Refinement of 2q and 7p loci in a large multiplex NTD family

Stamm, Demetra S.; Siegel, Deborah G.; Mehltretter, Lorraine; Connelly, Jessica J.; Trott, Alison; Ellis, Nathen; Zismann, Victoria; Stephan, Dietrich A.; George, Timothy M.; Vekemans, Michel; Ashley-Koch, Allison E.; Gilbert, John R.; Gregory, Simon G.; Speer, Marcy C.; Aben, Joanna; Aylsworth, Arthur S.; Powell, Cynthia M.; Mackey, Joanne; Worley, Gordon; Brei, Timothy J.; Buran, Connie; Bodurtha, Joann; Sawin, Kathleen J.; Mack, Philip W.; Meeropol, Elli; Lasarsky, Nicole; McLone, David G.; Ito, Joy; Oakes, W. Jerry; Walker, Marion L.; Iskandar, Bermans

doi:10.1002/bdra.20462

Cited by 12 publications

(7 citation statements)

References 38 publications

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“…The genomic region of human chromosome 2q34 proximal to LanCL1 has been implicated in early-onset AD susceptibility (Scott et al 2003); forms of familial schizophrenia (Aberg et al 2008); and neural tube defects (Stamm et al 2008). Several prior, separate associations of schizophrenia with CRMP2, STXBP1, and the LanCL1-containing region of chromosome 2q34 offer an intriguing coincidence amongst these three candidate LK-binding proteins that is worthy of further inquiry.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Identification of Binding Partners for the Brain Metabolite Lanthionine Ketimine (LK) and Documentation of LK Effects on Microglia and Motoneuron Cell Cultures

Hensley¹,

Christov²,

Kamat³

et al. 2010

J. Neurosci.

122

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Section: Discussionmentioning

confidence: 99%

Proteomic Identification of Binding Partners for the Brain Metabolite Lanthionine Ketimine (LK) and Documentation of LK Effects on Microglia and Motoneuron Cell Cultures

Hensley¹,

Christov²,

Kamat³

et al. 2010

J. Neurosci.

122

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“…Nevertheless, genome-wide studies using collections of smaller multiplex families have implicated chromosomes 2, 7 and 10 as harbouring candidate risk loci for spina bifida (6–8). Although the causative genes are yet to be identified, these studies may result in identification of candidate sequences that can be evaluated in larger populations.…”

Section: Genetic Analysis Of Human Ntdsmentioning

confidence: 99%

Genetics of human neural tube defects

Greene¹,

Stanier²,

Copp³

2009

Human Molecular Genetics

286

284

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Neural tube defects (NTDs) are common, severe congenital malformations whose causation involves multiple genes and environmental factors. Although more than 200 genes are known to cause NTDs in mice, there has been rather limited progress in delineating the molecular basis underlying most human NTDs. Numerous genetic studies have been carried out to investigate candidate genes in cohorts of patients, with particular reference to those that participate in folate one-carbon metabolism. Although the homocysteine remethylation gene MTHFR has emerged as a risk factor in some human populations, few other consistent findings have resulted from this approach. Similarly, attention focused on the human homologues of mouse NTD genes has contributed only limited positive findings to date, although an emerging association between genes of the non-canonical Wnt (planar cell polarity) pathway and NTDs provides candidates for future studies. Priorities for the next phase of this research include: (i) larger studies that are sufficiently powered to detect significant associations with relatively minor risk factors; (ii) analysis of multiple candidate genes in groups of well-genotyped individuals to detect possible gene–gene interactions; (iii) use of high throughput genomic technology to evaluate the role of copy number variants and to detect ‘private’ and regulatory mutations, neither of which have been studied to date; (iv) detailed analysis of patient samples stratified by phenotype to enable, for example, hypothesis-driven testing of candidates genes in groups of NTDs with specific defects of folate metabolism, or in groups of fetuses with well-defined phenotypes such as craniorachischisis.

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“…Other candidate gene approaches investigated the role of folate‐related genes in the etiology of human NTDs and identified few NTD‐associated variants that accounted for a small part of the disease etiology (Zhang et al., ). Whole‐genome linkage analysis has shown significant association to three chromosomal regions on chromosome 2, 7, and 10, but failed to identify any causative gene (Rampersaud et al., ; Stamm et al., ). These results need to be interpreted with caution as these kinds of studies are most likely complicated by clinical and genetic heterogeneity of NTDs.…”

Section: Introductionmentioning

confidence: 99%

Rare deleterious variants in GRHL3 are associated with human spina bifida

et al. 2017

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Neural tube defects, including spina bifida, are among the most common birth defects caused by failure of neural tube closure during development. They have a complex etiology involving largely undetermined environmental and genetic factors. Previous studies in mouse models have implicated the transcription factor Grhl3 as an important factor in the pathogenesis of spina bifida. In the present study, we conducted a resequencing analysis of GRHL3 in a cohort of 233 familial and sporadic cases of spina bifida. We identified two novel truncating variants: one homozygous frameshift variant, p.Asp16Aspfs*10, in two affected siblings and one heterozygous intronic splicing variant, p.Ala318Glyfs*26. We also identified five missense variants, one of which was demonstrated to reduce the activation of gene targets in a luciferase reporter assay. With the previously identified p.Arg391Cys variant, eight variants were found in GRHL3. Comparison of the variant rate between our cohort and the ExAC database identified a significant enrichment of deleterious variants in GRHL3 in the whole gene and the transactivation region in spina bifida patients. These data provide strong evidence for a role of GRHL3 as a predisposing factor to spina bifida and will help dissect the complex etiology and pathogenic mechanisms of these malformations.

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Refinement of 2q and 7p loci in a large multiplex NTD family

Cited by 12 publications

References 38 publications

Proteomic Identification of Binding Partners for the Brain Metabolite Lanthionine Ketimine (LK) and Documentation of LK Effects on Microglia and Motoneuron Cell Cultures

Proteomic Identification of Binding Partners for the Brain Metabolite Lanthionine Ketimine (LK) and Documentation of LK Effects on Microglia and Motoneuron Cell Cultures

Genetics of human neural tube defects

Rare deleterious variants in GRHL3 are associated with human spina bifida

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