Menstrual hygiene management among adolescent girls in West Africa: A systematic review.

A systematic literature review was conducted to examine all recent academic, peer-reviewed studies of menstrual hygiene management (MHM) across adolescent girls in Anglophone West Africa. The objective was to assess the status of the scholarship surrounding the knowledge, attitudes, and practices of MHM across English-speaking West African countries and identify gaps in the literature for further research. The authors searched the epidemiological literatures indexed in PubMed and cross-referenced bibliographies for studies published between 2010-2022. Of 59 abstracts and articles screened, 35 met the final inclusion criteria. Despite differences in study design, setting, and data sources, the study results concurred on an average age of menarche between 12-15 years old among adolescent girls. The knowledge of MHM came from multiple sources, most commonly mothers, female siblings, and teachers and higher knowledge was associated with age, source, wealth, religion, and education level. Less than half of the adolescent girls knew about menstruation before menarche. Many studies showed that girls were shocked by their first period and fearful of staining. Menstruation was associated with dysmenorrhea, fear/embarrassment, and missing school. The existing studies suggest that more implementation and evaluation of menstrual hygiene management materials, education, and facilities are needed to address the educational, physical, and social disparities that exist among girls in West African countries.

Une revue systématique de la littérature a été menée pour examiner toutes les études universitaires récentes évaluées par des pairs sur la gestion de l'hygiène menstruelle (MHM) chez les adolescentes d'Afrique de l'Ouest anglophone. L'objectif était d'évaluer l'état de la recherche sur les connaissances, les attitudes et les pratiques de la GHM dans les pays anglophones d'Afrique de l'Ouest et d'identifier les lacunes dans la littérature pour des recherches plus approfondies. Les auteurs ont recherché dans la littérature épidémiologique indexée dans PubMed et des bibliographies croisées pour les études publiées entre 2010 et 2022. Sur les 59 résumés et articles examinés, 35 répondaient aux critères d'inclusion finaux. Malgré les différences dans la conception, le cadre et les sources de données de l'étude, les résultats de l'étude concordaient sur un âge moyen des premières règles entre 12 et 15 ans chez les adolescentes. La connaissance de la GHM provenait de sources multiples, le plus souvent des mères, des frères et sœurs et des enseignants, et les connaissances supérieures étaient associées à l'âge, à la source, à la richesse, à la religion et au niveau d'éducation. Moins de la moitié des adolescentes connaissaient leurs règles avant les premières règles. De nombreuses études ont montré que les filles étaient choquées par leurs premières règles et craignaient les taches. Les menstruations étaient associées à la dysménorrhée, à la peur/à la gêne et à l'absence à l'école. Les études existantes suggèrent qu'une plus grande mise en œuvre et une plus grande évaluation du matériel, de l'éducation et des installations de gestion de l'hygiène menstruelle sont nécessaires pour remédier aux disparités éducatives, physiques et sociales qui existent parmi les filles dans les pays d'Afrique de l'Ouest.

Predictors of Seat-Belt Use among Bus Passengers in Ghana: An Application of the Theory of Planned Behaviour and Health Belief Model.

BACKGROUND: Seat-belt use is effective in preventing traffic fatalities and injuries yet its use is not universal. This study sought to determine the predictors of self-reported seat-belt use among bus passengers in Ghana based on the theory of planned behaviour and health belief model. METHODS: A quantitative cross-sectional study design with 633 randomly selected intercity bus passengers was conducted using a structured questionnaire in Kumasi, Ghana. The resulting data were analysed using SPSS version 23.0. Ordinal regression was employed to determine the predictors of self-reported seat-belt use. RESULTS: Majority of the respondents were male (61.5%) with a mean age of 32.2 (SD = 11.6). A third (33.0%) reported that they always wear their seat-belt as bus passengers. The results indicated that intention (OR = 1.49, 95% CI = 1.21-1.84, p = 0.001), subjective norm (OR = 1.57, 95% CI = 1.15-2.13, p = 0.004) and perceived behavioural control (OR = 1.53; 95% CI = 1.21-1.92, p = 0.001) variables from the theory of planned behaviour were significant independent predictors of seat-belt use. Among the health belief model variables, perceived severity (OR = 1.57, 95% CI = 1.15-2.16, p = 0.005) and perceived barriers (OR = 0.52, 95% CI = 0.39-0.67, p = 0.001) were the only significant independent predictors of self-reported seat-belt use. CONCLUSION: The findings suggest that intention, subjective norm, perceived behavioural control, perceived severity and perceived barriers play an important role in determining bus passengers' seat-belt use behaviour. Road safety programmes to increase seat-belt use will gain from giving serious attention to these factors in the design and implementation of such programmes.

Barriers to the enforcement of mandatory seat belt laws in Ghana: an exploratory study.

Road traffic accidents claim millions of lives every year across the world. Fortunately, effective safety and preventive measures such as routine maintenance of vehicles and roads and the use of seat belts exist. Yet, authorities in some countries fail to enforce laws on these measures. One of the barriers to compliance with traffic laws is poor enforcement. Using a cross-sectional study design, we explored the barriers to the enforcement of mandatory seat belt laws in Ghana. We employed an open-ended key informant interview guide to interview 26 staff of the Motor Traffic and Transport Department of the Ghana Police Service, National Road Safety Authority and the Driver and Vehicle Licensing Authority. The interviews which lasted between 30 and 45 min per session were analysed through a thematic approach facilitated by ATLAS.ti. The findings showed that the barriers to the enforcement of seat belt laws mentioned by the participants were institutional factors (inadequate resources and logistics and inability to enforce vehicle safety standards) political factors (external interference and lack of consensus on seat belt law implementation) and human factors (poor public attitudes and non- recognition of road safety as both individual and collective responsibility). The enforcement of road safety laws could be enhanced by adequately resourcing officers, addressing external interference of police duties and empowering officers to perform their duties without fear or favour. These findings are also useful in continuous public education and enhanced enforcement of the seat belt laws.

Effect of a theory-based hand hygiene educational intervention for enhancing behavioural outcomes in Ghanaian schools: a cluster-randomised controlled trial.

OBJECTIVES: The study sought to determine whether a hand hygiene educational intervention underpinned by educational and psychosocial theories is effective in enhancing behavioural intention and proper handwashing practices among school children. METHODS: The study was a cluster-randomised controlled trial, with schools constituting the clusters. At baseline, 717 pupils organised in four clusters were recruited. Techniques for data collection included a structured observation. The Student's t test was used for data analysis. RESULTS: At follow-up, a statistically significant difference was observed between the study arms with regard to intention to wash hands with soap [after toilet use (p = 0.032, d = 0.5); before meals (p = 0.020, d = 0.2)]. Similarly, a statistically significant difference was identified between the study arms with regard to the practice of handwashing with soap (HWWS) [after toilet use (p = 0.005); before meals (p = 0.012)]. CONCLUSIONS: A theory-driven hand hygiene educational intervention involving school children can have a medium to a very large effect size, with respect to the practice of HWWS, and a low to a medium effect size with respect to behavioural intention.

Insights into the Etiology of Mammalian Neural Tube Closure Defects from Developmental, Genetic and Evolutionary Studies.

The human neural tube defects (NTD), anencephaly, spina bifida and craniorachischisis, originate from a failure of the embryonic neural tube to close. Human NTD are relatively common and both complex and heterogeneous in genetic origin, but the genetic variants and developmental mechanisms are largely unknown. Here we review the numerous studies, mainly in mice, of normal neural tube closure, the mechanisms of failure caused by specific gene mutations, and the evolution of the vertebrate cranial neural tube and its genetic processes, seeking insights into the etiology of human NTD. We find evidence of many regions along the anterior⁻posterior axis each differing in some aspect of neural tube closure-morphology, cell behavior, specific genes required-and conclude that the etiology of NTD is likely to be partly specific to the anterior⁻posterior location of the defect and also genetically heterogeneous. We revisit the hypotheses explaining the excess of females among cranial NTD cases in mice and humans and new developments in understanding the role of the folate pathway in NTD. Finally, we demonstrate that evidence from mouse mutants strongly supports the search for digenic or oligogenic etiology in human NTD of all types.

Examining school-based hygiene facilities: a quantitative assessment in a Ghanaian municipality.

BACKGROUND: The crucial role of adequate water, sanitation and hygiene (WASH) facilities in influencing children's handwashing behaviour is widely reported. Report from UNICEF indicates a dearth of adequate data on WASH facilities in schools, especially in the developing world. This study sought to contribute to building the evidence-base on school hygiene facilities in Ghana. The study further explored for possible associations and differences between key variables within the context of school water, sanitation and hygiene. METHODS: Data was collected from 37 junior high schools using an observational checklist. Methods of data analysis included a Scalogram model, Fisher's exact test, and a Student's t-test. RESULTS: Results of the study showed a facility deficiency in many schools: 33% of schools had students washing their hands in a shared receptacle (bowl), 24% had students using a single cotton towel to dry hands after handwashing, and only 16% of schools had a functional water facility. Furthermore, results of a proportion test indicated that 83% of schools which had functional water facilities also had functional handwashing stations. On the other hand, only 3% of schools which had functional water facilities also had a functional handwashing stations. A test of difference in the proportions of the two sets of schools showed a statistically significant difference (p < 0.001). In addition, 40% of schools which had financial provisions for water supply also had functional handwashing stations. On the other hand, only 7% of schools which had financial provisions for water supply also had functional handwashing stations. There was a statistically significant difference in the proportions of the two sets of schools (p = 0.02). CONCLUSION: We conclude that it is essential to have a financial provision for water supply in schools as this can potentially influence the existence of a handwashing station in a school. An intervention by government, educational authorities and civil society organisations towards enabling schools in low resource areas to have a sustainable budgetary allocation for WASH facilities would be timely.

A framework for designing hand hygiene educational interventions in schools.

OBJECTIVES: Hygiene education appears to be the commonest school-based intervention for preventing infectious diseases, especially in the developing world. Nevertheless, there remains a gap in literature regarding a school-specific theory-based framework for designing a hand hygiene educational intervention in schools. We sought to suggest a framework underpinned by psychosocial theories towards bridging this knowledge gap. Furthermore, we sought to propound a more comprehensive definition of hand hygiene which could guide the conceptualisation of hand hygiene interventions in varied settings. METHODS: Literature search was guided by a standardized tool and literature was retrieved on the basis of a predetermined inclusion criteria. Databases consulted include PubMed, ERIC, and EBSCO host (Medline, CINAHL, PsycINFO, etc.). Evidence bordering on a theoretical framework to aid the design of school-based hand hygiene educational interventions is summarized narratively. RESULTS: School-based hand hygiene educational interventions seeking to positively influence behavioural outcomes could consider enhancing psychosocial variables including behavioural capacity, attitudes and subjective norms (normative beliefs and motivation to comply). CONCLUSIONS: A framework underpinned by formalized psychosocial theories has relevance and could enhance the design of hand hygiene educational interventions, especially in schools.

Development of a set of community-informed Ebola messages for Sierra Leone.

The West African Ebola epidemic of 2013-2016 was by far the largest outbreak of the disease on record. Sierra Leone suffered nearly half of the 28,646 reported cases. This paper presents a set of culturally contextualized Ebola messages that are based on the findings of qualitative interviews and focus group discussions conducted in 'hotspot' areas of rural Bombali District and urban Freetown in Sierra Leone, between January and March 2015. An iterative approach was taken in the message development process, whereby (i) data from formative research was subjected to thematic analysis to identify areas of community concern about Ebola and the national response; (ii) draft messages to address these concerns were produced; (iii) the messages were field tested; (iv) the messages were refined; and (v) a final set of messages on 14 topics was disseminated to relevant national and international stakeholders. Each message included details of its rationale, audience, dissemination channels, messengers, and associated operational issues that need to be taken into account. While developing the 14 messages, a set of recommendations emerged that could be adopted in future public health emergencies. These included the importance of embedding systematic, iterative qualitative research fully into the message development process; communication of the subsequent messages through a two-way dialogue with communities, using trusted messengers, and not only through a one-way, top-down communication process; provision of good, parallel operational services; and engagement with senior policy makers and managers as well as people in key operational positions to ensure national ownership of the messages, and to maximize the chance of their being utilised. The methodological approach that we used to develop our messages along with our suggested recommendations constitute a set of tools that could be incorporated into international and national public health emergency preparedness and response plans.

Epigenetic mechanism causes Wnt9b deficiency and nonsyndromic cleft lip and palate in the A/WySn mouse strain.

BACKGROUND: The heritable multifactorial etiology of human nonsyndromic cleft lip with or without cleft palate (CL ± P) is not understood. CL ± P occurs in 15% of neonates in the homozygous A/WySn mouse strain, with a multifactorial genetic etiology, the clf1 and clf2 variant genes. Clf1 acts as a mutant allele of Wnt9b but its coding sequence is normal. An IAP (intracisternal A particle) retrotransposon inserted near the Wnt9b gene is associated with clf1. METHODS: Transcription of noncoding sequence between the IAP and the Wnt9b gene was examined in A/WySn embryos. The levels of Wnt9b transcript and of an "IAP antisense" transcript initiated in the IAP and extending into the noncoding interval were assayed in A/WySn and C57BL/6J whole embryos or heads across embryonic days 8 to 12. Methylation of the 5' LTR of the IAP was examined in E12 A/WySn embryo heads. RESULTS: Mean Wnt9b transcript levels were lower in A/WySn than in C57BL/6J at all ages examined and lower in CL ± P embryos than in their normal littermates. The "IAP antisense" transcript was found in all A/WySn embryos and was highest in CL ± P embryos. The IAP at Wnt9b was generally unmethylated in CL ± P embryos and approximately 50% methylated in normal littermates. CONCLUSION: The clf1 mutation in A/WySn is a "metastable epiallele", in which stochastic deficiency in some individuals of DNA methylation of a retrotransposon uniquely inserted near the Wnt9b gene allows transcriptional activity of the retrotransposon and interference with transcription from Wnt9b. Methylation of metastable epialleles should be investigated in human nonsyndromic CL ± P.

A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects.

A variety of human birth defects originate in failure of closure of the embryonic neural tube. The genetic cause of the most common nonsyndromic defects, spina bifida (SB) or anencephaly, is considered to be combinations of variants at multiple genes. The genes contributing to the etiology of neural tube closure defects (NTDs) are unknown. Mutations in planar cell polarity (PCP) genes in mice cause a variety of defects including the NTD, craniorachischisis, and sometimes SB or exencephaly (EX); they also demonstrate the role of digenic combinations of PCP mutants in NTDs. Recent studies have sought rare predicted-to-be-deleterious alterations (putative mutations) in coding sequence of PCP genes in human cases with various anomalies of the neural tube. This review summarizes the cumulative results of these studies according to a framework based on the embryopathogenesis of NTDs, and considers some of the insights from the approaches used and the limitations. Rare putative mutations in the PCP genes VANGL2, SCRIB, DACT1, and CELSR1 cumulatively contributed to over 20% of cases with craniorachischisis, a rare defect; no contributing variants were found for PRICKLE1 or PTK7. PCP rare putative mutations had a weaker role in myelomeningocele (SB), being found in approximately 6% of cases and cumulated across CELSR1, FUZ, FZD6, PRICKLE1, VANGL1, and VANGL2. These results demonstrate that PCP gene alterations contribute to the etiology of human NTDs. We recommend that future research should explore other types of PCP gene variant such as regulatory mutations and low frequency (1 to 5%) deleterious polymorphisms.

Hypothesis: the female excess in cranial neural tube defects reflects an epigenetic drag of the inactivating X chromosome on the molecular mechanisms of neural fold elevation.

Females have long been known to be in excess among cranial neural tube defect (NTD) cases. Up to two thirds of human anencephalics and mouse exencephalics from various genetic causes are female, but the cause of this female excess is unknown. It appears not to be attributable to gonadal hormones, developmental delay in females, or preferential death of affected males. Recent studies of the Trp53 mouse mutant showed that exencephaly susceptibility depends on the presence of two X chromosomes, not the absence of the Y. Over a decade ago, we hypothesized that the relevant difference between female and male mammalian embryos at the time of cranial neural tube closure is the fact that females methylate most of the DNA in the large inactive X chromosome after every cell division, reducing the methylation available for other needs in female cells. Recently, the Whitelaw laboratory identified several proteins in mice (Momme D genes) involved in epigenetic silencing and methylation and shared in the silencing of transgenes, retrotransposons, and the inactive-X, and suggested that the inactive-X acts as a "sink" for epigenetic silencing proteins. The "inactive-X sink" hypothesis can be used to suggest expected changes in sex ratio in cranial NTDs in response to various genetic or environmental alterations. We recommend that observation of sex ratio become a standard component of all NTD studies. We suggest that the female excess among cranial NTDs is an epigenetic phenomenon whose molecular investigation will produce insight into the mechanisms underlying NTDs.

Why take an HIV test? Concerns, benefits, and strategies to promote HIV testing among low-income heterosexual African American young adults.

A qualitative study examined perceptions of HIV testing and strategies to enhance HIV testing among HIV-negative African American heterosexual young adults (ages 18-25 years). Twenty-six focus groups (13 male groups, 13 female groups) were conducted in two low-income communities (urban and rural). All sessions were audio-recorded and transcribed. Data analysis was completed using AnSWR software. Many participants expressed that learning one's HIV status, regardless of the result, was a benefit of taking an HIV test because this was perceived to produce emotional relief. Additional benefits included the avoidance of unknowingly spreading the virus, being offered treatment access if HIV-positive, and taking time to assess and modify risky sexual behaviors if HIV-negative. If diagnosed HIV-positive, HIV testing concerns included the recognition of one's mortality, the experience of social stigma, and concerns about accessing affordable treatment. Recommended promotion strategies included the use of HIV-positive individuals, pop culture icons, and the media to promote HIV testing messages.

The clf2 gene has an epigenetic role in the multifactorial etiology of cleft lip and palate in the A/WySn mouse strain.

BACKGROUND: The A/WySn mouse strain with 15 to 20% penetrance of cleft lip and palate (CLP) is an animal model for human multifactorial CLP. The CLP is due to two unlinked genes that interact epistatically, Wnt9b(clf1) and clf2, plus a maternal effect. The Wnt9b(clf1) mutation is an IAP transposon insertion. The clf2 gene, with unknown function, was located in a 13.6 Mb region of chromosome 13 containing 145 genes. METHODS: To reduce the clf2 candidate region, 1146 mice segregating for A/WySn and C57BL/6J alleles at clf2 were screened for recombinants by simple sequence-length polymorphism haplotypes; recombinants' testcross progeny were typed for CLP and simple-sequence length polymorphisms. To identify the function of clf2, the effect of clf2 genotype on risk of CLP was tested in Wnt9b(null/null) knockouts and in compound mutants (Wnt9b(clf1/null) ), and the methylation of the IAP at Wnt9b was assayed in the Wnt9b(clf1/null) mutants by combined bisulfite restriction analysis. RESULTS: The location of clf2 was redefined to 3.0 Mb between Cntnap3 and AK029746 containing 48 genes, of which 30 are Zfp genes. The clf2 genotype had no detectable effect on Wnt9b(null/null) embryos, but strongly affected risk of CLP and methylation of the IAP in Wnt9b(clf1/null) embryos. CLP was associated with low levels of methylation of the IAP. CONCLUSIONS: The clf2 gene is the first identified polymorphism that affects the epigenetic methylation and silencing of IAP retrotransposons. This CLP model raises the question of whether parallel epigenetic factors are involved in risk and environmental sensitivity of human CLP.

An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure.

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.

Insights into prevention of human neural tube defects by folic acid arising from consideration of mouse mutants.

Almost 30 years after the initial study by Richard W. Smithells and coworkers, it is still unknown how maternal periconceptional folic acid supplementation prevents human neural tube defects (NTDs). In this article, questions about human NTD prevention are considered in relation to three groups of mouse models: NTD mutants that respond to folate, NTD mutants and strains that do not respond to folate, and mutants involving folate-pathway genes. Of the 200 mouse NTD mutants, only a few have been tested with folate; half respond and half do not. Among responsive mutants, folic acid supplementation reduces exencephaly and/or spina bifida aperta frequency in the Sp(2H), Sp, Cd, Cited2, Cart1, and Gcn5 mutants. Prevention ranges from 35 to 85%. The responsive Sp(2H) (Pax3) mutant has abnormal folate metabolism, but the responsive Cited2 mutant does not. Neither folic nor folinic acid reduces NTD frequency in Axd, Grhl3, Fkbp8, Map3k4, or Nog mutants or in the curly tail or SELH/Bc strains. Spina bifida frequency is reduced in Axd by methionine and in curly tail by inositol. Exencephaly frequency is reduced in SELH/Bc by an alternative commercial ration. Mutations in folate-pathway genes do not cause NTDs, except for 30% exencephaly in folate-treated Folr1. Among folate-pathway mutants, neural tube closure is normal in Cbs, Folr2, Mthfd1, Mthfd2, Mthfr, and Shmt1 mutants. Embryos die by midgestation in Folr1, Mtr, Mtrr, and RFC1 mutants. The mouse models point to genetic heterogeneity in the ability to respond to folic acid and also to heterogeneity in genetic cause of NTDs that can be prevented by folic acid.

Accelerated embryonic development associated with increased risk of neural tube defects induced by maternal diet in offspring of SELH/Bc mice.

BACKGROUND: The SELH/Bc mouse strain has a high risk of the NTD, exencephaly, caused by multifactorial genetics. All SELH/Bc embryos have delayed elevation of neural folds; some never elevate (future exencephalics). Maternal diets affect SELH/Bc exencephaly rates: 25-35% on Purina Diet 5015 versus 5-10% on Purina Diet 5001. We hypothesized that in SELH/Bc, the diets affect maternal blood glucose and embryonic developmental rate. METHODS: We compared mice fed the two diets. On GD 9.4 we tested maternal blood glucose and examined embryos for developmental age (somite count) and cranial neural fold morphology. We observed GD 14 exencephaly rates. RESULTS: Diet 5015 caused fivefold more exencephaly (40 vs. 7% on GD 14), significantly higher mean maternal blood glucose in replicate experiments (6.3 vs. 5.5, p < .05; 6.3 vs. 5.3 mmol/L, p < .05), and significantly higher mean litter somite count on GD 9.4 (18.4 vs. 15.0, p < .05; 16.7 vs. 14.4 somites, p < .05). Among midrange embryos (15-16 somites), embryos from Diet 5015 were significantly shifted to earlier stages of midbrain fold morphology and had significantly more distance between the tips of the folds (p < .05). CONCLUSIONS: In SELH/Bc mice, the 5015 diet causes higher maternal blood glucose, a faster overall embryonic developmental rate during neural tube closure, and delayed midbrain fold elevation relative to overall development. This pattern suggests that maternal dietary effects that modestly increase embryonic growth rate may exacerbate a lack of coordination between genetically delayed neural folds and normally developing underlying tissues, increasing risk of NTD.

Mouse genetic models of cleft lip with or without cleft palate.

Nonsyndromic cleft lip and palate (CLP) is among the most common human birth defects. Transmission patterns suggest that the causes are "multifactorial" combinations of genetic and nongenetic factors, mostly distinct from those causing cleft secondary palate (CP). The major etiological factors are largely unknown, and the embryological mechanisms are not well understood. In contrast to CP or neural tube defects (NTD), CLP is uncommon in mouse mutants. Fourteen known mutants or strains express CLP, often as part of a severe syndrome, whereas nonsyndromic CLP is found in two conditional mutants and in two multifactorial models based on a hypomorphic variant with an epigenetic factor. This pattern suggests that human nonsyndromic CLP is likely caused by regulatory and hypomorphic gene variants, and may also involve epigenetics. The developmental pathogenic mechanism varies among mutants and includes deficiencies of growth of the medial, lateral or maxillary facial prominences, defects in the fusion process itself, and shifted midline position of the medial prominences. Several CLP mutants also have NTD, suggesting potential genetic overlap of the traits in humans. The mutants may reflect two interacting sets of genetic signaling pathways: Bmp4, Bmpr1a, Sp8, and Wnt9b may be in one set, and Tcfap2a and Sox11 may be in another. Combining the results of chromosomal linkage studies of unidentified human CLP genes with insights from the mouse models, the following previously unexamined genes are identified as strong candidate genes for causative roles in human nonsyndromic CLP: BMP4, BMPR1B, TFAP2A, SOX4, WNT9B, WNT3, and SP8.

Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects.

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.

Wnt9b is the mutated gene involved in multifactorial nonsyndromic cleft lip with or without cleft palate in A/WySn mice, as confirmed by a genetic complementation test.

BACKGROUND: Nonsyndromic cleft lip (CL) with or without cleft palate (CLP) is a common human birth defect with complex genetic etiology. One of the unidentified genes maps to chromosome 17q21. A mouse strain, A/WySn, has CLP with complex genetic etiology that models the human defect, and 1 of its causative genes, clf1, maps to a region homologous to human 17q21. Extensive studies of the candidate region pointed to a novel insertion of an IAP transposon 3' from the gene Wnt9b as the clf1 mutation. Independently a recessive knockout mutation of Wnt9b (Wnt9b-) was reported to cause a lethal syndrome that includes some CLP. METHODS: A standard genetic test of allelism between clf1 and the Wnt9b- mutation was done. A total of 83 F1 embryos at gestation day 14 (GD 14) from Wnt9b-/+ males crossed with A/WySn females, and 79 BC1 GD 14 embryos from F1 Wnt9b-/clf1 males back-crossed to A/WySn females were observed for CL. Embryo genotypes at clf1 and Wnt9b were obtained from DNA markers. Genotypes for a second unlinked modifier locus from A/WySn, clf2, were similarly obtained. RESULTS: The compound mutant embryos (Wnt9b-/clf1) had high frequencies of CL: 27% in the F1 and 63% in the BC1. The clf2 modifier gene was found to have 3 alleles segregating in this study and to strongly influence the penetrance of CL in the compound mutant. CONCLUSIONS: The noncomplementation of clf1 and Wnt9b- confirms that clf1 is a mutation of the Wnt9b gene. The homologous human WNT9B gene and 3' conserved noncoding region should be examined for a role in human nonsyndromic CLP.