Association of retinoic acid receptor genes with meningomyelocele

Tran, Phong X.; Au, Kit Sing; Morrison, Alanna C.; Fletcher, Jack Μ.; Ostermaier, Kathryn K.; Tyerman, Gayle H.

doi:10.1002/bdra.20744

Cited by 15 publications

(16 citation statements)

References 28 publications

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“…Our experimental results emphasize the loss‐of‐function characteristics of these rare mutations encoding for the RA degradation enzyme CYP26B1 . Our findings together with genetic association studies by others (Deak et al., ; Rat et al., ; Tran et al., ) highlight this functional pathway in the genetic contribution of rare mutations to human NTDs.…”

Section: Discussionsupporting

confidence: 82%

Genetic contribution of retinoid-related genes to neural tube defects

Zhang

Chen

et al. 2018

Human Mutation

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Rare variants are considered underlying causes of complex diseases. The complex and severe group of disorders called neural tube defects (NTDs) results from failure of the neural tube to close during early embryogenesis. Neural tube closure requires the coordination of numerous signaling pathways, including the precise regulation of retinoic acid (RA) concentration, which is controlled by enzymes involved in RA synthesis and degradation. Here, we used a case-control mutation screen study to reveal rare variants in retinoid-related genes in a Han Chinese NTD population by sequencing six genes in 355 NTD cases and 225 controls. More specific rare variants were found in exonic and upstream regions in NTD cases. The RA-responsive genes CYP26A1, CRABP1, and ALDH1A2 harbored NTD-specific rare variants in their upstream regions. Unexpectedly, the majority of missense variants in NTD cases were found in CYP26B1, which encodes a RA degradation enzyme, whereas no missense variants in this gene were found in controls. Functional analysis indicated that the CYP26B1 NTD variants were inefficient in the degradation of RA using assays of RA-induced transcription and RA-initiated neuronal differentiation. Our study supports the contribution of rare variants in RA-related genes to the etiology of human NTDs.

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Section: Discussionsupporting

confidence: 82%

Genetic contribution of retinoid-related genes to neural tube defects

Zhang

Chen

et al. 2018

Human Mutation

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“…Overall, there were 329 trios (affected child and both parents) and 279 duos (affected child and one parent) whose DNA samples were available for testing. The patient demographics have been described previously and are available for review (Tran et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

“…Patient selection has been described previously (Au et al, 2008; Davidson et al, 2008; Tran et al, 2011). Briefly, patients born between 1955 and 2008 (ages 0.4–53 years) with a diagnosis of an isolated nonsyndromic MM at birth were eligible for study inclusion.…”

Section: Methodsmentioning

confidence: 99%

“…As described previously (Au et al, 2008; Davidson et al, 2008; Tran et al, 2011), whole blood samples and saliva samples were collected from patients with MM and parents when feasible. Genomic DNA from blood cells was extracted using the Puregene DNA extraction Kit (Gentra Systems, Minneapolis, MN) and from saliva using Oragene DNA Collection Kit (DNA Genotek; Ottawa, Ontario, Canada).…”

Section: Methodsmentioning

confidence: 99%

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Association of copper‐zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes with nonsyndromic myelomeningocele

Kase¹,

Morrison

Davidson

et al. 2012

Birth Defects Research

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Background A common and severe neural tube defect (NTD) phenotype, myelomeningocele (MM), results from the defective closure of the caudal end of the neural tube with herniation of the spinal cord and meninges through the vertebral column. The exact mechanisms for NTDs are unknown, but excessive oxidative stress, particularly in association with maternal diabetes, has been postulated as a mechanism for MM. Methods The SNPlex Genotyping (ABI, Foster City, CA) platform was used to investigate single nucleotide polymorphisms (SNPs) across the superoxide dismutase (SOD) 1 and 2 genes to assess their association with MM risk. The study population included 329 trio (affected child and both parents) and 281 duo (affected child and one parent) families. Only cases with documented MM were studied. Seventeen SNPs across the SOD1 and SOD2 genes met the quality control criteria to be considered for statistical analysis. Genetic association was assessed using the family-based Transmission Disequilibrium Test in PLINK. Results Four SNPs in the SOD1 gene (rs 202446, rs202447, rs4816405 and rs2070424) and one SNP in the SOD2 gene (rs5746105) appeared to be associated with MM risk in our population. After adjusting for multiple testing, these SNPs remained significant. Conclusion The study provides the first genetic evidence to support association of myelomeningocele with superoxide scavenging. The rare alleles of the five specific SNPs within SOD1 and SOD2 appear to confer a protective effect on the susceptibility for MM risk in the MM population tested. Further evaluation of the roles of superoxide scavenging and neural tube development is warranted.

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“…In terms of genetic underpinnings, monozygotic twinning and single gene disorders have long been associated with NTDs (8). Numerous studies have explored a variety of candidate gene pathways (reviewed in (9)), such as the folate/1-methyl carbon metabolic pathway (10, 11), glucose metabolism/transport (9), DNA repair (12), oxidative stress pathway (9), retinoic acid receptors (13), and the WNT/Planar Cell Polarity (PCP) signaling network (14). In a following section, we discuss animal studies that are shedding new light on genetic factors that govern NTC.…”

Section: Epidemiology Of Human Ntdsmentioning

confidence: 99%

The Continuing Challenge of Understanding, Preventing, and Treating Neural Tube Defects

Wallingford

Niswander

Shaw

et al. 2013

Science

393

354

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Prevention or Repair Neural tube defects, such as spina bifida, remain remarkably common, despite widespread efforts to prevent them through supplementing maternal diets with folic acid. Surgery early in development has seen some success, but problems often remain. Wallingford et al. ( 10.1126/science.1222002 ) review normal and abnormal neural tube development and suggest that discovering the genetic risk factors for these serious birth defects could provide ways to prevent and treat neural tube defects.

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Association of retinoic acid receptor genes with meningomyelocele

Cited by 15 publications

References 28 publications

Genetic contribution of retinoid-related genes to neural tube defects

Genetic contribution of retinoid-related genes to neural tube defects

Association of copper‐zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes with nonsyndromic myelomeningocele

The Continuing Challenge of Understanding, Preventing, and Treating Neural Tube Defects

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