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Iain Mcintosh - One of the best experts on this subject based on the ideXlab platform.
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increased symptoms of attention deficit hyperactivity disorder and major depressive disorder symptoms in Nail Patella Syndrome potential association with lmx1b loss of function
American Journal of Medical Genetics, 2011Co-Authors: Carmen Lopezarvizu, Iain Mcintosh, Elizabeth P Sparrow, Michael J Strube, Chris Slavin, Caroline Deoleo, Justin James, Julie Hooverfong, Elaine TierneyAbstract:Nail-Patella Syndrome (NPS) is an autosomal dominant disorder that is the result of heterozygous loss-of-function mutations in LMX1B, coding for a LIM homeobox (LIM-HD) transcription factor. Analyses of lmx1b mutant mice have revealed the role of Lmx1b in the development of mesencephalic dopaminergic neurons and the serotonergic system; these areas have been linked with symptoms of attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD). Fifty adults (38 females, 12 males) with NPS completed the Conners' Adult ADHD Rating Scales-Self-report: Long Version (CAARS) and Beck Depression Inventory-II (BDI-II). The objective was to describe the neurobehavioral phenotype of these subjects and examine possible relationships between neurobehavioral symptoms and NPS. Elevated levels of DSM-IV-TR ADHD Inattentive symptoms were reported on the CAARS by 22% of the NPS sample. The BDI-II Total score was elevated for 40% of the NPS sample. There was a significant increase in the odds of an elevated BDI-II Total score when any of the three CAARS scales were elevated (odds ratios ranging from 11.455 to 15.615). The CAARS and BDI-II did not significantly differ with gender, age, or education level. There was no significant association between genetic mutation-predicted protein status and elevations on CAARS or BDI-II. Individuals with NPS reported co-occurring symptoms of ADHD and MDD, with higher levels of co-occurrence than reported in the literature for the general population. The co-occurrence of these symptoms may be related to mesencephalic dopaminergic neurologic pathway abnormalities that are a consequence of LMX1B loss of function.
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phenotype severity and genetic variation at the disease locus an investigation of Nail dysplasia in the Nail Patella Syndrome
Annals of Human Genetics, 2005Co-Authors: J A Dunston, S Lin, Ji Wan Park, M Malbroux, Iain McintoshAbstract:Summary The genetic bases underlying the range and severity of phenotypes in Mendelian disorders is poorly understood; however, improvements in this area have the potential to facilitate analysis of oligogenic disorders. The Nail dysplasia observed in Nail Patella Syndrome (NPS) was selected as a quantifiable variable within a Mendelian disorder, for which data could be readily obtained, to allow investigation of the genetic basis of variation. Analysis of SNP haplotypes across the LMX1B gene demonstrated association between the haplotype of the mutant allele and the variability in the Nail score (p = 0.024). These results are in contrast to those obtained previously, which supported a modifying role for the wild-type allele. Since there is no evidence that particular mutations, or classes of mutation, are associated with the variation (p > 0.5), further work is required to identify the elements associated with the LMX1B gene that mediate phenotypic severity.
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Nail Patella Syndrome a review of the phenotype aided by developmental biology
Journal of Medical Genetics, 2003Co-Authors: Elizabeth Sweeney, Alan Fryer, R Mountford, A Green, Iain McintoshAbstract:Nail Patella Syndrome (NPS) is an autosomal dominant condition affecting the Nails, skeletal system, kidneys, and eyes. Skeletal features include absent or hypoplastic Patellae, Patella dislocations, elbow abnormalities, talipes, and iliac horns on x ray. Kidney involvement may lead to renal failure and there is also a risk of glaucoma. There is marked inter- and intrafamilial variability. The results of a British study involving 123 NPS patients are compared with previously published studies and it is suggested that neurological and vasomotor symptoms are also part of the NPS phenotype. In addition, the first data on the incidence of glaucoma and gastrointestinal (GI) symptoms in NPS are presented. NPS is caused by loss of function mutations in the transcription factor LMX1B at 9q34. The expansion of the clinical phenotype is supported by the role of LMX1B during development.
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twenty two novel lmx1b mutations identified in Nail Patella Syndrome nps patients
Human Mutation, 2001Co-Authors: Jeanette D Hamlington, Cheron Jones, Iain McintoshAbstract:We report twenty-two novel mutations in the gene encoding the transcription factor LMX1B, previously shown to be mutated in persons with Nail Patella Syndrome (NPS). The mutations comprised eight missense, one splice-site, three insertion/deletion and ten nonsense or frameshift mutations. A sub-set of five recurrent mutations within the homeodomain represents over one-quarter of the described NPS mutations. The type and distribution of the mutations is consistent with the hypothesis that NPS is the result of haploinsufficiency for LMX1B. © Wiley-Liss, Inc.
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restricted distribution of loss of function mutations within the lmx1b genes of Nail Patella Syndrome patients
Human Mutation, 1999Co-Authors: Mark V Clough, Iain Mcintosh, Jeanette D HamlingtonAbstract:Nail-Patella Syndrome (NPS) is a pleiotropic condition characterized by dysplasia of the Nails, hypoplasia of the Patellae, elbow dysplasia, and progressive kidney disease. The Syndrome is inherited in an autosomal dominant manner and has been shown to result from mutations in the LIM-homeodomain encoding LMX1B gene. The LMX1B transcription factor plays a role in defining the development of dorsal-specific structures during limb development. To date, a total of 64 point mutations and small deletions or insertions have been reported, concentrated within either the LIM or homeodomains. No NPS mutations have been observed within the carboxy-terminal third of the coding sequence, suggesting that mutations in this region are not inactivating. These findings support the hypothesis that NPS results from a 50% reduction in LMX1B function via a reduction in synthesis, disruption of secondary structure, or failure to bind DNA.
Ernie M.h.f. Bongers - One of the best experts on this subject based on the ideXlab platform.
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J Am Soc Nephrol 11: 1762–1766, 2000 Nail-Patella Syndrome: Identification of Mutations in the LMX1B Gene
2013Co-Authors: In Dutch Families, Ernie M.h.f. Bongers, Nine V A M Knoers, S E C Van Beersum, J. P. Lommen, Hans Van Bokhoven, Frans A. HolAbstract:Abstract. Nail-Patella Syndrome is an autosomal dominant disorder characterized by dyplasia of finger Nails, skeletal anomalies, and, frequently, renal disease. It has recently been shown that this disorder is caused by putative loss-of-function mutations in a transcription factor (LMX1B) belonging to the LIMhomeodomain family, members of which are known to be important for pattern formation during development. A cohort of eight Dutch NPS families were screened for mutations in the LMX1B gene; seven different mutations, including one novel variant, were identified. Three of the mutations are very likely to result in truncated LMX1B proteins, three are predicted to influence sequence-specific DNA binding, and one is presumed to prevent the formation of a stable protein by abolishing the Zn(II) binding site of the protein. Although there was a remarkable high incidence of renal disease in one of the families
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Identification of entire LMX1B gene deletions in Nail Patella Syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man.
European journal of human genetics : EJHG, 2008Co-Authors: Ernie M.h.f. Bongers, Ilse J. De Wijs, Carlo Marcelis, Lies H. Hoefsloot, Nine V A M KnoersAbstract:Heterozygous mutations in the LMX1B gene cause Nail Patella Syndrome (NPS) that is associated with Nail and skeletal malformations, nephropathy, and glaucoma. Previous phenotype studies of Lmx1b null mice revealed dorsal limb and renal anomalies similar to human NPS, which contributed to the identification of heterozygous mutations in this LIM-homeodomain protein LMX1B as the genetic defect responsible for NPS. Despite advanced insight into the role of the Lmx1b transcription factor in a broad range of animal developmental programs, the pathogenic mechanism underlying dominant inheritance of NPS in man remained unclear. Here, we describe for the first time the detection of two entire LMX1B gene deletions and one smaller exonic LMX1B deletion by multiplex ligation-dependent probe amplification (MLPA) in a series of eight unrelated families with classical features of NPS in whom no pathogenic LMX1B mutation was found by sequence analysis. The identification of entire LMX1B deletions strongly confirms that haploinsufficiency is the principal pathogenetic mechanism of NPS and suggests a difference in dosage sensitivity for this gene between mice and man.
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Genotype-phenotype studies in Nail-Patella Syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy.
European journal of human genetics : EJHG, 2005Co-Authors: Ernie M.h.f. Bongers, F.t.m. Huysmans, Elena Levtchenko, Jacky W. J. De Rooy, Johan G. Blickman, Ronald J.c. Admiraal, Patrick L. M. Huygen, Johannes R.m. Cruysberg, Pauline A M P Toolens, Judith B. PrinsAbstract:Nail-Patella Syndrome (NPS) is characterized by developmental defects of dorsal limb structures, nephropathy, and glaucoma and is caused by heterozygous mutations in the LIM homeodomain transcription factor LMX1B. In order to identify possible genotype-phenotype correlations, we performed LMX1B mutation analysis and comprehensive investigations of limb, renal, ocular, and audiological characteristics in 106 subjects from 32 NPS families. Remarkable phenotypic variability at the individual, intrafamilial, and interfamilial level was observed for different NPS manifestations. Quantitative urinanalysis revealed proteinuria in 21.3% of individuals. Microalbuminuria was detected in 21.7% of subjects without overt proteinuria. Interestingly, nephropathy appeared significantly more frequent in females. A significant association was established between the presence of clinically relevant renal involvement in an NPS patient and a positive family history of nephropathy. We identified normal-tension glaucoma (NTG) and sensorineural hearing impairment as new symptoms associated with NPS. Sequencing of LMX1B revealed 18 different mutations, including six novel variants, in 28 families. Individuals with an LMX1B mutation located in the homeodomain showed significantly more frequent and higher values of proteinuria compared to subjects carrying mutations in the LIM domains. No clear genotype-phenotype association was apparent for extrarenal manifestations. This is the first study indicating that family history of nephropathy and mutation location might be important in precipitating individual risks for developing NPS renal disease. We suggest that the NPS phenotype is broader than previously described and that NTG and hearing impairment are part of NPS. Further studies on modifier factors are needed to understand the mechanisms underlying phenotypic heterogeneity.
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confirmation of clim2 lmx1b interaction by yeast two hybrid screening and analysis of its involvement in Nail Patella Syndrome
International Journal of Molecular Medicine, 2003Co-Authors: Monica Marini, Ernie M.h.f. Bongers, Nine V A M Knoers, Marco Seri, Roberto Cusano, Marco Di Duca, Roberto RavazzoloAbstract:Nail-Patella Syndrome (NPS), an autosomal dominant disorder characterized by Nail dysplasia, absent or hypoplastic Patellae, iliac horns, and often associated with nephropathy and, less frequently, with open angle glaucoma, is caused by mutations in the LMX1B gene. Inter-familial and intra-familial phenotypic variability raises the question whether modifier genes can be identified to explain differences in the expression and severity of clinical features of NPS. Genes encoding proteins that interact with the LMX1B protein are good candidates and, therefore, methods to search for interactions can be used to this purpose. By the yeast two-hybrid screening we detected the CLIM2 gene as a LMX1B interactor, confirming previous reports which described the same interaction by biochemical methods. Sequencing of the CLIM2 coding region in seven NPS cases in which no LMX1B mutation had been found, did not detect any molecular variant in these patients. Moreover, by genotyping a polymorphic dinucleotide repeat close to the CLIM2 gene in affected members of a large Dutch NPS family with high incidence of nephropathy, we were unable to find a correlation between the presence of a specific allele and the expression of nephropathy. In conclusion, although the results of this study could not provide any proof of CLIM2 involvement in the pathogenesis of NPS or in determination of the clinical phenotype, we suggest that the CLIM2 gene can be considered as a good candidate for further studies on normal and disturbed kidney development associated with NPS or other hereditary glomerulopathies.
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in vivo expression of putative lmx1b targets in Nail Patella Syndrome kidneys
American Journal of Pathology, 2003Co-Authors: Laurence Heidet, Ernie M.h.f. Bongers, Mireille Sich, Shaoyu Zhang, Chantal Loirat, Alain Meyrier, M Broyer, Gerard Landthaler, Bernadette Faller, Yoshikazu SadoAbstract:The Nail-Patella Syndrome (NPS) is characterized by Nail and bone abnormalities, associated with glomerular involvement in ∼40% of patients. Typical glomerular changes consist of fibrillar material in the irregularly thickened glomerular basement membrane. NPS is inherited as an autosomal dominant trait and caused by heterozygous loss of function mutations in LMX1B, a member of the LIM homeodomain protein family. Mice with homozygous inactivation of the gene exhibit Nail and skeletal defects, similar to those observed in patients, associated with glomerular abnormalities. Strong reduction in the glomerular expression of the α3 and α4 chains of type IV collagen, and of podocin and CD2AP, two podocyte proteins critical for glomerular function, has been observed in Lmx1b null mice. The expression of these proteins appeared to be regulated by Lmx1b. To determine whether these changes in podocyte gene expression are involved in the development of NPS nephropathy, using immunohistological techniques, we analyzed the podocyte phenotype and the renal distribution of type IV collagen chains in the kidneys of seven NPS patients with severe glomerular disease. We also examined the nature of the fibrillar material present within the glomerular extracellular matrix. The glomerular basement membrane fibrillar material was specifically labeled with anti-type III collagen antibodies, suggesting a possible regulation of type III collagen expression by LMX1B. The expression of the α3 and α4 chains of type IV collagen, and of podocin and CD2AP, was found to be normal in the seven patients. These findings indicate that heterozygous mutations of LMX1B do not appear to dramatically affect the expression of type IV collagen chains, podocin, or CD2AP in NPS patients.
Sandra D Dreyer - One of the best experts on this subject based on the ideXlab platform.
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regulation of glomerular basement membrane collagen expression by lmx1b contributes to renal disease in Nail Patella Syndrome
Nature Genetics, 2001Co-Authors: Roy Morello, Yoshifumi Ninomiya, Guang Zhou, Sandra D Dreyer, Scott J Harvey, Paul S Thorner, Jeffrey H Miner, William W Cole, Andreas WinterpachtAbstract:Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV) collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport Syndrome, cell differentiation in hereditary leiomyomatosis, and autoimmunity in Goodpasture Syndrome; however, the transcriptional and developmental regulation of type IV collagen expression is unknown. Nail Patella Syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain transcription factor. Some patients have nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha(3)IV and alpha(4)IV collagen is strongly diminished in GBM, whereas that of alpha1, alpha2 and alpha5(IV) collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of alpha 3(IV) and alpha 4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.
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lmx1b transactivation and expression in Nail Patella Syndrome
Human Molecular Genetics, 2000Co-Authors: Sandra D Dreyer, Roy Morello, Andreas Winterpacht, Kerby C. Oberg, Bernhard Zabel, Michael S. German, Gregory P. Lunstrum, William A. Horton, Brendan LeeAbstract:Lmx1b, a member of the LIM homeodomain protein family, is essential for the specification of dorsal limb fates at the zeugopodal and autopodal level in vertebrates. We and others have shown that a skeletal dysplasia, Nail-Patella Syndrome (NPS), results from mutations in LMX1B. While it is a unique mesenchymal determinant of dorsal limb patterning during vertebrate development, the mechanism by which LMX1B mutations generate the NPS phenotype has not been addressed at a transcriptional level or correlated with its spatial pattern of gene expression. In this study, in situ hybridizations of Lmx1b on murine limb sections reveal strong expression in dorsal mesenchymal tissues (precursors of muscle, tendons, joints and Patella) and, interestingly, also in anterior structures of the limb, explaining the anterior to posterior gradient of joint and Nail dysplasia observed in NPS patients. Transfection studies showed that both the LIM domain-interacting protein, LDB1, and the helix-loop-helix protein, E47/shPan1, can regulate LMX1B action. While co--transfections of E47/shPan1 with LMX1B result in a synergistic effect on reporter activity, LDB1 down-regulated LMX1B-mediated transactivation irrespective of E47/shPan1. Mutant LMX1B proteins containing human mutations affecting each of the helices or the N-terminal arm of the homeodomain abolished transactivation, while LIM B and truncation mutations retained residual activity. These mutations fail to act in a dominant-negative manner on wild-type LMX1B in mixing studies, thereby supporting haploinsufficiency as the mechanism underlying NPS pathogenesis.
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mutation in lmx1b causes skeletal and renal dysplasia in mice and Nail Patella Syndrome in humans 710
Pediatric Research, 1998Co-Authors: Sandra D Dreyer, Randy L. Johnson, Guang Zhou, William W Cole, Andreas Winterpacht, Kerby C. Oberg, Antonio Baldini, Haixu Chen, Benhard Zabel, Brendan LeeAbstract:Mutation in lmx1b Causes Skeletal and Renal Dysplasia in Mice and Nail Patella Syndrome in Humans • 710
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Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in Nail Patella Syndrome
Nature genetics, 1998Co-Authors: Sandra D Dreyer, Randy L. Johnson, Guang Zhou, William W Cole, Andreas Winterpacht, Bernhard Zabel, Antonio Baldini, Brendan LeeAbstract:The LIM-homeodomain protein Lmx1b plays a central role in dorso-ventral patterning of the vertebrate limb. Targeted disruption of Lmx1b results in skeletal defects including hypoplastic Nails, absent Patellae and a unique form of renal dysplasia (see accompanying manuscript by H. Chen et al.; ref. 2). These features are reminiscent of the dominantly inherited skeletal malformation Nail Patella Syndrome (NPS). We show that LMX1B maps to the NPS locus and that three independent NPS patients carry de novo heterozygous mutations in this gene. Functional studies show that one of these mutations disrupts sequence-specific DNA binding, while the other two mutations result in premature termination of translation. These data demonstrate a unique role for LMX1B in renal development and in patterning of the skeletal system, and suggest that alteration of Lmx1b/LMX1B function in mice and humans results in similar phenotypes. Furthermore, we provide evidence for the first described mutations in a LIM-homeodomain protein which account for an inherited form of abnormal skeletal patterning and renal failure.
Nine V A M Knoers - One of the best experts on this subject based on the ideXlab platform.
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J Am Soc Nephrol 11: 1762–1766, 2000 Nail-Patella Syndrome: Identification of Mutations in the LMX1B Gene
2013Co-Authors: In Dutch Families, Ernie M.h.f. Bongers, Nine V A M Knoers, S E C Van Beersum, J. P. Lommen, Hans Van Bokhoven, Frans A. HolAbstract:Abstract. Nail-Patella Syndrome is an autosomal dominant disorder characterized by dyplasia of finger Nails, skeletal anomalies, and, frequently, renal disease. It has recently been shown that this disorder is caused by putative loss-of-function mutations in a transcription factor (LMX1B) belonging to the LIMhomeodomain family, members of which are known to be important for pattern formation during development. A cohort of eight Dutch NPS families were screened for mutations in the LMX1B gene; seven different mutations, including one novel variant, were identified. Three of the mutations are very likely to result in truncated LMX1B proteins, three are predicted to influence sequence-specific DNA binding, and one is presumed to prevent the formation of a stable protein by abolishing the Zn(II) binding site of the protein. Although there was a remarkable high incidence of renal disease in one of the families
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Identification of entire LMX1B gene deletions in Nail Patella Syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man.
European journal of human genetics : EJHG, 2008Co-Authors: Ernie M.h.f. Bongers, Ilse J. De Wijs, Carlo Marcelis, Lies H. Hoefsloot, Nine V A M KnoersAbstract:Heterozygous mutations in the LMX1B gene cause Nail Patella Syndrome (NPS) that is associated with Nail and skeletal malformations, nephropathy, and glaucoma. Previous phenotype studies of Lmx1b null mice revealed dorsal limb and renal anomalies similar to human NPS, which contributed to the identification of heterozygous mutations in this LIM-homeodomain protein LMX1B as the genetic defect responsible for NPS. Despite advanced insight into the role of the Lmx1b transcription factor in a broad range of animal developmental programs, the pathogenic mechanism underlying dominant inheritance of NPS in man remained unclear. Here, we describe for the first time the detection of two entire LMX1B gene deletions and one smaller exonic LMX1B deletion by multiplex ligation-dependent probe amplification (MLPA) in a series of eight unrelated families with classical features of NPS in whom no pathogenic LMX1B mutation was found by sequence analysis. The identification of entire LMX1B deletions strongly confirms that haploinsufficiency is the principal pathogenetic mechanism of NPS and suggests a difference in dosage sensitivity for this gene between mice and man.
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confirmation of clim2 lmx1b interaction by yeast two hybrid screening and analysis of its involvement in Nail Patella Syndrome
International Journal of Molecular Medicine, 2003Co-Authors: Monica Marini, Ernie M.h.f. Bongers, Nine V A M Knoers, Marco Seri, Roberto Cusano, Marco Di Duca, Roberto RavazzoloAbstract:Nail-Patella Syndrome (NPS), an autosomal dominant disorder characterized by Nail dysplasia, absent or hypoplastic Patellae, iliac horns, and often associated with nephropathy and, less frequently, with open angle glaucoma, is caused by mutations in the LMX1B gene. Inter-familial and intra-familial phenotypic variability raises the question whether modifier genes can be identified to explain differences in the expression and severity of clinical features of NPS. Genes encoding proteins that interact with the LMX1B protein are good candidates and, therefore, methods to search for interactions can be used to this purpose. By the yeast two-hybrid screening we detected the CLIM2 gene as a LMX1B interactor, confirming previous reports which described the same interaction by biochemical methods. Sequencing of the CLIM2 coding region in seven NPS cases in which no LMX1B mutation had been found, did not detect any molecular variant in these patients. Moreover, by genotyping a polymorphic dinucleotide repeat close to the CLIM2 gene in affected members of a large Dutch NPS family with high incidence of nephropathy, we were unable to find a correlation between the presence of a specific allele and the expression of nephropathy. In conclusion, although the results of this study could not provide any proof of CLIM2 involvement in the pathogenesis of NPS or in determination of the clinical phenotype, we suggest that the CLIM2 gene can be considered as a good candidate for further studies on normal and disturbed kidney development associated with NPS or other hereditary glomerulopathies.
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the small Patella Syndrome description of five cases from three families and examination of possible allelism with familial Patella aplasia hypoplasia and Nail Patella Syndrome
Journal of Medical Genetics, 2001Co-Authors: Ernie M.h.f. Bongers, Nine V A M Knoers, H Van Bokhoven, M N Van Thienen, M A Kooyman, S E C Van Beersum, C Boetes, B C J HamelAbstract:Editor—The small Patella Syndrome (SPS, *MIM 14789), also known as ischioPatellar dysplasia, coxopodo Patellar Syndrome, or Scott-Taor Syndrome, is a rare autosomal dominant disorder, characterised by a/hypoplasia of the Patellae and various anomalies of the pelvis and feet. This Syndrome was first described by Scott and Taor1 in 1979 in a large family with bilateral small or absent Patellae accompanied by anomalies of the pelvic girdle and upper femora in most of the affected subjects. To our knowledge, 42 patients have been reported with this disorder,1-9comprising 35 cases from five families and seven sporadic cases. This bone dysplasia is characterised by Patellar a/hypoplasia and pelvic anomalies, including bilateral absent or delayed ossification of the ischiopubic junction and infra-acetabular axe cut notches. Other major signs are a wide gap between the first and second toes, short fourth and fifth rays of the feet, and pes planus. Various other skeletal anomalies have been reported, such as elongated femoral necks, flattened and widened proximal femoral epiphyses, hypoplasia of the lesser trochanter, and tarsal anomalies. SPS should be clinically differentiated from disorders with a/hypoplastic Patellae, in particular the autosomal dominant disorders isolated familial Patella aplasia-hypoplasia (PTLAH) Syndrome10 and the more severe Nail-Patella Syndrome (NPS).11 The latter is caused by mutations of the LMX1B gene on chromosome 9q34. Recently, a locus for PTLAH has been identified on chromosome 17q21-22. As yet, it is unknown whether SPS and PTLAH are allelic disorders. Here we report on five cases from three families with SPS, compare their clinical and radiological anomalies with those of previously reported cases, and propose minimal diagnostic criteria for SPS. Given the clinical overlap between SPS, PTLAH, and NPS, we have studied the possible involvement of candidate regions for these Syndromes on chromosome 17q21-22 and 9q34, respectively, …
Andreas Winterpacht - One of the best experts on this subject based on the ideXlab platform.
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regulation of glomerular basement membrane collagen expression by lmx1b contributes to renal disease in Nail Patella Syndrome
Nature Genetics, 2001Co-Authors: Roy Morello, Yoshifumi Ninomiya, Guang Zhou, Sandra D Dreyer, Scott J Harvey, Paul S Thorner, Jeffrey H Miner, William W Cole, Andreas WinterpachtAbstract:Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV) collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport Syndrome, cell differentiation in hereditary leiomyomatosis, and autoimmunity in Goodpasture Syndrome; however, the transcriptional and developmental regulation of type IV collagen expression is unknown. Nail Patella Syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain transcription factor. Some patients have nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha(3)IV and alpha(4)IV collagen is strongly diminished in GBM, whereas that of alpha1, alpha2 and alpha5(IV) collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of alpha 3(IV) and alpha 4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.
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lmx1b transactivation and expression in Nail Patella Syndrome
Human Molecular Genetics, 2000Co-Authors: Sandra D Dreyer, Roy Morello, Andreas Winterpacht, Kerby C. Oberg, Bernhard Zabel, Michael S. German, Gregory P. Lunstrum, William A. Horton, Brendan LeeAbstract:Lmx1b, a member of the LIM homeodomain protein family, is essential for the specification of dorsal limb fates at the zeugopodal and autopodal level in vertebrates. We and others have shown that a skeletal dysplasia, Nail-Patella Syndrome (NPS), results from mutations in LMX1B. While it is a unique mesenchymal determinant of dorsal limb patterning during vertebrate development, the mechanism by which LMX1B mutations generate the NPS phenotype has not been addressed at a transcriptional level or correlated with its spatial pattern of gene expression. In this study, in situ hybridizations of Lmx1b on murine limb sections reveal strong expression in dorsal mesenchymal tissues (precursors of muscle, tendons, joints and Patella) and, interestingly, also in anterior structures of the limb, explaining the anterior to posterior gradient of joint and Nail dysplasia observed in NPS patients. Transfection studies showed that both the LIM domain-interacting protein, LDB1, and the helix-loop-helix protein, E47/shPan1, can regulate LMX1B action. While co--transfections of E47/shPan1 with LMX1B result in a synergistic effect on reporter activity, LDB1 down-regulated LMX1B-mediated transactivation irrespective of E47/shPan1. Mutant LMX1B proteins containing human mutations affecting each of the helices or the N-terminal arm of the homeodomain abolished transactivation, while LIM B and truncation mutations retained residual activity. These mutations fail to act in a dominant-negative manner on wild-type LMX1B in mixing studies, thereby supporting haploinsufficiency as the mechanism underlying NPS pathogenesis.
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mutation in lmx1b causes skeletal and renal dysplasia in mice and Nail Patella Syndrome in humans 710
Pediatric Research, 1998Co-Authors: Sandra D Dreyer, Randy L. Johnson, Guang Zhou, William W Cole, Andreas Winterpacht, Kerby C. Oberg, Antonio Baldini, Haixu Chen, Benhard Zabel, Brendan LeeAbstract:Mutation in lmx1b Causes Skeletal and Renal Dysplasia in Mice and Nail Patella Syndrome in Humans • 710
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Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in Nail Patella Syndrome
Nature genetics, 1998Co-Authors: Sandra D Dreyer, Randy L. Johnson, Guang Zhou, William W Cole, Andreas Winterpacht, Bernhard Zabel, Antonio Baldini, Brendan LeeAbstract:The LIM-homeodomain protein Lmx1b plays a central role in dorso-ventral patterning of the vertebrate limb. Targeted disruption of Lmx1b results in skeletal defects including hypoplastic Nails, absent Patellae and a unique form of renal dysplasia (see accompanying manuscript by H. Chen et al.; ref. 2). These features are reminiscent of the dominantly inherited skeletal malformation Nail Patella Syndrome (NPS). We show that LMX1B maps to the NPS locus and that three independent NPS patients carry de novo heterozygous mutations in this gene. Functional studies show that one of these mutations disrupts sequence-specific DNA binding, while the other two mutations result in premature termination of translation. These data demonstrate a unique role for LMX1B in renal development and in patterning of the skeletal system, and suggest that alteration of Lmx1b/LMX1B function in mice and humans results in similar phenotypes. Furthermore, we provide evidence for the first described mutations in a LIM-homeodomain protein which account for an inherited form of abnormal skeletal patterning and renal failure.
