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Frontiers in Pediatrics 2018The glomerular basement membrane (GBM) is a specialized structure with a significant role in maintaining the glomerular filtration barrier. This GBM is formed from the... (Review)
Review
The glomerular basement membrane (GBM) is a specialized structure with a significant role in maintaining the glomerular filtration barrier. This GBM is formed from the fusion of two basement membranes during development and its function in the filtration barrier is achieved by key extracellular matrix components including type IV collagen, laminins, nidogens, and heparan sulfate proteoglycans. The characteristics of specific matrix isoforms such as laminin-521 (α5β2γ1) and the α3α4α5 chain of type IV collagen are essential for the formation of a mature GBM and the restricted tissue distribution of these isoforms makes the GBM a unique structure. Detailed investigation of the GBM has been driven by the identification of inherited abnormalities in matrix proteins and the need to understand pathogenic mechanisms causing severe glomerular disease. A well-described hereditary GBM disease is Alport syndrome, associated with a progressive glomerular disease, hearing loss, and lens defects due to mutations in the genes , or . Other proteins associated with inherited diseases of the GBM include laminin β2 in Pierson syndrome and in nail patella syndrome. The knowledge of these genetic mutations associated with GBM defects has enhanced our understanding of cell-matrix signaling pathways affected in glomerular disease. This review will address current knowledge of GBM-associated abnormalities and related signaling pathways, as well as discussing the advances toward disease-targeted therapies for patients with glomerular disease.
PubMed: 29435440
DOI: 10.3389/fped.2018.00011 -
BMC Medical Genetics Apr 2020Pierson syndrome (PS) is a rare autosomal recessive disorder, characterized by congenital nephrotic syndrome and microcoria. Advances in renal replacement therapies have...
BACKGROUND
Pierson syndrome (PS) is a rare autosomal recessive disorder, characterized by congenital nephrotic syndrome and microcoria. Advances in renal replacement therapies have extended the lifespan of patients, whereas the full clinical spectrum of PS in infancy and beyond remains elusive.
CASE PRESENTATION
We present the case of a 12-month-old boy with PS, manifesting as the bilateral microcoria and congenital nephrotic syndrome. He was born without asphyxia, and was neurologically intact from birth through the neonatal period. Generalized muscle weakness and hypotonia were recognized from 3 months of age. The infant showed recurrent vomiting at age 5 months of age, and was diagnosed with gastroesophageal reflux and intestinal malrotation. Despite the successful surgical treatment, vomiting persisted and led to severely impaired growth. Tulobuterol treatment was effective in reducing the frequency of vomiting. Targeted sequencing confirmed that he had a compound heterozygous mutation in LAMB2 (NM_002292.3: p.Arg550X and p.Glu1507X). A search of the relevant literature identified 19 patients with severe neuro-muscular phenotypes. Among these, only 8 survived the first 12 months of life, and one had feeding difficulty with similar gastrointestinal problems.
CONCLUSIONS
This report demonstrated that severe neurological deficits and gastrointestinal dysfunction may emerge in PS patients after the first few months of life.
Topics: Abnormalities, Multiple; Gastrointestinal Tract; Humans; Infant; Laminin; Male; Mutation; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Phenotype; Pupil Disorders
PubMed: 32295525
DOI: 10.1186/s12881-020-01019-9 -
Journal of Pediatric Ophthalmology and... Jun 2009Pierson syndrome is a recently described autosomal recessive genetic disorder that presents in the neonatal period with bilateral microcoria and congenital nephrotic...
Pierson syndrome is a recently described autosomal recessive genetic disorder that presents in the neonatal period with bilateral microcoria and congenital nephrotic syndrome. This report describes a case of Pierson syndrome with an emphasis on the ocular findings.
PubMed: 19645379
DOI: 10.3928/01913913-20090616-14 -
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 -
Prenatal Diagnosis Mar 2006To describe the prenatal findings in Pierson syndrome, a newly defined autosomal recessive entity, comprising congenital nephrotic syndrome (CNS) with diffuse mesangial...
OBJECTIVE
To describe the prenatal findings in Pierson syndrome, a newly defined autosomal recessive entity, comprising congenital nephrotic syndrome (CNS) with diffuse mesangial sclerosis and distinct eye abnormalities due to LAMB2 mutations.
METHODS
Serial prenatal ultrasound examinations were performed in four consecutive pregnancies affected by Pierson syndrome in the same family. LAMB2 mutations were demonstrated in retrospect by direct sequencing of the gene in the newborn index patient and three abortuses.
RESULTS
Fetal ultrasound consistently revealed marked renal hyperechogenicity associated with variable degree of pyelectasis. These features were detectable by 15 weeks of gestation in all fetuses. Hydrops fetalis due to severe hypalbuminemia demonstrated by chordocentesis occurred in one fetus. Placentas were significantly enlarged. Development of oligohydramnios indicated prenatal decline of renal excretory function. Anencephaly was detected in another fetus with molecularly proven Pierson syndrome at 12 weeks of gestation.
CONCLUSION
We conclude that Pierson syndrome has to be considered in the differential diagnosis of nephrotic disorders with prenatal onset. Ultrasound criteria for differentiation from the most common type of CNS-congenital nephrosis of the Finnish type (CNF)-are discussed. Because of its prognostic relevance, we advocate molecular genetic testing of LAMB2 in any case of prenatally detected nephrotic syndrome with negative results of NPHS1 mutational screening, especially in the presence of the typical sonomorphologic findings of the kidneys and the development of oligohydramnios.
Topics: Abnormalities, Multiple; Anencephaly; Consanguinity; Eye Abnormalities; Fatal Outcome; Female; Fetal Death; Fetal Diseases; Glomerular Mesangium; Humans; Infant; Lamin Type B; Male; Mutation; Nephrotic Syndrome; Pedigree; Pregnancy; Syndrome; Ultrasonography, Prenatal
PubMed: 16450351
DOI: 10.1002/pd.1393 -
Journal of AAPOS : the Official... Oct 2018Pierson syndrome, an autosomal recessive disorder caused by a mutation in laminin ß2 (LAMB2) gene, is characterized by congenital nephrotic syndrome and various ocular...
Pierson syndrome, an autosomal recessive disorder caused by a mutation in laminin ß2 (LAMB2) gene, is characterized by congenital nephrotic syndrome and various ocular abnormalities. The ocular findings in Pierson syndrome are not well understood, because the incidence of this syndrome is very rare. We report ocular findings in a 5-month-old boy with Pierson syndrome with a novel mutation in LAMB2. We performed a pupilloplasty for his microcoria. Ophthalmic examinations after surgery revealed that he had cataract, severe retinal degeneration, and high myopia. Optical coherence tomography showed the collapse of retinal layer structures and a marked decrease of choroidal thickness. Immunohistochemistry and electron microscopy examinations revealed abnormal iris differentiation and thinning or defect of basal membranes. These results suggest that the development of the iris, lens, retina, and choroid are affected in this type of mutation.
Topics: Abnormalities, Multiple; Cataract; Eye Abnormalities; Humans; Infant; Laminin; Male; Mutation; Myasthenic Syndromes, Congenital; Myopia, Degenerative; Nephrotic Syndrome; Pupil Disorders; Retinal Degeneration
PubMed: 30120985
DOI: 10.1016/j.jaapos.2018.03.016 -
Nephron. Clinical Practice 2011This review provides current information about glomerular disorders that arise directly from inherited abnormalities in extracellular matrix proteins intrinsic to the... (Review)
Review
This review provides current information about glomerular disorders that arise directly from inherited abnormalities in extracellular matrix proteins intrinsic to the glomerular basement membrane (Alport syndrome, thin basement membrane nephropathy, HANAC syndrome and Pierson syndrome). The authors also discuss disorders involving genetic defects in cellular proteins that result in structural defects in glomerular basement membranes (MYH9-related disorders, nail-patella syndrome).
Topics: Animals; Genetic Predisposition to Disease; Glomerular Basement Membrane; Humans; Kidney; Kidney Diseases
PubMed: 21071975
DOI: 10.1159/000320876 -
Development (Cambridge, England) Mar 2006Pierson syndrome is a recently defined disease usually lethal within the first postnatal months and caused by mutations in the gene encoding laminin beta2 (LAMB2). The...
Pierson syndrome is a recently defined disease usually lethal within the first postnatal months and caused by mutations in the gene encoding laminin beta2 (LAMB2). The hallmarks of Pierson syndrome are congenital nephrotic syndrome accompanied by ocular abnormalities, including microcoria (small pupils), with muscular and neurological developmental defects also present. Lamb2(-/-) mice are a model for Pierson syndrome; they exhibit defects in the kidney glomerular barrier, in the development and organization of the neuromuscular junction, and in the retina. Lamb2(-/-) mice fail to thrive and die very small at 3 weeks of age, but to what extent the kidney and neuromuscular defects each contribute to this severe phenotype has been obscure, though highly relevant to understanding Pierson syndrome. To investigate this, we generated transgenic mouse lines expressing rat laminin beta2 either in muscle or in glomerular epithelial cells (podocytes) and crossed them onto the Lamb2(-/-) background. Rat beta2 was confined in skeletal muscle to synapses and myotendinous junctions, and in kidney to the glomerular basement membrane. In transgenic Lamb2(-/-) mice, beta2 deposition in only glomeruli prevented proteinuria but did not ameliorate the severe phenotype. By contrast, beta2 expression in only muscle restored synaptic architecture and led to greatly improved health, but the mice died from kidney disease at 1 month. Rescue of both glomeruli and synapses was associated with normal weight gain, fertility and lifespan. We conclude that muscle defects in Lamb2(-/-) mice are responsible for the severe failure to thrive phenotype, and that renal replacement therapy alone will be an inadequate treatment for Pierson syndrome.
Topics: Animals; Glomerular Basement Membrane; Kidney Diseases; Laminin; Mice; Mice, Knockout; Mice, Transgenic; Muscle, Skeletal; Muscular Diseases; Mutation; Neuromuscular Junction; Podocytes; Rats; Synapses; Syndrome
PubMed: 16452099
DOI: 10.1242/dev.02270 -
Nephrology, Dialysis, Transplantation :... Mar 2010Pierson syndrome is typically manifested with congenital nephrotic syndrome (CNS) and peculiar ocular changes. LAMB2 was the causative gene.
BACKGROUND
Pierson syndrome is typically manifested with congenital nephrotic syndrome (CNS) and peculiar ocular changes. LAMB2 was the causative gene.
METHODS
A 3.25-year-old girl presenting with childhood-onset heavy proteinuria, bilateral myosis and nystagmus was detected on mutations of LAMB2 gene by PCR direct sequencing.
RESULTS
Two novel mutations were identified, C757fsX767 and P1413fsX1451, which predicted truncated proteins and were confirmed in the paternal and maternal origins, respectively.
CONCLUSIONS
This is the first Chinese case of Pierson syndrome diagnosed by clinical manifestations and LAMB2 gene mutations. The phenotype may be different in different ethics.
Topics: Child, Preschool; China; Eye Abnormalities; Female; Gene Deletion; Humans; Kidney Diseases; Laminin; Mutation; Nystagmus, Congenital; Proteinuria; Syndrome
PubMed: 19861315
DOI: 10.1093/ndt/gfp563 -
Journal of the American Society of... May 2018Laminin 521 (LM-521) is a major component of the GBM. Mutations in that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic...
Laminin 521 (LM-521) is a major component of the GBM. Mutations in that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic syndrome with diffuse mesangial sclerosis and ocular and neurologic defects. Because the GBM is uniquely accessible to plasma, which permeates endothelial cell fenestrae, we hypothesized that intravenous delivery of LM-521 could replace the missing LM-521 in the GBM of mutant mice and restore glomerular permselectivity. We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of -/- pups daily. Deposition of hLM-521 into the GBM was investigated by fluorescence microscopy. We assayed the effects of hLM-521 on glomerular permselectivity by urinalysis and the effects on podocytes by desmin immunostaining and ultrastructural analysis of podocyte architecture. Injected hLM-521 rapidly and stably accumulated in the GBM of all glomeruli. Super-resolution imaging showed that hLM-521 accumulated in the correct orientation in the GBM, primarily on the endothelial aspect. Treatment with hLM-521 greatly reduced the expression of the podocyte injury marker desmin and attenuated the foot process effacement observed in untreated pups. Moreover, treatment with hLM-521 delayed the onset of proteinuria but did not prevent nephrotic syndrome, perhaps due to its absence from the podocyte aspect of the GBM. These studies show that GBM composition and function can be altered vascular delivery of even very large proteins, which may advance therapeutic options for patients with abnormal GBM composition, whether genetic or acquired.
Topics: Abnormalities, Multiple; Animals; Desmin; Disease Models, Animal; Eye Abnormalities; Glomerular Basement Membrane; Injections, Intravenous; Laminin; Mice; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Permeability; Podocytes; Proteinuria; Pupil Disorders; Recombinant Proteins
PubMed: 29472414
DOI: 10.1681/ASN.2017060690