Evidence for a functional genetic polymorphism of the human retinoic acid–metabolizing enzyme CYP26A1, an enzyme that may be involved in spina bifida

Rat, Emmanuel; Billaut-Laden, Ingrid; Allorge, Delphine; Lo-Guidice, Jean-Marc; Tellier, Marie; Cauffiez, Christelle; Jonckheere, Nicolas; Seuningen, Isabelle Van; Lhermitte, Michel; Romano, Antonino; Guéant, Jean Louis; Broly, Franck

doi:10.1002/bdra.20275

Cited by 20 publications

(20 citation statements)

References 38 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%

“…A polymorphism discovery screen was carried out for ALDH1A2 (MIM# 603687), CYP26A1 (MIM# 602239), CYP26B1 (MIM# 605207), CRABP1 (MIM# 180230), and CRABP2 (MIM# 180231) genes in 230 individuals with lumbosacral myelomeningocele (including spina bifida aperta or spina bifida cystica), and a significant association between three polymorphisms in ALDH1A2 and this spinal NTD was identified (Deak et al., ). In another study, a deletion (g.3116delT) in the CYP26A1 gene, which creates a premature stop codon, was found in a sample of 40 spina bifida patients of Caucasian origin from southern Italy (Rat et al., ). Moreover, investigation of the three RA receptors encoded by RARA (MIM# 180240), RARB (MIM# 180220), and RARG (MIM# 180190) in 329 affected family trios and 281 affected family duos of patients with meningomyelocele from Texas, identified SNPs in each of these genes and these were associated with a protective effect against meningomyelocele (Tran et al., ).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

confidence: 99%

Genetic contribution of retinoid-related genes to neural tube defects

Zhang

Chen

et al. 2018

Human Mutation

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“…Mice lacking either Cyp26a1 or Aldh1a2 display an open neural tube (Abu-Abed et al, 2001;Ribes et al, 2006), and human mutations in both ALDH1A2 and CYP26A1 have been linked to spina bifida (Deak et al, 2005;Rat et al, 2006). These results suggest that too much or too little RA is deleterious for neural tube closure.…”

Section: Discussionmentioning

confidence: 81%

Hmx4 regulates Sonic hedgehog signaling through control of retinoic acid synthesis during forebrain patterning

Gongal

March

Holly

et al. 2011

Developmental Biology

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Mutations in H6-homeobox (HMX) genes are linked to neural mispatterning and neural tube closure defects in humans. We demonstrate that zebrafish Hmx4 regulates the signaling of two morphogens critical for neural development, retinoic acid (RA) and Sonic hedgehog (Shh). Hmx4-depleted embryos have a strongly narrowed eye field and reduced forebrain Shh target gene expression. hmx4 morphants fail to properly transcribe the Shh signal transducer gli3, and have reduced ventral forebrain specification. Hmx4-depleted embryos also have neural tube patterning defects that phenocopy RA-deficiency. We show that Hmx4 is required for the initiation and maintenance of aldh1a2, the principal RA-synthesizing gene. Loss of RA is the primary defect in Hmx4-depleted embryos, as RA treatment rescues a number of the neural patterning defects. Surprisingly, RA treatment also rescues forebrain morphology, gli3 transcription, and Shh signaling. We propose that Hmx4 is a critical regulator of retinoic acid synthesis in a developing embryo, and that this regulation is essential for controlling Shh signaling and forebrain development.

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“…Some congenital defects that are consistent with retinoid embryopathy and have been either mechanistically or anecdotally associated with functional defects in CYP26 enzymes include spina bifida and cleft palate, DiGeorge syndrome, and Klippel‐Feil anomaly (De Marco et al,2006; Rat et al,2006; Roberts et al,2006; Laue et al,2008). Mutational screening of CYP26A1 polymorphisms in patients with spina bifida and caudal regression syndrome revealed that SNPs exist that affect the rate of RA metabolism, but none were homozygous and were not able to be statistically linked to the observed phenotypes (De Marco et al,2006; Rat et al,2006). These studies suggested that CYP26A1 mutations may not play a predominant causative role in spina bifida or caudal regression syndrome, but the small cohorts used in each study may not have allowed for the detection of the potentially rare incidence of involvement of hypomorphs/mutations of CYP26A1.…”

Section: Associations Of Cyp26 Mutations With Human Congenital Malformentioning

confidence: 99%

The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis

Pennimpede

Cameron

MacLean

et al. 2010

Birth Defects Research

125

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Retinoic acid (RA) is a pleiotropic derivative of vitamin A, or retinol, which is responsible for all of the bioactivity associated with this vitamin. The teratogenic influences of vitamin A deficiency and excess RA in rodents were first observed more than 50 years ago. Efforts over the last 15-20 years have refined these observations by defining the molecular mechanisms that control RA availability and signaling during murine embryonic development. This review will discuss our current understanding of the role of RA in teratogenesis, with specific emphasis on the essential function of the RA catabolic CYP26 enzymes in preventing teratogenic consequences caused by uncontrolled distribution of RA. Particular focus will be paid to the RA-sensitive tissues of the caudal and cranial regions, the limb, and the testis, and how genetic mutation of factors controlling RA distribution have revealed important roles for RA during embryogenesis.

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Evidence for a functional genetic polymorphism of the human retinoic acid–metabolizing enzyme CYP26A1, an enzyme that may be involved in spina bifida

Cited by 20 publications

References 38 publications

Genetic contribution of retinoid-related genes to neural tube defects

Genetic contribution of retinoid-related genes to neural tube defects

Hmx4 regulates Sonic hedgehog signaling through control of retinoic acid synthesis during forebrain patterning

The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis

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