The human LMX1B gene: transcription unit, promoter, and pathogenic mutations

Dunston, Jennifer A.; Hamlington, Jeanette; Zaveri, Jayshree; Sweeney, Elizabeth; Sibbring, Julie; Tran, Catherine; Malbroux, M.; O’Neill, John P.; Mountford, Roger; McIntosh, Iain

doi:10.1016/j.ygeno.2004.06.002

Cited by 49 publications

(66 citation statements)

References 41 publications

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“…1 -9 These pathogenic LMX1B mutations are concentrated in the LIM domains encoded by exons 2 -3 that facilitate the interaction with other transcription factors and in the homeodomain encoded by exons 4 -6, which is involved in DNA binding. Dunston et al (2004) identified the first mutations in exon 1, upstream of the LIM domains and in exon 6, downstream of the homeodomain. 10 As yet, no mutations have been described in exons 7 and 8 encoding the transcriptional activation domain at the carboxy terminus suggesting that mutations in the latter domain not cause the NPS phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…Dunston et al (2004) identified the first mutations in exon 1, upstream of the LIM domains and in exon 6, downstream of the homeodomain. 10 As yet, no mutations have been described in exons 7 and 8 encoding the transcriptional activation domain at the carboxy terminus suggesting that mutations in the latter domain not cause the NPS phenotype. In addition, a 17 bp intronic deletion was detected in one NPS family and balanced translocations, presumably disrupting LMX1B have been reported.…”

Section: Introductionmentioning

confidence: 99%

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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

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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Section: Introductionmentioning

confidence: 99%

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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“…Subsequent work has identified approximately 120 distinct loss-of-function mutations. 8 LMX1B is a member of the LIM-homeodomain family of transcription factors that play a variety of roles during development to determine body pattern in vertebrates and invertebrates. 9,10 Both the expression of Lmx1b during development and the spectrum of abnormalities observed in the lmx1b À/À mouse correlate with the NPS phenotype in terms of the ocular, kidney and limb abnormalities.…”

Section: Introductionmentioning

confidence: 99%

A neurological phenotype in nail patella syndrome (NPS) patients illuminated by studies of murine Lmx1b expression

Dunston

Reimschisel²,

Ding³

et al. 2004

Eur J Hum Genet

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Nail patella syndrome (NPS) is an autosomal dominant disorder affecting development of the limb, kidney and eye. NPS is the result of heterozygous loss-of-function mutations in the LIM-homeodomain transcription factor, LMX1B. Recent studies suggest that the NPS phenotype may be more extensive than recognized previously including neurologic and neurobehavioral aspects. To determine whether these findings correlated with the expression of Lmx1b during development, an internal ribosomal entry siteLacZ reporter was inserted into the 3 0 UTR of the endogenous murine gene. The pattern of Lmx1b expression during the development of the limb, eye and kidney correlates with the NPS phenotype. Additional sites of expression were observed in the central nervous system (CNS). The effects of the absence of Lmx1b in the CNS were determined in lmx1b À/À mice by histology and immunocytochemistry. Lmx1b is required for the differentiation and migration of neurons within the dorsal spinal cord. The inability of afferent sensory neurons to migrate into the dorsal horn is entirely consistent with diminished pain responses in NPS patients.

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“…2 In 1998, the first mutations in LMX1B, a gene encoding a LIM homeodomain transcription factor, were reported to be responsible for nail-patella syndrome. [3][4][5] With few exceptions, 6 the more than 100 mutations described so far affect the protein binding LIM domains and the DNA binding homeodomain. 6,7 The clinical manifestation shows a high variability in severity and penetrance, 2 which may be caused by the nature of the mutation or the presence of modifier genes.…”

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confidence: 99%

LMX1B is Essential for the Maintenance of Differentiated Podocytes in Adult Kidneys

Burghardt

Kastner

Suleiman

et al. 2013

Journal of the American Society of Nephrology

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Mutations of the LMX1B gene cause nail-patella syndrome, a rare autosomal-dominant disorder affecting the development of the limbs, eyes, brain, and kidneys. The characterization of conventional Lmx1b knockout mice has shown that LMX1B regulates the development of podocyte foot processes and slit diaphragms, but studies using podocyte-specific Lmx1b knockout mice have yielded conflicting results regarding the importance of LMX1B for maintaining podocyte structures. In order to address this question, we generated inducible podocyte-specific Lmx1b knockout mice. One week of Lmx1b inactivation in adult mice resulted in proteinuria with only minimal foot process effacement. Notably, expression levels of slit diaphragm and basement membrane proteins remained stable at this time point, and basement membrane charge properties also did not change, suggesting that alternative mechanisms mediate the development of proteinuria in these mice. Cell biological and biophysical experiments with primary podocytes isolated after 1 week of Lmx1b inactivation indicated dysregulation of actin cytoskeleton organization, and time-resolved DNA microarray analysis identified the genes encoding actin cytoskeleton-associated proteins, including Abra and Arl4c, as putative LMX1B targets. Chromatin immunoprecipitation experiments in conditionally immortalized human podocytes and gel shift assays showed that LMX1B recognizes AT-rich binding sites (FLAT elements) in the promoter regions of ABRA and ARL4C, and knockdown experiments in zebrafish support a model in which LMX1B and ABRA act in a common pathway during pronephros development. Our report establishes the importance of LMX1B in fully differentiated podocytes and argues that LMX1B is essential for the maintenance of an appropriately structured actin cytoskeleton in podocytes.

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The human LMX1B gene: transcription unit, promoter, and pathogenic mutations

Cited by 49 publications

References 41 publications

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

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

A neurological phenotype in nail patella syndrome (NPS) patients illuminated by studies of murine Lmx1b expression

LMX1B is Essential for the Maintenance of Differentiated Podocytes in Adult Kidneys

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