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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 -
Pediatric Transplantation Dec 2017Congenital nephrotic syndrome is commonly associated with mutations in genes that encode podocyte and slit diaphragm proteins or the structural and regulatory proteins...
Congenital nephrotic syndrome is commonly associated with mutations in genes that encode podocyte and slit diaphragm proteins or the structural and regulatory proteins of the GBM. These mutations lead to the formation of dysfunctional proteins, which account for the resistance of the renal manifestations to conventional treatment methods. Consequently, patients become renal replacement therapy dependent. Mutation of the LAMB2 gene is associated with Pierson syndrome, which is an autosomal recessive disorder characterized by congenital nephrotic syndrome and ocular abnormalities. In this report, a 2-year-old male patient who was diagnosed with Pierson syndrome is presented. He had bilateral microcoria and developmental delay in addition to nephrotic syndrome. His renal function deteriorated rapidly, and he underwent a deceased donor kidney transplantation. He showed dramatic improvement after kidney transplantation; in addition to having good renal function, he started to catch up to his peers in terms of growth. Pierson syndrome should be considered during the diagnostic investigations of children with renal manifestations and ocular abnormalities. Children with Pierson syndrome must be evaluated in terms of kidney transplantation as soon as they are diagnosed.
Topics: Abnormalities, Multiple; Child, Preschool; Eye Abnormalities; Humans; Kidney Transplantation; Male; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders
PubMed: 29094445
DOI: 10.1111/petr.13076 -
Kidney International Reports Dec 2020
PubMed: 33305134
DOI: 10.1016/j.ekir.2020.09.023 -
Current Topics in Membranes 2015Cell-extracellular matrix (ECM) interactions are essential for tissue development, homeostasis, and response to injury. Basement membranes (BMs) are specialized ECMs... (Review)
Review
Cell-extracellular matrix (ECM) interactions are essential for tissue development, homeostasis, and response to injury. Basement membranes (BMs) are specialized ECMs that separate epithelial or endothelial cells from stromal components and interact with cells via cellular receptors, including integrins and discoidin domain receptors. Disruption of cell-BM interactions due to either injury or genetic defects in either the ECM components or cellular receptors often lead to irreversible tissue injury and loss of organ function. Animal models that lack specific BM components or receptors either globally or in selective tissues have been used to help with our understanding of the molecular mechanisms whereby cell-BM interactions regulate organ function in physiological and pathological conditions. We review recently published works on animal models that explore how cell-BM interactions regulate kidney homeostasis in both health and disease.
Topics: Animals; Basement Membrane; Epithelial Cells; Humans; Kidney; Kidney Diseases; Protein Binding; Receptors, Cell Surface
PubMed: 26610916
DOI: 10.1016/bs.ctm.2015.07.003 -
Ophthalmic Genetics Jun 2021: To report a patient with Pierson syndrome who presented with neovascular glaucoma (NVG) after cataract surgery.: Retrospective case report.: A 17-year old monocular...
: To report a patient with Pierson syndrome who presented with neovascular glaucoma (NVG) after cataract surgery.: Retrospective case report.: A 17-year old monocular female presented with sudden onset of pain and decreased vision in the right eye. On examination, she had intraocular pressure (IOP) of 50 mmHg, aggressive iris neovascularization (NVI) and 3-piece IOL. Fundus examination revealed pale disc with tessellated fundus and parapapillary atrophy. Vascular arcades were vertically stretched with avascular ischemic retina starting from the near periphery. Macula appeared thin and atrophic. An intravitreal injection of 0.05 mg/0.1 ml bevacizumab was given to the right eye followed by Ahmed glaucoma valve (AGV) implantation. Assessment of her brother revealed similar posterior segment changes. A subsequent urine analysis showed proteinuria and high albumin to creatinine ratio. Next-generation sequencing for gene revealed a homozygous c.4573 + 1 G > A variant confirming the diagnosis of Pierson syndrome.: This case expands our knowledge on retinal ischemia in the setting of Pierson syndrome. Close monitoring after intraocular surgery is recommended to look for the development of NVG.
Topics: Adolescent; Angiogenesis Inhibitors; Bevacizumab; Combined Modality Therapy; Female; Glaucoma Drainage Implants; Glaucoma, Neovascular; High-Throughput Nucleotide Sequencing; Humans; Intraocular Pressure; Laminin; Lens Implantation, Intraocular; Male; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Phacoemulsification; Pupil Disorders; Retrospective Studies; Siblings; Tonometry, Ocular; Young Adult
PubMed: 33554690
DOI: 10.1080/13816810.2021.1881982 -
Journal of the American Society of... May 2018
Topics: Abnormalities, Multiple; Eye Abnormalities; Glomerular Basement Membrane; Humans; Laminin; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Podocytes; Pupil Disorders
PubMed: 29650536
DOI: 10.1681/ASN.2018030294 -
Current Topics in Membranes 2015Studies on extracellular matrix proteins, cells, and genetically modified animals have converged to reveal mechanisms of basement membrane self-assembly as mediated by... (Review)
Review
Studies on extracellular matrix proteins, cells, and genetically modified animals have converged to reveal mechanisms of basement membrane self-assembly as mediated by γ1 subunit-containing laminins, the focus of this chapter. The basic model is as follows: A member of the laminin family adheres to a competent cell surface and typically polymerizes followed by laminin binding to the extracellular adaptor proteins nidogen, perlecan, and agrin. Assembly is completed by the linking of nidogen and heparan sulfates to type IV collagen, allowing it to form a second stabilizing network polymer. The assembled matrix provides structural support, anchoring the extracellular matrix to the cytoskeleton, and acts as a signaling platform. Heterogeneity of function is created in part by the isoforms of laminin that vary in their ability to polymerize and to interact with integrins, dystroglycan, and other receptors. Mutations in laminin subunits, affecting expression or LN domain-specific functions, are a cause of human diseases that include those of muscle, nerve, brain, and kidney.
Topics: Animals; Basement Membrane; Cell Adhesion; Collagen Type IV; Cytoskeleton; Humans; Laminin; Protein Multimerization
PubMed: 26610910
DOI: 10.1016/bs.ctm.2015.05.001 -
BMC Nephrology Aug 2020Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) cause substantial morbidity and mortality. In Japan, there is a lack of knowledge regarding... (Observational Study)
Observational Study
BACKGROUND
Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) cause substantial morbidity and mortality. In Japan, there is a lack of knowledge regarding the characteristics of CNS and INS. This study aimed to clarify the characteristics of CNS and INS in Japan.
METHODS
This cross-sectional nationwide survey obtained data from 44 institutions in Japan managing 92 patients with CNS or INS, by means of two survey questionnaires sent by postal mail. Patients aged < 16 years by 1 April 2015, with a diagnosis of CNS or INS, were included in this study. The primary outcome was end-stage kidney disease.
RESULTS
A total of 83 patients with CNS or INS were analyzed. The most frequent disease type was non-Finnish (60.2%); 33 patients (39.8%) had Finnish type. Among those with non-Finnish-type disease, 26 had no syndrome and 24 had a syndrome, of which the most frequent was Denys-Drash syndrome (70.8%). Patients with non-Finnish-type disease with syndrome showed the earliest progression to end-stage kidney disease compared with the other two groups, whereas patients with non-Finnish-type disease without syndrome progressed more slowly compared with the other two groups. In the Finnish-type group, the disease was diagnosed the earliest; a large placenta was reported more frequently; genetic testing was more frequently performed (93.8%); mental retardation was the most frequent extra-renal symptom (21.2%); and thrombosis and infection were more frequent compared with the other groups. Patients with non-Finnish-type disease with syndrome had a higher frequency of positive extra-renal symptoms (79.2%), the most common being urogenital symptoms (54.2%). Treatment with steroids and immunosuppressants was more frequent among patients with non-Finnish-type disease without syndrome. Two patients with non-Finnish-type disease without syndrome achieved complete remission. In all groups, unilateral nephrectomy was performed more often than bilateral nephrectomy and peritoneal dialysis was the most common renal replacement therapy.
CONCLUSIONS
The present epidemiological survey sheds light on the characteristics of children with CNS and INS in Japan. A high proportion of patients underwent genetic examination, and patient management was in accord with current treatment recommendations and practices.
TRIAL REGISTRATION
Not applicable.
Topics: Adolescent; Child; Child, Preschool; Denys-Drash Syndrome; Disease Progression; Female; Genetic Testing; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Intellectual Disability; Japan; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Myasthenic Syndromes, Congenital; Nephrectomy; Nephrotic Syndrome; Organ Size; Placenta; Pregnancy; Pupil Disorders; Renal Replacement Therapy; Surveys and Questionnaires; Syndrome
PubMed: 32838745
DOI: 10.1186/s12882-020-02010-5 -
Journal of Human Genetics Apr 2020Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete...
Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete negativity for laminin β2 expression on glomerular basement membrane (GBM). In contrast, missense variants outside the laminin N-terminal (LN) domain in LAMB2 lead to milder phenotypes. However, we experienced cases not showing these typical genotype-phenotype correlations. In this paper, we report six PS patients: four with mild phenotypes and two with severe phenotypes. We conducted molecular studies including protein expression and transcript analyses. The results revealed that three of the four cases with milder phenotypes had missense variants located outside the LN domain and one of the two severe PS cases had a homozygous missense variant located in the LN domain; these variant positions could explain their phenotypes. However, one mild case possessed a splicing site variant (c.3797 + 5G>A) that should be associated with a severe phenotype. Upon transcript analysis, this variant generated some differently sized transcripts, including completely normal transcript, which could have conferred the milder phenotype. In one severe case, we detected the single-nucleotide substitution of c.4616G>A located outside the LN domain, which should be associated with a milder phenotype. However, we detected aberrant splicing caused by the creation of a novel splice site by this single-base substitution. These are novel mechanisms leading to an atypical genotype-phenotype correlation. In addition, all four cases with milder phenotypes showed laminin β2 expression on GBM. We identified novel mechanisms leading to atypical genotype-phenotype correlation in PS.
Topics: Amino Acid Substitution; Child; Child, Preschool; Female; Glomerular Basement Membrane; Humans; Infant; Laminin; Male; Mutation, Missense; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Protein Domains; Pupil Disorders; RNA Splicing
PubMed: 31959872
DOI: 10.1038/s10038-019-0715-0 -
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