Deletion of a branch-point consensus sequence in the LMX1B gene causes exon skipping in a family with nail patella syndrome

Hamlington, Jeanette; Clough, Mark V.; Dunston, Jennifer A.; McIntosh, Iain

doi:10.1038/sj.ejhg.5200448

Cited by 14 publications

(9 citation statements)

References 16 publications

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“…4) (this article; [1,29,40,41,63,64,65,66]). Here, we present three new LMX1B mutations, including the mutation (V240D) identified in the female patient with rapid progression of kidney disease described above (Fig.…”

Section: Lmx1b Mutations In Nps and Their Putative Effectmentioning

confidence: 96%

Nail-patella syndrome. Overview on clinical and molecular findings

Bongers

Gubler

Knoers

2002

Pediatric Nephrology

157

133

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Nail-patella syndrome (NPS) is a rare autosomal dominant pleiotropic disorder characterized by dysplasia of the nails, patellar aplasia or hypoplasia, iliac horns, dysplasia of the elbows, and frequently glaucoma and progressive nephropathy. The recent identification of the causative gene for this syndrome has initiated further studies of the phenotype and molecular pathogenesis of kidney disease in NPS. The gene underlying NPS, LMX1B, is a LIM-homeodomain transcription factor involved in normal patterning of the dorsoventral axis of the limb during development and early morphogenesis of the glomerular basement membrane. Molecular studies of Lmx1b, combined with genetic and immunohistochemical investigation of different alpha chains of type IV collagen in the Lmx1b null mice kidney, a mouse model for NPS, have provided evidence that Lmx1b is involved in the pathogenesis of NPS glomerulopathy. At present evidence for a correlation between the presence and severity of the renal and extrarenal anomalies and LMX1B genotype is lacking. This review focuses on the recent advances in clinical and molecular genetic studies of NPS.

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Section: Lmx1b Mutations In Nps and Their Putative Effectmentioning

confidence: 96%

Nail-patella syndrome. Overview on clinical and molecular findings

Bongers

Gubler

Knoers

2002

Pediatric Nephrology

157

133

View full text Add to dashboard Cite

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“…In addition, a 17 bp intronic deletion was detected in one NPS family and balanced translocations, presumably disrupting LMX1B have been reported. 11,12 Linkage studies in NPS families did not reveal evidence for locus heterogeneity thus far. Molecular studies in Lmx1b null mice modelling the NPS phenotype have proven to be pivotal to our understanding of the role of Lmx1b in the normal and disrupted development of dorsal limb structures, the kidney, the eye, and the central nervous system, and particularly focussed on the pathogenesis underlying glomerulopathy in the past decade.…”

Section: Introductionmentioning

confidence: 99%

Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man

et al. 2008

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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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“…Likewise, the presence of two regions of reduced variation from À23 through À27 and À35 through À39 suggests the localization of functionally important sequences from nucleotide positions À23 through À32 and À35 through À44 (e.g., the branch site). Next, we examined 46 intron sequences with experimentally determined branch site locations (Ruskin et al 1984(Ruskin et al , 1985Zeitlin and Efstratiadis 1984;Padgett et al 1985;Reed and Maniatis 1985;Hornig et al 1986;Harmuth and Barta 1988;Kuivenhoven et al 1996;Query et al 1997;Gozani et al 1998;Hamlington et al 2000;Ast et al 2001;Khan et al 2004;Kralovicova et al 2004;Kol et al 2005;Vivenza et al 2006;Vuillaumier-Barrot et al 2006) and found that the average position of the branch site adenosine is at position À26, which is consistent with the region from À23 through À32 harboring branch site sequences.…”

Section: Splice Sitementioning

confidence: 60%

Human genetic variation recognizes functional elements in noncoding sequence

Lomelin¹,

Jorgenson²,

Risch³

2009

Genome Res.

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Noncoding DNA, particularly intronic DNA, harbors important functional elements that affect gene expression and RNA splicing. Yet, it is unclear which specific noncoding sites are essential for gene function and regulation. To identify functional elements in noncoding DNA, we characterized genetic variation within introns using ethnically diverse human polymorphism data from three public databases-PMT, NIEHS, and SeattleSNPs. We demonstrate that positions within introns corresponding to known functional elements involved in pre-mRNA splicing, including the branch site, splice sites, and polypyrimidine tract show reduced levels of genetic variation. Additionally, we observed regions of reduced genetic variation that are candidates for distance-dependent localization sites of functional elements, possibly intronic splicing enhancers (ISEs). Using several bioinformatics approaches, we provide additional evidence that supports our hypotheses that these regions correspond to ISEs. We conclude that studies of genetic variation can successfully discriminate and identify functional elements in noncoding regions. As more noncoding sequence data become available, the methods employed here can be utilized to identify additional functional elements in the human genome and provide possible explanations for phenotypic associations.

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Deletion of a branch-point consensus sequence in the LMX1B gene causes exon skipping in a family with nail patella syndrome

Cited by 14 publications

References 16 publications

Nail-patella syndrome. Overview on clinical and molecular findings

Nail-patella syndrome. Overview on clinical and molecular findings

Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man

Human genetic variation recognizes functional elements in noncoding sequence

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