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1.
J Hum Genet ; 65(4): 355-362, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31959872

RESUMO

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 ß2 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 ß2 expression on GBM. We identified novel mechanisms leading to atypical genotype-phenotype correlation in PS.


Assuntos
Membrana Basal Glomerular , Laminina , Mutação de Sentido Incorreto , Síndromes Miastênicas Congênitas , Síndrome Nefrótica , Distúrbios Pupilares , Splicing de RNA , Substituição de Aminoácidos , Criança , Pré-Escolar , Feminino , Membrana Basal Glomerular/metabolismo , Membrana Basal Glomerular/patologia , Humanos , Lactente , Laminina/biossíntese , Laminina/genética , Masculino , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/metabolismo , Síndromes Miastênicas Congênitas/patologia , Síndrome Nefrótica/genética , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Domínios Proteicos , Distúrbios Pupilares/genética , Distúrbios Pupilares/metabolismo , Distúrbios Pupilares/patologia
2.
J Pediatr Ophthalmol Strabismus ; 56: e45-e48, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31282960

RESUMO

Ectopia lentis is displacement of the lens from its original position. It can be inherited or acquired with isolated or systemic findings. The authors describe a 4-year-old girl with isolated ectopia lentis et pupillae caused by pathogenic variants in the ADAMTSL4 gene and discuss the molecular genetic work-up of individuals with ectopia lentis. [J Pediatr Ophthalmol Strabismus. 2019;56:e45-e48.].


Assuntos
Proteínas ADAMTS/genética , Algoritmos , DNA/genética , Ectopia do Cristalino/genética , Cristalino/diagnóstico por imagem , Mutação , Distúrbios Pupilares/genética , Proteínas ADAMTS/metabolismo , Pré-Escolar , Análise Mutacional de DNA , Ectopia do Cristalino/diagnóstico , Ectopia do Cristalino/metabolismo , Feminino , Humanos , Linhagem , Distúrbios Pupilares/diagnóstico , Distúrbios Pupilares/metabolismo , Tomografia de Coerência Óptica
3.
Matrix Biol ; 71-72: 250-261, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29673759

RESUMO

The glomerular basement membrane (GBM) is an important component of the kidney's glomerular filtration barrier. Like all basement membranes, the GBM contains type IV collagen, laminin, nidogen, and heparan sulfate proteoglycan. It is flanked by the podocytes and glomerular endothelial cells that both synthesize it and adhere to it. Mutations that affect the GBM's collagen α3α4α5(IV) components cause Alport syndrome (kidney disease with variable ear and eye defects) and its variants, including thin basement membrane nephropathy. Mutations in LAMB2 that impact the synthesis or function of laminin α5ß2γ1 (LM-521) cause Pierson syndrome (congenital nephrotic syndrome with eye and neurological defects) and its less severe variants, including isolated congenital nephrotic syndrome. The very different types of kidney diseases that result from mutations in collagen IV vs. laminin are likely due to very different pathogenic mechanisms. A better understanding of these mechanisms should lead to targeted therapeutic approaches that can help people with these rare but important diseases.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades do Olho/genética , Membrana Basal Glomerular/patologia , Nefrite Hereditária/genética , Síndrome Nefrótica/genética , Distúrbios Pupilares/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Colágeno Tipo IV/química , Colágeno Tipo IV/genética , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Membrana Basal Glomerular/metabolismo , Humanos , Laminina/química , Laminina/genética , Mutação , Síndromes Miastênicas Congênitas , Nefrite Hereditária/metabolismo , Nefrite Hereditária/patologia , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Distúrbios Pupilares/metabolismo , Distúrbios Pupilares/patologia
4.
J Am Soc Nephrol ; 29(5): 1426-1436, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29472414

RESUMO

Background Laminin α5ß2γ1 (LM-521) is a major component of the GBM. Mutations in LAMB2 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 Lamb2 mutant mice and restore glomerular permselectivity.Methods We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of Lamb2-/- 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.Results 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.Conclusions These studies show that GBM composition and function can be altered in vivovia vascular delivery of even very large proteins, which may advance therapeutic options for patients with abnormal GBM composition, whether genetic or acquired.


Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/metabolismo , Anormalidades do Olho/tratamento farmacológico , Anormalidades do Olho/metabolismo , Membrana Basal Glomerular/metabolismo , Laminina/genética , Laminina/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/metabolismo , Distúrbios Pupilares/tratamento farmacológico , Distúrbios Pupilares/metabolismo , Anormalidades Múltiplas/genética , Animais , Desmina/metabolismo , Modelos Animais de Doenças , Anormalidades do Olho/complicações , Anormalidades do Olho/genética , Injeções Intravenosas , Laminina/administração & dosagem , Camundongos , Síndromes Miastênicas Congênitas , Síndrome Nefrótica/complicações , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/genética , Permeabilidade/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Podócitos/ultraestrutura , Proteinúria/etiologia , Proteinúria/prevenção & controle , Distúrbios Pupilares/complicações , Distúrbios Pupilares/genética , Proteínas Recombinantes/uso terapêutico
5.
Bone ; 106: 187-193, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29051055

RESUMO

INTRODUCTION: Pierson syndrome is caused by a mutation of LAMB2, encoding for laminin ß2. Clinical phenotype is variable but usually associates congenital nephrotic syndrome (CNS) and ocular abnormalities. Neuromuscular impairment has also been described. METHODS: We report on a 15-year old girl, suffering from Pierson Syndrome, who developed severe bone deformations during puberty. This patient initially displayed CNS and microcoria, leading to the clinical diagnosis of Pierson syndrome. Genetic analysis revealed a truncating mutation and a splice site mutation of LAMB2. The patient received a renal transplantation (R-Tx) at the age of 3. After R-Tx, renal evolution was simple, the patient receiving low-dose corticosteroids, tacrolimus and mycophenolate mofetil. At the age of 12, bone deformations progressively appeared. At the time of bone impairment, renal function was subnormal (glomerular filtration rate using iohexol clearance 50mL/min per 1.73m2), and parameters of calcium/phosphate metabolism were normal (calcium 2.45mmol/L, phosphorus 1.30mmol/L, PTH 81ng/L, ALP 334U/L, 25OH-D 73nmol/L). Radiographs showed major deformations such as scoliosis, genu varum and diffuse epiphyseal abnormalities. A high resolution scanner (HR-pQCT) was performed, demonstrating a bone of "normal low" quantity and quality; major radial and cubital deformations were observed. Stainings of laminin ß2 were performed on bone and renal samples from the patient and healthy controls: as expected, laminin ß2 was expressed in the control kidney but not in the patient's renal tissue, and a similar pattern was observed in bone. CONCLUSION: This is the first case of skeletal impairment ever described in Pierson syndrome. Integrin α3ß1, receptor for laminin ß2, are found in podocytes and osteoblasts, and the observation of both the presence of laminin ß2 staining in healthy bone and its absence in the patient's bone raises the question of a potential role of laminin ß2 in bone physiology.


Assuntos
Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/fisiopatologia , Anormalidades do Olho/metabolismo , Anormalidades do Olho/fisiopatologia , Laminina/metabolismo , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/fisiopatologia , Distúrbios Pupilares/metabolismo , Distúrbios Pupilares/fisiopatologia , Anormalidades Múltiplas/genética , Adolescente , Anormalidades do Olho/genética , Feminino , Humanos , Laminina/genética , Mutação , Síndromes Miastênicas Congênitas , Síndrome Nefrótica/genética , Doenças Neuromusculares/genética , Doenças Neuromusculares/metabolismo , Doenças Neuromusculares/fisiopatologia , Distúrbios Pupilares/genética
6.
Matrix Biol ; 57-58: 86-105, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27614294

RESUMO

The synapse between motor neurons and skeletal muscle is known as the neuromuscular junction (NMJ). Proper alignment of presynaptic and post-synaptic structures of motor neurons and muscle fibers, respectively, is essential for efficient motor control of skeletal muscles. The synaptic cleft between these two cells is filled with basal lamina. Laminins are heterotrimer extracellular matrix molecules that are key members of the basal lamina. Laminin α4, α5, and ß2 chains specifically localize to NMJs, and these laminin isoforms play a critical role in maintenance of NMJs and organization of synaptic vesicle release sites known as active zones. These individual laminin chains exert their role in organizing NMJs by binding to their receptors including integrins, dystroglycan, and voltage-gated calcium channels (VGCCs). Disruption of these laminins or the laminin-receptor interaction occurs in neuromuscular diseases including Pierson syndrome and Lambert-Eaton myasthenic syndrome (LEMS). Interventions to maintain proper level of laminins and their receptor interactions may be insightful in treating neuromuscular diseases and aging related degeneration of NMJs.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades do Olho/genética , Síndrome Miastênica de Lambert-Eaton/genética , Laminina/genética , Síndrome Nefrótica/genética , Distúrbios Pupilares/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Animais , Membrana Basal/metabolismo , Membrana Basal/patologia , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Distroglicanas/genética , Distroglicanas/metabolismo , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Expressão Gênica , Humanos , Integrinas/genética , Integrinas/metabolismo , Síndrome Miastênica de Lambert-Eaton/metabolismo , Síndrome Miastênica de Lambert-Eaton/patologia , Laminina/metabolismo , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Síndromes Miastênicas Congênitas , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Ligação Proteica , Distúrbios Pupilares/metabolismo , Distúrbios Pupilares/patologia , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/patologia
8.
J Pathol ; 233(1): 18-26, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24293254

RESUMO

The study of mutations causing the steroid-resistant nephrotic syndrome in children has greatly advanced our understanding of the kidney filtration barrier. In particular, these genetic variants have illuminated the roles of the podocyte, glomerular basement membrane and endothelial cell in glomerular filtration. However, in a significant number of familial and early onset cases, an underlying mutation cannot be identified, indicating that there are likely to be multiple unknown genes with roles in glomerular permeability. We now show how the combination of N-ethyl-N-nitrosourea mutagenesis and next-generation sequencing could be used to identify the range of mutations affecting these pathways. Using this approach, we isolated a novel mouse strain with a viable nephrotic phenotype and used whole-genome sequencing to isolate a causative hypomorphic mutation in Lamb2. This discovery generated a model for one part of the spectrum of human Pierson's syndrome and provides a powerful proof of principle for accelerating gene discovery and improving our understanding of inherited forms of renal disease.


Assuntos
Anormalidades Múltiplas/genética , Análise Mutacional de DNA/métodos , Anormalidades do Olho/genética , Sequenciamento de Nucleotídeos em Larga Escala , Laminina/genética , Mutação , Síndrome Nefrótica/congênito , Distúrbios Pupilares/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Animais , Modelos Animais de Doenças , Etilnitrosoureia , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Estudos de Associação Genética , Predisposição Genética para Doença , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Síndromes Miastênicas Congênitas , Síndrome Nefrótica/genética , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Linhagem , Fenótipo , Proteinúria/genética , Proteinúria/metabolismo , Distúrbios Pupilares/metabolismo , Distúrbios Pupilares/patologia
9.
J Am Soc Nephrol ; 24(8): 1223-33, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23723427

RESUMO

Mutations in the laminin ß2 gene (LAMB2) cause Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects. LAMB2 is a component of the laminin-521 (α5ß2γ1) 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.


Assuntos
Anormalidades Múltiplas/genética , Estresse do Retículo Endoplasmático/genética , Anormalidades do Olho/genética , Membrana Basal Glomerular/metabolismo , Laminina/genética , Síndrome Nefrótica/genética , Podócitos/metabolismo , Distúrbios Pupilares/genética , Anormalidades Múltiplas/metabolismo , Animais , Anormalidades do Olho/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Mutação de Sentido Incorreto , Síndromes Miastênicas Congênitas , Síndrome Nefrótica/metabolismo , Distúrbios Pupilares/metabolismo , Ratos
10.
Pediatr Int ; 55(2): 229-31, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23679161

RESUMO

Pierson syndrome (OMIM 609049) is typically characterized by congenital nephritic syndrome and peculiar ocular anomalies with microcoria. It is caused by mutations in LAMB2, which encodes laminin ß2. Approximately 50 mutations of LAMB2 from approximately 40 unrelated families have been identified; however, most of them were from Western countries. Although three patients in Asia with mutations of LAMB2 have been reported, they were not typical cases. We report the first Japanese case of Pierson syndrome with proven causative LAMB2 mutations. She presented with congenital nephrotic syndrome and bilateral microcoria at birth, and developed end-stage renal disease at 2 months of age. This is the first report of a typical case from Asia. LAMB2 analysis by direct sequencing revealed the compound heterozygous mutations c.3974_3975insA (p.N1325KfsX1331, maternal, novel) in exon 25 and c.4519C>T (p.Q1507X, paternal) in exon 27. The phenotype due to LAMB2 mutations appears to be similar between different ethnic groups.


Assuntos
Anormalidades Múltiplas/genética , DNA/genética , Anormalidades do Olho/genética , Laminina/genética , Mutação , Síndrome Nefrótica/genética , Distúrbios Pupilares/genética , Anormalidades Múltiplas/metabolismo , Análise Mutacional de DNA , Anormalidades do Olho/metabolismo , Feminino , Humanos , Recém-Nascido , Japão , Laminina/metabolismo , Síndromes Miastênicas Congênitas , Síndrome Nefrótica/metabolismo , Fenótipo , Distúrbios Pupilares/metabolismo
11.
Ann N Y Acad Sci ; 1274: 24-32, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23252894

RESUMO

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 ß2 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 ß2 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.


Assuntos
Envelhecimento/metabolismo , Junção Neuromuscular/metabolismo , Anormalidades Múltiplas/imunologia , Anormalidades Múltiplas/metabolismo , Animais , Autoanticorpos/imunologia , Canais de Cálcio/imunologia , Canais de Cálcio/metabolismo , Anormalidades do Olho/imunologia , Anormalidades do Olho/metabolismo , Humanos , Síndrome Miastênica de Lambert-Eaton/imunologia , Síndrome Miastênica de Lambert-Eaton/metabolismo , Síndromes Miastênicas Congênitas , Síndrome Nefrótica/imunologia , Síndrome Nefrótica/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Terminações Pré-Sinápticas/metabolismo , Distúrbios Pupilares/imunologia , Distúrbios Pupilares/metabolismo
12.
Pediatr Nephrol ; 27(5): 865-8, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22228401

RESUMO

BACKGROUND: Pierson syndrome, caused by mutations in the LAMB2 gene, was originally described as a combination of microcoria and congenital nephrotic syndrome, rapidly progressing to end-stage renal failure. CASE-DIAGNOSIS/TREATMENT: We report a minor variant of Pierson syndrome in a teenage girl with severe myopia since early infancy and proteinuria first detected at age 6. At the age of 11 she was found to carry a unique homozygous non-truncating LAMB2 mutation in exon 2: c.T240G (p.S80R). Renal biopsy revealed mild diffuse mesangial sclerosis and residual expression of laminin ß2. Today at age 14, on treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, she continues to have nephrotic range proteinuria, but a normal glomerular filtration rate. CONCLUSIONS: LAMB2 mutations should be considered in all patients with glomerular proteinuria and abnormal ocular phenotype, irrespective of age and disease severity.


Assuntos
Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/fisiopatologia , Anormalidades do Olho/metabolismo , Anormalidades do Olho/fisiopatologia , Taxa de Filtração Glomerular/fisiologia , Proteinúria/etiologia , Proteinúria/fisiopatologia , Distúrbios Pupilares/metabolismo , Distúrbios Pupilares/fisiopatologia , Adolescente , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Biópsia , Feminino , Humanos , Rim/patologia , Laminina/genética , Losartan/uso terapêutico , Mutação/genética , Mutação/fisiologia , Mutação de Sentido Incorreto/genética , Mutação de Sentido Incorreto/fisiologia , Síndromes Miastênicas Congênitas , Miopia/etiologia , Síndrome Nefrótica/patologia , Fenótipo , Ramipril/uso terapêutico , Descolamento Retiniano/etiologia , Transtornos da Visão/etiologia
13.
Ophthalmology ; 118(6): 1137-44, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21236492

RESUMO

PURPOSE: To describe a novel laminin ß-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 ß-2 chain. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Assuntos
DNA/genética , Predisposição Genética para Doença , Laminina/genética , Mutação de Sentido Incorreto , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Cromossomos Humanos Par 3 , DNA/metabolismo , Análise Mutacional de DNA , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Feminino , Seguimentos , Humanos , Lactente , Laminina/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Miastênicas Congênitas , Síndrome Nefrótica , Linhagem , Fenótipo , Distúrbios Pupilares/genética , Distúrbios Pupilares/metabolismo , Estudos Retrospectivos , Adulto Jovem
14.
Proc Natl Acad Sci U S A ; 97(17): 9579-84, 2000 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-10944224

RESUMO

Muscarinic acetylcholine receptors consist of five distinct subtypes and have been important targets for drug development. In the periphery, muscarinic acetylcholine receptors mediate cholinergic signals to autonomic organs, but specific physiological functions of each subtype remain poorly elucidated. Here, we have constructed and analyzed mutant mice lacking the M(3) receptor and have demonstrated that this subtype plays key roles in salivary secretion, pupillary constriction, and bladder detrusor contractions. However, M(3)-mediated signals in digestive and reproductive organs are dispensable, likely because of redundant mechanisms through other muscarinic acetylcholine receptor subtypes or other mediators. In addition, we have found prominent urinary retention only in the male, which indicates a considerable sex difference in the micturition mechanism. Accordingly, this mutant mouse should provide a useful animal model for investigation of human diseases that are affected in the peripheral cholinergic functions.


Assuntos
Deleção de Genes , Distúrbios Pupilares/fisiopatologia , Receptores Muscarínicos/deficiência , Receptores Muscarínicos/metabolismo , Glândulas Salivares/fisiopatologia , Bexiga Urinária/fisiopatologia , Animais , Peso Corporal , Carbacol/farmacologia , Sistema Digestório/fisiopatologia , Anormalidades do Sistema Digestório , Feminino , Fertilidade/genética , Marcação de Genes , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/fisiopatologia , Heterozigoto , Homozigoto , Masculino , Camundongos , Camundongos Knockout , Contração Muscular , Músculo Liso/fisiopatologia , Fenótipo , Pilocarpina/farmacologia , Pupila/efeitos dos fármacos , Distúrbios Pupilares/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Muscarínico M1 , Receptor Muscarínico M3 , Receptores Muscarínicos/genética , Saliva/metabolismo , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/metabolismo , Caracteres Sexuais , Bexiga Urinária/anormalidades , Bexiga Urinária/metabolismo
15.
Acta Ophthalmol Scand ; 76(4): 413-6, 1998 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9716326

RESUMO

PURPOSE: The aqueous flare intensity and pupillary size were studied before and after instillation of 10% phenylephrine and 4% pilocarpine in eyes with diabetes mellitus (DM). METHODS: Twenty-three patients with DM type I were compared with 30 age-matched controls, and 25 patients with DM type II were compared with 30 age-matched controls. Patients with DM were divided into two groups: 1) with mild-moderate nonproliferative diabetic retinopathy (NPDR), and 2) with advanced diabetic retinopathy (DR) which includes moderate-severe, severe NPDR and proliferative DR. The aqueous flare intensity and the horizontal diameter of the pupil were measured before and 60 minutes after topical instillation of 10% phenylephrine and 60 min after topical administration of 4% pilocarpine. RESULTS: Degree of induced mydriasis after phenylephrine instillation was not significantly different between diabetic groups and controls. Significantly less pronounced miosis was observed after stimulation of cholinergic receptors by pilocarpine in eyes with mild-moderate NPDR with DM type II and in eyes with advanced DR with DM type I and type II when compared to controls (p<0.05). Phenylephrine decreased flare intensity in all groups without a significant difference between groups. Pilocarpine instillation increased flare intensity in all groups as compared to flare intensity before any treatment. Also, a significantly smaller increase in flare intensity in eyes with advanced retinopathy in both DM type I and type II was found when compared to controls (p<0.05). CONCLUSION: Pharmacological response to cholinergic stimulation on pupil size and flare intensity is weaker in advanced stages of DR.


Assuntos
Humor Aquoso/metabolismo , Diabetes Mellitus/metabolismo , Fenilefrina/administração & dosagem , Pilocarpina/administração & dosagem , Distúrbios Pupilares/metabolismo , Pupila/efeitos dos fármacos , Administração Tópica , Adulto , Idoso , Retinopatia Diabética/metabolismo , Proteínas do Olho/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Muscarínicos/administração & dosagem , Midriáticos/administração & dosagem , Soluções Oftálmicas
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