmental; Humans; Intracellular Signaling Peptides and Proteins; Lamin Type B; Male; Membrane Proteins; Nephrotic Syndrome; Steroids
PubMed: 18058136
DOI: 10.1007/s00467-007-0695-8 -
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