LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy

Isojima, Tsuyoshi; Harita, Yutaka; Furuyama, Masayuki; Sato, Noriko; Ishizuka, Kiyonobu; Horita, Shigeru; Kajiho, Yuko; Miura, Kenichiro; Igarashi, Takashi; Hattori, Motoshi; Kitanaka, Susumu

doi:10.1093/ndt/gft359

Cited by 41 publications

(56 citation statements)

References 23 publications

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“…This pathological entity is characterized by nephropathy without the typical nail and skeletal malformations as in common presentation of NPS. As the respective mutation still resulted in residual transcriptional activity, the authors suggested that LMX1B haploinsufficiency might be causative for the nephropathy-only phenotype in NPLRD patients [142]. In analogy to this study, the segregation of the same mutation within the LMX1B gene in pedigrees of patients with features of autosomal dominant focal segmental glomerulosclerosis has been described [143].…”

Section: Lmx1bsupporting

confidence: 53%

Glomerular development – Shaping the multi-cellular filtration unit

Schell

Wanner

Huber

2014

Seminars in Cell & Developmental Biology

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The glomerulus represents a highly structured filtration unit, composed of glomerular endothelial cells, mesangial cells, podocytes and parietal epithelial cells. During glomerulogenesis an intricate network of signaling pathways involving transcription factors, secreted factors and cell-cell communication is required to guarantee accurate evolvement of a functional, complex 3-dimensional glomerular architecture. Here, we want to provide an overview on the critical steps and relevant signaling cascades of glomerular development.

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Section: Lmx1bsupporting

confidence: 53%

Glomerular development – Shaping the multi-cellular filtration unit

Schell

Wanner

Huber

2014

Seminars in Cell & Developmental Biology

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“…Two groups have reported the detection of novel missense mutations affecting R246 in the homeodomain of LMX1B in patients with isolated renal disease. In one report a patient with nail-patella-like renal disease was found to have an R246Q mutation that has residual transcription activity [40]. In the other report patients with autosomal dominant focal and segmental glomerular sclerosis either with the same R246Q mutation or with a different mutation affecting the same amino acid, R246P, were described [41].…”

Section: Discussionmentioning

confidence: 99%

A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation

et al. 2014

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Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsufficient disorder. Studies in the mouse have shown that during development Lmx1b controls limb dorsal-ventral patterning and is also required for kidney and eye development, midbrain-hindbrain boundary establishment and the specification of specific neuronal subtypes. Mice completely deficient for Lmx1b die at birth. In contrast to the situation in humans, heterozygous null mice do not have a mutant phenotype. Here we report a novel mouse mutant Icst, an N-ethyl-N-nitrosourea-induced missense substitution, V265D, in the homeodomain of LMX1B that abolishes DNA binding and thereby the ability to transactivate other genes. Although the homozygous phenotypic consequences of Icst and the null allele of Lmx1b are the same, heterozygous Icst elicits a phenotype whilst the null allele does not. Heterozygous Icst causes glaucomatous eye defects and is semi-lethal, probably due to kidney failure. We show that the null phenotype is rescued more effectively by an Lmx1b transgene than is Icst. Co-immunoprecipitation experiments show that both wild-type and Icst LMX1B are found in complexes with LIM domain binding protein 1 (LDB1), resulting in lower levels of functional LMX1B in Icst heterozygotes than null heterozygotes. We conclude that Icst is a dominant-negative allele of Lmx1b. These findings indicate a reassessment of whether nail-patella syndrome is always haploinsufficient. Furthermore, Icst is a rare example of a model of human glaucoma caused by mutation of the same gene in humans and mice.

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“…NPS and glomerulopathy (AD) [69][70][71]144 Mutations associated with an isolated glomerulopathy are located in the homeodomain of LMX1B, possibly disrupting the interaction between LMX1B and (podocyte specific) DNA targets [69][70][71] …”

Section: Lmx1bmentioning

confidence: 99%

“…Finally, different inheritance patterns or mutation types in genes involved in syndromic kidney disease can cause an isolated kidney phenotype at the mild end of the phenotypic spectrum. Examples are mutations in LMX1B, which are associated with nail-patella syndrome (OMIM 161200) but can also cause an isolated glomerulopathy [69][70][71] , and mutations in OCRL1, which cause Lowe oculocerebrorenal syndrome (OMIM 309000), but also cause Dent disease 2 (OMIM 300555) 72 . Another example is provided by FRAS1 and FREM2, in which biallelic truncating mutations cause Fraser syndrome (OMIM 219000).…”

Section: Different Presentations Of the Same Phenotypementioning

confidence: 99%

The expanding phenotypic spectra of kidney diseases: insights from genetic studies

et al. 2016

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Next-generation sequencing (NGS) has led to the identification of previously unrecognized phenotypes associated with classic kidney disease genes. In addition to improving diagnostics for genetically heterogeneous diseases and enabling a faster rate of gene discovery, NGS has enabled an expansion and redefinition of nephrogenetic disease categories. Findings from these studies raise the question of whether disease diagnoses should be made on clinical grounds, on genetic evidence or a combination thereof. Here, we discuss the major kidney disease-associated genes and gene categories for which NGS has expanded the phenotypic spectrum. For example, COL4A3-5 genes, which are classically associated with Alport syndrome, are now understood to also be involved in the aetiology of focal segmental glomerulosclerosis. DGKE, which is associated with nephrotic syndrome, is also mutated in patients with atypical haemolytic uraemic syndrome. We examine how a shared genetic background between diverse clinical phenotypes can provide insight into the function of genes and novel links with essential pathophysiological mechanisms. In addition, we consider genetic and epigenetic factors that contribute to the observed phenotypic heterogeneity of kidney diseases and discuss the challenges in the interpretation of genetic data. Finally, we discuss the implications of the expanding phenotypic spectra associated with kidney disease genes for clinical practice, genetic counselling and personalized care, and present our recommendations for the use of NGS-based tests in routine nephrology practice.

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LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy

Cited by 41 publications

References 23 publications

Glomerular development – Shaping the multi-cellular filtration unit

Glomerular development – Shaping the multi-cellular filtration unit

A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation

The expanding phenotypic spectra of kidney diseases: insights from genetic studies

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