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An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure Abstract The number of mouse mutants and strains with neural tube defects (NTDs) now exceeds 240, including 205 representing specific genes, 30 for unidentified genes, and 9 multifactorial strains. These mutants identify genes needed for embryonic neural tube closure. Reports of 50 new NTD mutants since our 2007 review (Harris and Juriloff,2007 ) were considered in relation to the previously reviewed mutants to obtain new insights into mechanisms of NTD etiology. In addition to null mutations, some are hypomorphs or conditional mutants. Some mutations do not cause NTDs on their own, but do so in digenic, trigenic, and oligogenic combinations, an etiology that likely parallels the nature of genetic etiology of human NTDs. Mutants that have only exencephaly are fourfold more frequent than those that have spina bifida aperta with or without exencephaly. Many diverse cellular functions and biochemical pathways are involved; the NTD mutants draw new attention to chromatin modification (epigenetics), the protease‐activated receptor cascade, and the ciliopathies. Few mutants directly involve folate metabolism. Prevention of NTDs by maternal folate supplementation has been tested in 13 mutants and reduces NTD frequency in six diverse mutants. Inositol reduces spina bifida aperta frequency in the curly tail mutant, and three new mutants involve inositol metabolism. The many NTD mutants are the foundation for a future complete genetic understanding of the processes of neural fold elevation and fusion along mechanistically distinct cranial‐caudal segments of the neural tube, and they point to several candidate processes for study in human NTD etiology. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.
Wiley - Tập 88 Số 8 - Trang 653-669 - 2010
Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects Abstract BACKGROUND : The number of mouse mutants and strains with neural tube closure defects (NTDs) now exceeds 190, including 155 involving known genes, 33 with unidentified genes, and eight “multifactorial” strains. METHODS : The emerging patterns of mouse NTDs are considered in relation to the unknown genetics of the common human NTDs, anencephaly, and spina bifida aperta. RESULTS : Of the 150 mouse mutants that survive past midgestation, 20% have risk of either exencephaly and spina bifida aperta or both, parallel to the majority of human NTDs, whereas 70% have only exencephaly, 5% have only spina bifida, and 5% have craniorachischisis. The primary defect in most mouse NTDs is failure of neural fold elevation. Most null mutations (>90%) produce syndromes of multiple affected structures with high penetrance in homozygotes, whereas the “multifactorial” strains and several null‐mutant heterozygotes and mutants with partial gene function (hypomorphs) have low‐penetrance nonsyndromic NTDs, like the majority of human NTDs. The normal functions of the mutated genes are diverse, with clusters in pathways of actin function, apoptosis, and chromatin methylation and structure. The female excess observed in human anencephaly is found in all mouse exencephaly mutants for which gender has been studied. Maternal agents, including folate, methionine, inositol, or alternative commercial diets, have specific preventative effects in eight mutants and strains. CONCLUSIONS : If the human homologs of the mouse NTD mutants contribute to risk of common human NTDs, it seems likely to be in multifactorial combinations of hypomorphs and low‐penetrance heterozygotes, as exemplified by mouse digenic mutants and the oligogenic SELH/Bc strain. Birth Defects Research (Part A), 2007. © 2006 Wiley‐Liss, Inc.
Wiley - Tập 79 Số 3 - Trang 187-210 - 2007
Prevalence of esophageal atresia among 18 international birth defects surveillance programs Abstract BACKGROUND: The prevalence of esophageal atresia (EA) has been shown to vary across different geographical settings. Investigation of geographical differences may provide an insight into the underlying etiology of EA. METHODS: The study population comprised infants diagnosed with EA during 1998 to 2007 from 18 of the 46 birth defects surveillance programs, members of the International Clearinghouse for Birth Defects Surveillance and Research. Total prevalence per 10,000 births for EA was defined as the total number of cases in live births, stillbirths, and elective termination of pregnancy for fetal anomaly (ETOPFA) divided by the total number of all births in the population. RESULTS: Among the participating programs, a total of 2943 cases of EA were diagnosed with an average prevalence of 2.44 (95% confidence interval [CI], 2.35–2.53) per 10,000 births, ranging between 1.77 and 3.68 per 10,000 births. Of all infants diagnosed with EA, 2761 (93.8%) were live births, 82 (2.8%) stillbirths, 89 (3.0%) ETOPFA, and 11 (0.4%) had unknown outcomes. The majority of cases (2020, 68.6%), had a reported EA with fistula, 749 (25.5%) were without fistula, and 174 (5.9%) were registered with an unspecified code. CONCLUSIONS: On average, EA affected 1 in 4099 births (95% CI, 1 in 3954–4251 births) with prevalence varying across different geographical settings, but relatively consistent over time and comparable between surveillance programs. Findings suggest that differences in the prevalence observed among programs are likely to be attributable to variability in population ethnic compositions or issues in reporting or registration procedures of EA, rather than a real risk occurrence difference. Birth Defects Research (Part A), 2012. © 2012 Wiley Periodicals, Inc.
Wiley - Tập 94 Số 11 - Trang 893-899 - 2012
Folic acid–containing supplement consumption during pregnancy and risk for oral clefts: A meta‐analysis Abstract BACKGROUND : There is equivocal evidence in the published literature that folic acid supplementation during pregnancy may protect against the common congenital anomalies cleft lip with or without cleft palate (CLP) and cleft palate alone (CP). We undertook this meta‐analysis to test the hypothesis that nonsyndromic oral cleft birth prevalences are different for those whose mothers took folic acid–containing supplements and for those whose mothers did not. METHODS : Human studies published in English were identified through MEDLINE, bibliography reviews, and contacting experts in the field. Within strata of prospective and case‐control studies, CLP, CP, and all clefts, respectively, were analyzed using either a fixed or random effects model, as appropriate. We assessed for publication bias using Begg and Mazumdar's rank correlation and Egger's regression‐based tests. RESULTS : Five prospective studies were analyzed, yielding combined relative risks of 0.51 (95% CI: 0.32, 0.95) for CLP, 1.19 (95% CI: 0.43, 3.28) for CP, and 0.55 (95% CI: 0.32, 0.95) for all clefts. Twelve case‐control studies were assessed, which resulted in combined relative risks of 0.77 (95% CI: 0.65, 0.90) for CLP, 0.80 (95% CI: 0.69, 0.93) for CP, and 0.78 (95% CI: 0.71, 0.85) for all clefts. CONCLUSIONS : In aggregate, our results support the hypothesis of a protective effect of folic acid–containing supplement intake during pregnancy on the risk for oral clefts, although this conclusion is tempered by the potential for bias and uncontrolled confounding. Birth Defects Research (Part A), 2007. © 2006 Wiley‐Liss, Inc.
Wiley - Tập 79 Số 1 - Trang 8-15 - 2007
Maternal polymorphisms in folic acid metabolic genes are associated with nonsyndromic cleft lip and/or palate in the Brazilian population Abstract BACKGROUND Polymorphisms in genes that are involved in folic acid metabolism may be important maternal risk factors for the birth of a child with nonsyndromic cleft lip and/or palate (NSCL/P). The aim of this study was to determine the involvement of polymorphic variants in four genes (MTHFR,
MTHFD1,
MTR, and SLC19A1 ) that encode proteins related to folic acid metabolism in the women with susceptibility for having a child with NSCL/P. METHODS DNA samples from 106 mothers of children with NSCL/P (case group) and from 184 mothers of healthy children (control group) were genotyped by polymerase chain reaction associated with restriction fragment length polymorphism (PCR‐RFLP). RESULTS One of 29 polymorphisms was associated with significantly increased maternal risk for NSCL/P. Mothers exhibiting the A variant allele (GA genotype) of the MTHFR rs2274976 polymorphism demonstrated a ∼6 times increased risk for having a child with NSCL/P compared to G allele carriers (OR, 5.76; 95% CI, 3.32–9.99, p = 0.000001). Among mothers who did not use vitamins, the OR of NSCL/P was increased to 8.34 (95% CI, 3.75–18.55, p = 0.000001) in the presence of the GA genotype of the MTHFR rs2274976 polymorphism compared to those with the GG genotype. Gene‐gene interaction analysis showed that the combination of MTHFR rs2274976, MTHFD1 rs2236225, and SLC19A1 rs1051266 was the best model for prediction of maternal risk for NSCL/P. CONCLUSION The findings of the present study suggested that genetic variants of folic acid metabolic genes may modulate maternal susceptibility for having an offspring with NSCL/P. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.
Wiley - Tập 88 Số 11 - Trang 980-986 - 2010
Folate‐related gene polymorphisms as risk factors for cleft lip and cleft palate Abstract BACKGROUND: Cleft lip with or without cleft palate (CLP) and cleft palate only (CPO) have an inherited component and, many studies suggest, a relationship with folate. Attempts to find folate‐related genes associated with clefts have, however, often been inconclusive. This study examined four SNPs related to folate metabolism (MTHFR 677 C→T, MTHFR 1298 A→C, MTHFD1 1958 G→A, and TC II 776 C→G) in a large Irish population to clarify their relationship with clefts. METHODS: Cases and their parents were recruited from major surgical centers performing cleft repairs in Ireland and a support organization. Data on risk factors, medical history, and DNA were collected. Controls were pregnant women from the greater Dublin area (n = 1,599). RESULTS: CLP cases numbered 536 and CPO cases 426 after exclusions. CPO mothers were significantly more likely than controls to be MTHFR 677 TT, OR 1.50 (95% CI: 1.05–2.16; p = .03). Log‐linear analysis showed a borderline association (p = .07). Isolated CPO case mothers were significantly more likely than controls to be homozygous for the MTHFD1 1958 G→A variant, OR 1.50 (95%CI: 1.08–2.09; p = .02). When multiple cases were added, both CPO cases and case mothers were significantly more likely to be AA (p = .02 and p = .007, respectively). The CLP case‐control and mother‐control analyses also showed significant effects, ORs 1.38 (95% CI: 1.05–1.82; p = .03) and 1.39 (95% CI: 1.04–1.85; p = .03), respectively. CONCLUSIONS: Associations were found for both CPO and CLP and MTHFD1 1958 G→A in cases and case mothers. MTHFR 677 C→T could be a maternal risk factor for clefts but the association was not strong. Because multiple comparisons were made, these findings require additional investigation. Given the known association between MTHFD1 1958 G→A and NTDs, these findings should be explored in more detail. Birth Defects Research (Part A) 2008. © 2008 Wiley‐Liss, Inc.
Wiley - Tập 82 Số 9 - Trang 636-643 - 2008
Folate pathway and nonsyndromic cleft lip and palate Abstract BACKGROUND Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common complex birth defect. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) single‐nucleotide polymorphisms (SNPs), C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. Here, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP, and were there detectable interactions between these genes and environmental exposures? METHODS: Fourteen folate metabolism‐related genes were interrogated using 89 SNPs in multiplex and simplex non‐Hispanic white and Hispanic NSCLP families. RESULTS: Evidence for a risk association between NSCLP and SNPs in NOS3 and TYMS was detected in the non‐Hispanic white group, whereas associations with MTR, BHMT2, MTHFS, and SLC19A1 were detected in the Hispanic group. Evidence for over‐transmission of haplotypes and gene interactions in the methionine arm was detected. CONCLUSIONS These results suggest that perturbations of the genes in the folate pathway may contribute to NSCLP. There was evidence for an interaction between several SNPs and maternal smoking, and for one SNP with gender of the offspring. These results provide support for other studies that suggest that high maternal homocysteine levels may contribute to NSCLP and should be further investigated. Birth Defects Research (Part A), 2011. © 2010 Wiley‐Liss, Inc.
Wiley - Tập 91 Số 1 - Trang 50-60 - 2011
Platelet‐derived growth factor C plays a role in the branchial arch malformations induced by retinoic acid Abstract BACKGROUND: All‐trans ‐retinoic acid (RA) can produce branchial arch abnormalities in postimplantation rodent embryos cultured in vitro . Platelet‐derived growth factor C (PDGF‐C) was recently identified as a member of the PDGF ligand family. Many members of the PDGF family are essential for branchial arch morphogenesis and can be regulated by RA. The roles of PDGF‐C in branchial arch malformations induced by RA and possible mechanisms were investigated. METHODS: In whole embryo culture (WEC), mouse embryos were exposed to RA at 0, 0.1, 0.4, 1.0, or 10.0 μM , PDGF‐C at 25, 50, or 75 ng/mL, or PDGF‐C at 25, 50, or 75 ng/mL containing 0.4 μM RA. After 48 h of culture, mouse embryos were examined for dysmorphogenesis, and whole‐mount immunohistochemistry was applied to PDGF‐C. In explant cultures, explants were exposed to the same doses of RA and PDGF‐C as WEC. Semiquantitative RT‐PCR, zymography, and reverse zymography were used to evaluate the expressions and activities of matrix metalloproteinase (MMP)‐2, MMP‐14, and tissue inhibitor of metalloproteinase (TIMP)‐2. RESULTS: PDGF‐C was reduced by RA, and exogenous PDGF‐C rescued the branchial arch malformations induced by RA. Moreover, PDGF‐C prevented RA‐induced inhibition of the migratory ability of mesenchymal cells in the first branchial arch, by regulating the expressions of MMP‐2, MMP‐14, and TIPM‐2. CONCLUSIONS: Our results suggest that RA exposure reduces the expression of PDGF‐C. The branchial arch malformations resulting from fetal RA exposure are caused at least partially by loss of PDGF‐C and subsequent misregulations of the expressions of MMP‐2, MMP‐14, and TIMP‐2. Birth Defects Research (Part A), 2007. © 2006 Wiley‐Liss, Inc.
Wiley - Tập 79 Số 3 - Trang 221-230 - 2007
Emerging data on the use of anti‐tumor necrosis factor‐alpha medications in pregnancy Abstract Anti‐tumor necrosis factor (TNF) α medications are used for the treatment of a number of autoimmune diseases. Evaluation of pregnancy safety for these medications is complicated by the contribution of the underlying maternal disease to adverse pregnancy outcomes, such as preterm delivery and reduced birth weight. Placental transport of these medications is thought to be minimal in the first trimester, thereby providing some reassurance regarding theoretical risks for congenital malformations. Available human exposure data are sparse; however, to date there has been no convincing evidence to support an increased risk for a specific pattern of major congenital malformations with any of the drugs in this group for which some data is currently available. As a result of the improvement of symptoms during pregnancy in some women with autoimmune diseases, it may be possible to discontinue treatment before or shortly after conception. However, in some cases the benefits of treatment and concerns for disease flares in pregnancy have warranted continued treatment during pregnancy. Because of the relatively long half‐life of these medications, and theoretical concerns for immune compromise of the infant following exposure in the latter two trimesters, some clinicians recommend discontinuation of treatment in the third trimester to avoid potentially prolonged infant exposure in the postpartum period. Currently ongoing controlled cohort studies for some of the TNF blocker medications will help to provide more definitive answers for clinicians and patients. Birth Defects Research (Part A) 94:607–611, 2012. © 2012 Wiley Periodicals, Inc.
Wiley - Tập 94 Số 8 - Trang 607-611 - 2012
Teratogen update: Methotrexate Abstract Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m2 (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low‐set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell‐related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate‐exposed children. Denominator‐based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure. Birth Defects Research (Part A), 2012. © 2012 Wiley Periodicals, Inc.
Wiley - Tập 94 Số 4 - Trang 187-207 - 2012
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