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Annals of the New York Academy of... Dec 2012Presynaptic active zones are synaptic vesicle release sites that play essential roles in the function and pathology of mammalian neuromuscular junctions (NMJs). The... (Review)
Review
Presynaptic active zones are synaptic vesicle release sites that play essential roles in the function and pathology of mammalian neuromuscular junctions (NMJs). The molecular mechanisms of active zone organization use presynaptic voltage-dependent calcium channels (VDCCs) in NMJs as scaffolding proteins. VDCCs interact extracellularly with the muscle-derived synapse organizer, laminin β2 and interact intracellularly with active zone-specific proteins, such as Bassoon, CAST/Erc2/ELKS2alpha, ELKS, Piccolo, and RIMs. These molecular mechanisms are supported by studies in P/Q- and N-type VDCCs double-knockout mice, and they are consistent with the pathological conditions of Lambert-Eaton myasthenic syndrome and Pierson syndrome, which are caused by autoantibodies against VDCCs or by a laminin β2 mutation. During normal postnatal maturation, NMJs maintain the density of active zones, while NMJs triple their size. However, active zones become impaired during aging. Propitiously, muscle exercise ameliorates the active zone impairment in aged NMJs, which suggests the potential for therapeutic strategies.
Topics: Abnormalities, Multiple; Aging; Animals; Autoantibodies; Calcium Channels; Eye Abnormalities; Humans; Lambert-Eaton Myasthenic Syndrome; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Nerve Tissue Proteins; Neuromuscular Junction; Presynaptic Terminals; Pupil Disorders
PubMed: 23252894
DOI: 10.1111/j.1749-6632.2012.06836.x -
Human Mutation Sep 2010Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities,... (Review)
Review
Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin beta2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin beta2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.
Topics: Genetic Association Studies; Genetic Predisposition to Disease; Haplotypes; Humans; Laminin; Mutation; Phenotype
PubMed: 20556798
DOI: 10.1002/humu.21304 -
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 -
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 -
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 -
Ophthalmology Jun 2011To describe a novel laminin β-2 (LAMB2) mutation associated with nephrotic syndrome and severe retinal disease without microcoria in a large, multigenerational family... (Comparative Study)
Comparative Study
PURPOSE
To describe a novel laminin β-2 (LAMB2) mutation associated with nephrotic syndrome and severe retinal disease without microcoria in a large, multigenerational family with Pierson syndrome.
DESIGN
Retrospective chart review and prospective family examination.
PARTICIPANTS
An extended consanguineous family of 52 members.
METHODS
The eyes, urine, and serum DNA were evaluated in all family members after discovering 2 patients, both younger than 10 years, with bilateral retinal detachments and concurrent renal dysfunction. Linkage analysis was performed in the 9 living affected individuals, 7 using the Illumina Human Hap370 Duo Bead Array (Illumina, San Diego, CA) and 2 using GeneChip 10K (Affymetrix, Santa Clara, CA) mapping arrays.
MAIN OUTCOME MEASURES
The prevalence and severity of ocular and kidney involvement and genetic findings.
RESULTS
Eleven affected family members were identified (9 living), all manifesting chronic kidney disease and bilateral chorioretinal pigmentary changes, with or without retinal detachments, but without microcoria or neurodevelopmental deficits, segregating in an autosomal recessive pattern. The causative gene was localized to a 9-Mb region on chromosome 3. Comprehensive gene sequencing revealed a novel LAMB2 variant (c.440A → G; His147R) that was homozygous in the 9 living, affected family members, observed at a frequency of 2.1% in the Old Order Mennonite population, and absent in 91 non-Mennonite controls. The mutation is located in a highly conserved site in the N-terminal domain VI of LAMB2.
CONCLUSIONS
This study describes a novel mutation of LAMB2 and further expands the spectrum of eye and renal manifestations associated with defects in the laminin β-2 chain.
FINANCIAL DISCLOSURE(S)
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Topics: Abnormalities, Multiple; Adolescent; Adult; Aged; Child; Child, Preschool; Chromosomes, Human, Pair 3; DNA; DNA Mutational Analysis; Eye Abnormalities; Female; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Infant; Laminin; Male; Middle Aged; Mutation, Missense; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pedigree; Phenotype; Pupil Disorders; Retrospective Studies; Young Adult
PubMed: 21236492
DOI: 10.1016/j.ophtha.2010.10.009 -
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 -
Frontiers in Medicine 2019Pierson syndrome (OMIM 609049) is a rare autosomal recessive disorder characterized by congenital nephrotic syndrome and complex ocular abnormalities. Severe renal...
Pierson syndrome (OMIM 609049) is a rare autosomal recessive disorder characterized by congenital nephrotic syndrome and complex ocular abnormalities. Severe renal symptoms had be associated with truncating mutations. Few Chinese patients from diverse ethnic background had been evaluated and reported with this syndrome. Here we report the first Uyghur patient with typical Pierson syndrome phenotypes and a novel pathogenic homozygous variant in gene. A thirty-nine-day old Uyghur girl was born to consanguineous parents, the girl presented with general edema, severe hypotonia and bilateral microcoria. Laboratory tests revealed severe proteinuria, microscopic haematuria, hypoalbuminaemia. By the age of 74 days, she died of renal failure and respiratory infection. We detected on mutations of gene by the sanger sequencing. Sanger sequencing detected a homozygous 2-bp deletion (c.2044_2045insTT/p.Cys682Phefs13) in the exon 16 of gene. Both parents are heterozygous carriers. We reported the first Uyghur case of gene homozygous mutation leading to severe phenotype Pierson syndrome. The clinical presentation of the patient and the novel pathogenic variant detected in this patient added to the overall knowledge of this rare condition.
PubMed: 30778388
DOI: 10.3389/fmed.2019.00012 -
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 -
Journal of the American Society of... Mar 2018Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin 2 (), a major component of the glomerular basement...
Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin 2 (), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient's nephrotic syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a mouse model of autosomal recessive Alport syndrome and increased proteinuria in females that exhibit a mild form of X-linked Alport syndrome due to mosaic deposition of collagen 345(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport syndrome onset and severity observed in patients with Alport syndrome, even for family members who share the same mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans.
Topics: Abnormalities, Multiple; Animals; Autoantigens; Collagen Type IV; Disease Models, Animal; Disease Progression; Eye Abnormalities; Female; Glomerular Basement Membrane; Humans; Kidney Failure, Chronic; Laminin; Mice; Mice, Transgenic; Mutation, Missense; Myasthenic Syndromes, Congenital; Nephritis, Hereditary; Nephrotic Syndrome; Phenotype; Polymerization; Proteinuria; Pupil Disorders
PubMed: 29263159
DOI: 10.1681/ASN.2017090997