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The Journal of Biological Chemistry Jun 2024Polymerizing laminins are multi-domain basement membrane (BM) glycoproteins that self-assemble into cell-anchored planar lattices to establish the initial BM scaffold.... (Review)
Review
Polymerizing laminins are multi-domain basement membrane (BM) glycoproteins that self-assemble into cell-anchored planar lattices to establish the initial BM scaffold. Nidogens, collagen-IV and proteoglycans then bind to the scaffold at different domain loci to create a mature BM. The LN domains of adjacent laminins bind to each other to form a polymer node, while the LG domains attach to cytoskeletal-anchoring integrins and dystroglycan, as well as to sulfatides and heparan sulfates. The polymer node, the repeating unit of the polymer scaffold, is organized into a near-symmetrical triskelion. The structure, recently solved by cryo-electron microscopy in combination with AlphaFold2 modeling and biochemical studies, reveals how the LN surface residues interact with each other and how mutations cause failures of self-assembly in an emerging group of diseases, the LN-lamininopathies, that include LAMA2-related dystrophy and Pierson syndrome.
PubMed: 38825010
DOI: 10.1016/j.jbc.2024.107429 -
Neuromuscular Disorders : NMD Jun 2024LAMB2 gene disorders present with different phenotypes. Pierson syndrome (PS) is a common phenotype associated with LAMB2 variants. Neuromuscular phenotype has been...
LAMB2 gene disorders present with different phenotypes. Pierson syndrome (PS) is a common phenotype associated with LAMB2 variants. Neuromuscular phenotype has been reported including hypotonia and developmental delay. However, neuromuscular junction abnormalities represented as congenital myasthenic syndrome (CMS) was reported in one adult patient only. Here, in this paper, we present two pediatric cases with a severe presentation of PS and have CMS so expanding the knowledge of LAMB2 related phenotypes. The first patient had hypotonia and global developmental delay. Targeted genetic testing panel demonstrated homozygous pathogenic variant in the LAMB2 gene (c.5182C>T, pGln1728*) which was reported by Maselli et al. 2009. Repetitive nerve stimulation (RNS) showed a decremental response at low frequency of 3 Hz. On the other hand, the second patient had profound weakness since birth. Tri-Whole exome sequencing showed homozygous pathogenic variant in the LAMB2 gene c.2890C>T, pArg964*. A trial of salbutamol did not improve the symptoms. Both patients passed away from sequala of PS. The spectrum of phenotypic changes associated with LAMB2 mutations is still expanding, and further investigation into the various clinical and morphologic presentations associated with these mutations is important to better identify and manage affected individuals.
Topics: Humans; Myasthenic Syndromes, Congenital; Male; Female; Eye Abnormalities; Laminin; Phenotype; Mutation; Abnormalities, Multiple; Infant; Neuromuscular Junction Diseases; Child, Preschool; Nephrotic Syndrome; Pupil Disorders
PubMed: 38723581
DOI: 10.1016/j.nmd.2024.03.007 -
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 -
Ophthalmology. Retina Feb 2024To describe the ocular and renal features, as well as outcomes of retinal detachment repair, in patients with a novel, homozygous laminin β-2 (LAMB2) pathogenic variant.
PURPOSE
To describe the ocular and renal features, as well as outcomes of retinal detachment repair, in patients with a novel, homozygous laminin β-2 (LAMB2) pathogenic variant.
DESIGN
Single-center retrospective chart review of patients with a homozygous variant, c.619T>C p.(Ser207Pro), in the LAMB2 gene.
SUBJECTS
Eleven patients (22 eyes) from 4 families.
METHODS
Demographic data and ocular findings were recorded. Patients were recalled for a detailed renal evaluation.
MAIN OUTCOME MEASURES
Ocular features, renal features, and outcomes of retinal detachment repair.
RESULTS
The mean age at presentation was 6.0 (range, 1-26) years. None of the study eyes had microcoria, and none of the patients had nephrotic-range proteinuria. The mean refraction and axial length were -7.9 diopters (range, -4.0 to -12.0 diopters) and 25.3 (range, 22.7-27.7) mm, respectively. Eleven eyes (50%) had cataract at presentation. Fifteen eyes had a clear view to the fundus and all showed tessellated myopic fundus, avascular peripheral retina evident clinically or on fluorescein angiography, and rudimentary fovea. Optic disc pallor was observed in 10 eyes (66.7%). Straightened retinal vessels, abnormal vascular emanation (situs inversus) from the optic disc, supernumerary vascular branching at the optic disc, and vascular tortuosity were observed in 10 (66.7%), 2 (13.4%), 2 (13.4%), and 2 (13.4%) eyes, respectively. Discrete areas of punched-out chorioretinal atrophy were observed in 4 (26.7%) eyes. Spectral-domain OCT showed retinal and choroidal thinning in 13 eyes (86.7%), retinoschisis temporal to the fovea in 2 eyes (13.4%), and rudimentary fovea in 15 eyes (100%). Among the 22 eyes, 14 eyes (63.6%) developed rhegmatogenous retinal detachment (RRD), mostly during childhood, of which 5 patients had bilateral RRD. Eight eyes were operated on and 6 (75%) achieved retinal reattachment at the last follow-up. The mean preoperative visual acuity was 20/300 and the mean postoperative visual acuity at the last follow-up was 20/400.
CONCLUSIONS
This study describes a distinct phenotype of LAMB2-related disease with a novel, homozygous LAMB2 variant, and further expands the spectrum of ophthalmic and renal features, and the molecular genetic basis, of LAMB2-related disease. Because the typical microcoria and nephrotic-range proteinuria might be absent, the retinal features can guide the diagnosis.
FINANCIAL DISCLOSURE(S)
The authors have no proprietary or commercial interest in any materials discussed in this article.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Young Adult; Eye Abnormalities; Myopia; Proteinuria; Retina; Retinal Detachment; Retrospective Studies
PubMed: 37678612
DOI: 10.1016/j.oret.2023.08.022 -
Ophthalmic Genetics Oct 2023Pierson syndrome and X-linked Alport syndrome result from pathogenic variants in and , respectively, and both affect basement membranes in the kidney and the eye. This... (Review)
Review
BACKGROUND
Pierson syndrome and X-linked Alport syndrome result from pathogenic variants in and , respectively, and both affect basement membranes in the kidney and the eye. This study describes the ocular features in an individual with a homozygous pathogenic variant and compares the reported abnormalities in Pierson syndrome with those in Alport syndrome.
METHODS
A 28-year-old man who developed kidney failure 10 years previously and subsequently had an atrial septal defect repair was suspected of having genetic kidney disease on the basis of his likely diagnosis of Focal and Segmental Glomerulosclerosis (FSGS), his young age at presentation, and his cardiac anomaly. He then underwent Whole Exome Sequencing and a formal ophthalmological examination.
RESULTS
The patient was found to have a homozygous Likely Pathogenic missense variant (p.(Arg1719Cys)) in consistent with the diagnosis of Pierson syndrome. He had normal visual acuity, normal optic globe and cornea size, and normal lens appearance on direct examination. Upon further testing, his cornea demonstrated central thinning. There was also increased corneal endothelial pleomorphism, a reduced foveal reflex, and a blunted foveal curvature, similar to the features seen in X-linked Alport syndrome.
CONCLUSION
Our patient had a later onset form of Pierson syndrome or "FSGS type 5, with or without ocular abnormalities," consistent with his "milder" missense variant. The resemblance of the ocular features in Pierson syndrome and X-linked Alport syndrome suggests that mutations in and have similar effects on basement membranes and the pathogenesis of ocular damage.
Topics: Male; Humans; Adult; Nephritis, Hereditary; Glomerulosclerosis, Focal Segmental; Nephrotic Syndrome; Mutation; Collagen Type IV
PubMed: 37537573
DOI: 10.1080/13816810.2023.2240881 -
Pediatric Hematology and Oncology 2023Although hematopoietic stem cell transplantation (HSCT) has been widely used to treat patients with beta-thalassemia major, evidence showing whether this treatment...
Thalassemia patients in transfussion dependent period and after hematopoietic stem cell transplantation: how are the psychiatric status and life quality of these patients?
Although hematopoietic stem cell transplantation (HSCT) has been widely used to treat patients with beta-thalassemia major, evidence showing whether this treatment improves mental health, self esteem and health-related quality of life (HRQoL) is limited. We aimed to describe psychiatric problems, HRQoL and self-esteem scores of patients who have thalassemia and compared with patients who underwent HSCT in the current study. A total of 24 patients with thalassemia major and 13 patients who underwent HSCT at least 2 years ago aged between 7-37 years were included. We used The Children's Depression Inventory, The Spielberger State-Trait Anxiety Inventory, and Pediatric Quality of LifeTM (PedsQL™) for assesment of children and Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), World Health Organization Quality of Life Scale Brief Version (WHOQOL-BREF) for assessment of adults. We also used Piers Harris Self Concept Scale for children and adults. Psychopathologies are common in both groups (50% in Thalassemia group and 69.2% in HSCT group). Popularity scores in Piers Haris scale of patients in HSCT group were significantly higher compared to thalassemia group ( = 0.03). Additionally, HSCT group had higher scores in physical health subscales of HRQoL in both children and parents'( = 0.02, = 0.03 respectively). Our findings suggest improved HRQoL and self-esteem in thalassemia patients after HSCT. However, due to the high prevalence of mental disorders in both groups, we would like to emphasize that clinicians should examine not only the physical but also the psychological state of the patients with thalessemia during the their treatment and follow-up period after HSCT.
Topics: Adult; Humans; Child; Adolescent; Young Adult; Quality of Life; beta-Thalassemia; Thalassemia; Parents; Hematopoietic Stem Cell Transplantation
PubMed: 37519029
DOI: 10.1080/08880018.2023.2220733 -
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