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

Bongers, Ernie M.H.F.; Wijs, Ilse J. de; Marcelis, Carlo; Hoefsloot, Lies H.; Knoers, Nine V A M

doi:10.1038/ejhg.2008.83

Cited by 47 publications

(46 citation statements)

References 25 publications

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“…Moreover, this observation challenges, at least for some cases, the concept of haploinsufficiency currently proposed for LMX1B mutation dominant effect. 35 In conclusion, we identified two novel mutations of the LMX1B gene in three unrelated families with AD FSGS and no extrarenal features. Our data demonstrate that isolated FSGS could be caused by mutations in genes also involved in syndromic forms of the disease and highlight the need to include these genes in all diagnosis approaches in FSGS.…”

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confidence: 67%

LMX1B Mutations Cause Hereditary FSGS without Extrarenal Involvement

Boyer

Woerner

Yang

et al. 2013

Journal of the American Society of Nephrology

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LMX1B encodes a homeodomain-containing transcription factor that is essential during development. Mutations in LMX1B cause nail-patella syndrome, characterized by dysplasia of the patellae, nails, and elbows and FSGS with specific ultrastructural lesions of the glomerular basement membrane (GBM). By linkage analysis and exome sequencing, we unexpectedly identified an LMX1B mutation segregating with disease in a pedigree of five patients with autosomal dominant FSGS but without either extrarenal features or ultrastructural abnormalities of the GBM suggestive of nail-patella-like renal disease. Subsequently, we screened 73 additional unrelated families with FSGS and found mutations involving the same amino acid (R246) in 2 families. An LMX1B in silico homology model suggested that the mutated residue plays an important role in strengthening the interaction between the LMX1B homeodomain and DNA; both identified mutations would be expected to diminish such interactions. In summary, these results suggest that isolated FSGS could result from mutations in genes that are also involved in syndromic forms of FSGS. This highlights the need to include these genes in all diagnostic approaches to FSGS that involve next-generation sequencing.

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confidence: 67%

LMX1B Mutations Cause Hereditary FSGS without Extrarenal Involvement

Boyer

Woerner

Yang

et al. 2013

Journal of the American Society of Nephrology

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“…3,10,12 mice and humans has been shown for LMX1B, for which haploinsufficiency in humans causes nail patella syndrome (OMIM 161200), whereas only complete knockout mice exhibit such a phenotype. 13 The function of the DSS1 gene in limb formation, however, is less clear. It was named deleted in split-hand/ split-foot 1 region (DSS1) because it was identified within the critical chromosomal region of SHFM1.…”

Section: Review Of Literature and Discussionmentioning

confidence: 99%

Split hand/foot malformation due to chromosome 7q aberrations(SHFM1): additional support for functional haploinsufficiency as the causative mechanism

et al. 2009

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We report on three patients with split hand/foot malformation type 1 (SHFM1). We detected a deletion in two patients and an inversion in the third, all involving chromosome 7q21q22. We performed conventional chromosomal analysis, array comparative genomic hybridization and fluorescence in situ hybridization. Both deletions included the known genes associated with SHFM1 (DLX5, DLX6 and DSS1), whereas in the third patient one of the inversion break points was located just centromeric to these genes. These observations confirm that haploinsufficiency due to either a simultaneous deletion of these genes or combined downregulation of gene expression due to a disruption in the region between these genes and a control element could be the cause of the syndrome. We review previously reported studies that support this hypothetical mechanism.

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“…Two deletions of the whole gene and another affecting exons 3 to 8 were identified in a series of eight unrelated families with classical features of NPS. 9 Although it is possible that apparently negative cases actually carry mutations affecting regulatory regions essential for gene expression either at the 5Ј end of the gene, or within introns, or in the 3Ј untranslated regions, no such mutations have been so far reported as unequivocally causative.…”

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confidence: 99%

A spectrum of LMX1B mutations in Nail-Patella syndrome: New point mutations, deletion, and evidence of mosaicism in unaffected parents

Marini

Bocciardi

Gimelli

et al. 2010

Genetics in Medicine

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Purpose: Nail-Patella syndrome (MIM 161200) is a rare autosomal dominant disorder characterized by hypoplastic or absent patellae, dystrophic nails, dysplasia of the elbows, and iliac horn. In 40% of cases, a glomerular defect is present and, less frequently, ocular damage is observed. Inter-and intrafamilial variable expressivity of the clinical phenotype is a common finding. Mutations in the human LMX1B gene have been demonstrated to be responsible for Nail-Patella syndrome in around 80% of cases. Methods: Standard polymerase chain reaction and sequencing methods were used for mutation and single nucleotide polymorphism identification and control of cloned sequences. Array-CGH (Agilent, 244A Kit) was used for detection of deletions. Standard cloning techniques and the Snapshot method were used for analysis of mosaicism. Results: In this study, we present the results of LMX1B screening of 20 Nail-Patella syndrome patients. The molecular defect was found in 17 patients. We report five novel mutations and a ϳ2 Mb deletion in chromosome 9q encompassing the entire LMX1B gene in a patient with a complex phenotype. We present evidence of somatic mosaicism in unaffected parents in two cases, which, to our knowledge, are the first reported cases of inheritance of a mutated LMX1B allele in Nail-Patella syndrome patients from a mosaic parent. Conclusion: The study of the described case series provides some original observations in an "old" genetic disorder. Genet Med 2010:12(7):431-439.

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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

Cited by 47 publications

References 25 publications

LMX1B Mutations Cause Hereditary FSGS without Extrarenal Involvement

LMX1B Mutations Cause Hereditary FSGS without Extrarenal Involvement

Split hand/foot malformation due to chromosome 7q aberrations(SHFM1): additional support for functional haploinsufficiency as the causative mechanism

A spectrum of LMX1B mutations in Nail-Patella syndrome: New point mutations, deletion, and evidence of mosaicism in unaffected parents

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