RESUMEN

The South African government recognises the value of traditional healing and supports an integrated healthcare system. In the veterinary field, successful integration depends on the perceptions of different animal healthcare practitioners (AHCPs). This study aimed to determine the perceptions of ethnoveterinary medicine among state-employed veterinarians and animal health technicians in the North West province. A mixed model questionnaire and non-probability sampling gathered quantitative and qualitative data from 53 participants. Statistical and thematic analysis processes were applied to quantitative and qualitative data, respectively. Overall, 77.4% of participants were aware of ethnoveterinary medicine practices. Approval of the use of ethnoveterinary medicine by farmers was above-average at a mean of 3.57, standard deviation (s.d.) = 1.016 on a 5-point Likert scale. However, 65.9% doubted the effectiveness of ethnoveterinary medicine, which suggests tolerance but no appreciation of its value. The Chi-square test revealed a significant relationship between district municipality of employment and awareness at χ2 = 17.490, df = 3, p = 0.001. Thematic analysis of comments showed that some participants perceived ethnoveterinary medicine as unscientific and interfering with Western veterinary medicine, while some considered it a good complement to Western veterinary medicine. The study also found that 20.8% of AHCPs use ethnoveterinary medicine to treat certain diseases. In conclusion, the lack of appreciation for ethnoveterinary medicine among AHCPs may hinder government-proposed integration, emphasising the need for programmes to improve perceptions among these stakeholders.Contribution: This is first such study to report on perceptions of ethnoveterinary medicine among AHCPs, and assess their readiness for an integrated animal health system.

Asunto(s)

RESUMEN

BACKGROUND: Pests and diseases are a major contributor to yield losses in sub-Saharan Africa, prompting smallholder farmers to seek cost-effective, accessible and ecologically friendly alternatives for crop protection. This study explored the management of pests and diseases affecting crops across eight selected villages in Ehlanzeni District, Mpumalanga Province, South Africa. METHODS: A total of 120 smallholder farmers were purposefully selected utilising the snowball technique. Information on the management of plant pests and diseases was collected through interviews and focus group discussions using semi-structured interview schedules. Ethnobotanical indices, including relative frequency of citation (RFC), use-value (UV) and informant consensus factor (Fic), were used to quantify and rank the plants used for crop protection in the study area. RESULTS: Twenty-three plant species (16 naturalised exotics and seven indigenous plants) belonging to 16 families were used for managing pests (vertebrates and invertebrates) and diseases (fungal and bacterial related) affecting crops in the study area. The dominant (100%) crops cultivated by the participants were Allium cepa L., Mangifera indica L., Solanum lycopersicum L. and Zea mays L. The RFC value ranged from 0.08 to 0.83 and the three most popular plants for crop protection were Capsium annuum L. (0.83), A. cepa (0.63) and Dichrostachys cinerea (L.) Wight & Arn. (0.43). In terms of the UV, the five most promising plants used as biocontrol were Tulbaghia violacea (0.13), A. cepa (0.12), C. annuum L. (0.09), Solanum campylacanthum Hochst. Ex A.Rich.(0.09) and Pinus pinaster (0.08). Based on the Fic, four categories were established and dominated by fungal diseases (0.64). Furthermore, T. violacea and A. cepa were the most often mentioned plants used against fungal conditions. Other categories cited were bacterial diseases (0.3), invertebrate pests (0.11) and vertebrate pests (0.14), an indication that smallholder farmers had limited agreement or common knowledge about the plants used for their management. The preparation methods included maceration (38%), decoction (38%) and burning (24%). Foliar application (67%) and soil drenching (33%) were used for administering plant extracts during the management of crop pests and diseases. CONCLUSION: The study highlights the importance of botanicals and associated indigenous knowledge among smallholder farmers in Mpumalanga Province, South Africa. It is pertinent to explore the valorisation of these botanicals by generating empirical data on their biological efficacies and phytochemical profiles.

Asunto(s)

RESUMEN

Introduction/background: Bladder exstrophy epispadias complex (BEEC) is a rare congenital anomaly of unknown etiology, although, genetic and environmental factors have been associated with its development. Variants in several genes expressed in the urogenital pathway have been reported as causative for bladder exstrophy in human and murine models. The expansion of next-generation sequencing and molecular genomics has improved our ability to identify the underlying genetic causes of similarly complex diseases and could thus assist with the investigation of the molecular basis of BEEC. Objective: The objective was to identify the presence of rare heterozygous variants in genes previously implicated in bladder exstrophy and correlate them with the presence or absence of bladder regeneration in our study population. Patients and Methods: We present a case series of 12 patients with BEEC who had bladder biopsies performed by pediatric urology during bladder neck reconstruction or bladder augmentation. Cases were classified as "sufficient" or "insufficient" (n = 5 and 7, respectively) based on a bladder volume of greater than or less than 40% of expected bladder size. Control bladder tissue specimens were obtained from patients (n = 6) undergoing biopsies for conditions other than bladder exstrophy. Whole exome sequencing was performed on DNA isolated from the bladder specimens. Based on the hypothesis of de novo mutations, as well as the potential implications of autosomal dominant conditions with incomplete penetrance, each case was evaluated for autosomal dominant variants in a set of genes previously implicated in BEEC. Results: Our review of the literature identified 44 genes that have been implicated in human models of bladder exstrophy. Our whole exome sequencing data analysis identified rare variants in two of these genes among the cases classified as sufficient, and seven variants in five of these genes among the cases classified as insufficient. Conclusion: We identified rare variants in seven previously implicated genes in our BEEC specimens. Additional research is needed to further understand the cellular signaling underlying this potentially genetically heterogeneous embryological condition.

RESUMEN

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

Asunto(s)

RESUMEN

BACKGROUND: In light of the rising global effort to lower maternal mortality rates, it is crucial for low- and middle-income countries with poor maternal indices to investigate the problem of maternal satisfaction and the key elements that affect it. To this effect, this study explored the experiences of postnatal women in relation to labour services and investigated the factors that contribute to their overall satisfaction. AIM: The study set out to explore factors influencing maternal satisfaction with labour care services in Ogbomoso, Oyo State, Nigeria. This study ultimately seeks to advance our understanding of this phenomenon to impact labour care and policy. SETTING: The study was conducted among multiparous women who had their antenatal care and delivery in Ogbomoso, Oyo State, Nigeria. METHODS: A qualitative study was performed using in-depth interviews among postnatal women. RESULTS: The results revealed a number of variables that could affect the women's satisfaction with labour care, including the choice of health facility, healthcare providers, environment of the facility, assurance of privacy, treating patients with dignity, provision of needed amenities and having a well-planned postnatal care assessment. CONCLUSION: The study revealed that the costs of care, the skill of the caregiver, the provision of confidential and dignified care, and the availability of supplies all have an impact on maternal satisfaction. Hospital administration should address these issues to enhance the experience of women and labour care services.Contribution: The study's findings provide insights that will inform strategies to improve the quality of care being provided to parturients in Nigeria.

Asunto(s)

RESUMEN

The cranial vault in humans is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conduct a joint multi-ancestry and admixed multivariate genome-wide association study on 3D cranial vault shape extracted from magnetic resonance images of 6772 children from the ABCD study cohort yielding 30 genome-wide significant loci. Follow-up analyses indicate that these loci overlap with genomic risk loci for sagittal craniosynostosis, show elevated activity cranial neural crest cells, are enriched for processes related to skeletal development, and are shared with the face and brain. We present supporting evidence of regional localization for several of the identified genes based on expression patterns in the cranial vault bones of E15.5 mice. Overall, our study provides a comprehensive overview of the genetics underlying normal-range cranial vault shape and its relevance for understanding modern human craniofacial diversity and the etiology of congenital malformations.

Asunto(s)

RESUMEN

We describe a case of neurosarcoidosis in a 64-year-old female who presented with proptosis and orbital inflammation together with bilateral lower extremity neuropathy and longitudinally extensive transverse myelitis. These two entities are not commonly associated, and the etiology of the transverse myelitis was facilitated by an orbital biopsy. The transverse myelitis caused numbness in her lower extremities and tightness in her chest and abdomen, which progressed over weeks to difficulty walking and bilateral neuromuscular weakness. Magnetic resonance imaging (MRI) revealed longitudinally extensive transverse myelitis in the cervical and thoracic spine. Computed tomography (CT) imaging of the chest revealed right hilar and mediastinal lymphadenopathy and calcified subcarinal nodes. Positron emission tomography (PET) scan revealed hypermetabolism in the mediastinum and medial left orbit. Orbital biopsy revealed non-necrotizing granulomatous inflammation suggestive of sarcoidosis. The neurologic deficits and orbital inflammation responded well to intravenous corticosteroids. Neurosarcoidosis can present with unusual clinical manifestations, as evidenced by this patient.

RESUMEN

The purpose of this data article is to report the quantum mechanical analysis by generalized gradient approximation (GGA) exchange-correlation functional using density functional theory (DFT). The predictions were based on the elastic constants and mechanical properties of stoichiometric hydroxyapatite (HAp) crystal. The elastic stiffness constants in hexagonal symmetry were obtained by fitting the Hookes' law for the energy-strain and stress-stain relations. Some of the theoretical datasets were compared to measured mechanical properties of produced HAp pellets obtained through micro and nanoindentation experiments. The datasets show considerable anisotropy in the stress-strain behaviour and are discussed in the context of the mechanical properties of HAp which are useful for tissue engineering. We also provide a pedagogical snapshot on the use of the datasets herein to teach and interpret DFT based atomistic simulations in a typical blended online teaching set-up for engineering students using a new pedagogy, CACPLA (Communicate, Active, Collaborate, Practice, Learning and Assessment).

RESUMEN

Background: The disease burden of gestational diabetes mellitus (GDM) in sub-Saharan African region have been on the rise. Proper assessment of current prevalence of GDM may inform policy changes and management approach for improved care delivery. Objective: To determine the current prevalence of Gestational Diabetes Mellitus (GDM) and evaluate its major risk factors amongst pregnant women in Makurdi, North-Central Nigeria. Method: This was a multi-center hospital-based prospective observational study. Maternal characteristics and clinical risk factors for GDM in a cohort of 281 pregnant women at 9 to 16 weeks gestational age was evaluated. The one-step 75g oral glucose tolerance test (OGTT) was carried out at 24 to 28 weeks of gestation. Result: Of the 356 women recruited, 281 (79.8%) completed the study. The GDM prevalence in the cohort was 16.7%. Increased early pregnancy BMI (adjusted OR = 1.154, 95% CI = 1.080 - 1.233, p<0.001) and presence of family history of diabetes mellitus (adjusted OR = 0.482, 95% CI = 0.233 - 0.997, P<0.05) were independent risk factors for GDM in the cohort. Conclusion: Increasing maternal age and early pregnancy BMI amongst other possible reasons, may account for the rising prevalence of GDM in the region.

Asunto(s)

RESUMEN

Osteoporosis is the most prevalent bone condition in the ageing population. This systemic disease is characterized by microarchitectural deterioration of bone, leading to increased fracture risk. In the past 15 years, genome-wide association studies (GWAS), have pinpointed hundreds of loci associated with bone mineral density (BMD), helping elucidate the underlying molecular mechanisms and genetic architecture of fracture risk. However, the challenge remains in pinpointing causative genes driving GWAS signals as a pivotal step to drawing the translational therapeutic roadmap. Recently, a skull BMD-GWAS uncovered an intriguing intersection with craniosynostosis, a congenital anomaly due to premature suture fusion in the skull. Here, we recapitulate the genetic contribution to both osteoporosis and craniosynostosis, describing the biological underpinnings of this overlap and using zebrafish models to leverage the functional investigation of genes associated with skull development and systemic skeletal homeostasis.

Asunto(s)

RESUMEN

Ulnar-mammary syndrome (UMS) is a rare, autosomal dominant disorder characterized by anomalies affecting the limbs, apocrine glands, dentition, and genital development. This syndrome is caused by haploinsufficiency in the T-Box3 gene (TBX3), with considerable variability in the clinical phenotype being observed even within families. We describe a one-year-old female with unilateral, postaxial polydactyly, and bilateral fifth fingernail duplication. Next-generation sequencing revealed a novel, likely pathogenic, variant predicted to affect the canonical splice site in intron 3 of the TBX3 gene (c.804 + 1G > A, IVS3 + 1G > A). This variant was inherited from the proband's father who was also diagnosed with UMS with the additional clinical finding of congenital, sagittal craniosynostosis. Subsequent whole genome analysis in the proband's father detected a variant in the EFNA4 gene (c.178C > T, p.His60Tyr), which has only been reported to be associated with sagittal craniosynostosis in one patient prior to this report but reported in other cranial suture synostosis. The findings in this family extend the genotypic spectrum of UMS, as well as the phenotypic spectrum of EFNA4-related craniosynostosis.

Asunto(s)

RESUMEN

There has been a steady rise in the disease burden of Gestational Diabetes Mellitus (GDM) in the sub-Saharan African region over time. Diagnostic testing for GDM is currently recommended at 24 - 28 weeks of gestation, leaving a narrow window for intervention before delivery. Hence the need for early prediction and preventive intervention. The performance of first trimester serum sex hormone-binding globulin (SHBG) assay as a predictor of GDM was determined by binary logistic regression. Women with GDM (n = 49) had a significantly lower mean first trimester SHBG level (104.7 ± 61.6 nmol/L) than did those without GDM (n = 180; 265.2 ± 141.5 nmol/L; p < .001). First trimester SHBG was significantly negatively correlated (rpb = -0.460, p value = <.001) with subsequent development of GDM and an area under receiver operator characteristics (ROC) curve of 0.874 (p < .001). A cut-off value of 158.0 nmol/L predictive of GDM had a diagnostic sensitivity of 81.5%, a specificity of 80.1%, and an overall diagnostic efficiency of 80.3%.IMPACT STATEMENTWhat is already known on this subject? GDM is associated with high risk of various complications and is commonly diagnosed at 24-28 weeks of gestation, leaving a narrow window for intervention. The performance of current maternal clinical and demographic risk factor-based prediction approaches is unreliable. Thus, more favourable prediction approaches need to be developed. Previous studies have suggested that SHBG, a readily assessable marker, has potential to predict GDM; however, these studies have mostly involved Caucasian and other non-African populations.What the results of this study add? SHBG may serve as a reliable first trimester screening tool for GDM development in Nigerian women with singleton pregnancies. This study demonstrates that first trimester SHBG can predict GDM development in sub-Saharan African women despite racial, ethnic and geographical differences.What are the implications of these findings for clinical practice and/or further research? Effective first trimester prediction of GDM using SHBG may enable preventive interventions, thereby mitigating the high burden of the disease in the sub-Saharan African region. It may also provide relevant information that may guide adaptation of current management guidelines to ensure effective management of GDM in the region.

Asunto(s)

RESUMEN

Craniosynostosis (CS) is a major birth defect in which one or more skull sutures fuse prematurely. We previously performed a genome-wide association study (GWAS) for sagittal non-syndromic CS (sNCS), identifying associations downstream from BMP2 on 20p12.3 and intronic to BBS9 on 7p14.3; analyses of imputed variants in DLG1 on 3q29 were also genome-wide significant. We followed this work with a GWAS for metopic non-syndromic NCS (mNCS), discovering a significant association intronic to BMP7 on 20q13.31. In the current study, we sequenced the associated regions on 3q29, 7p14.3, and 20p12.3, including two candidate genes (BMP2 and BMPER) near some of these regions in 83 sNCS child-parent trios, and sequenced regions on 7p14.3 and 20q13.2-q13.32 in 80 mNCS child-parent trios. These child-parent trios were selected from the original GWAS cohorts if the probands carried at least one copy of the top associated GWAS variant (rs1884302 C allele for sNCS; rs6127972 T allele for mNCS). Many of the variants sequenced in these targeted regions are strongly predicted to be within binding sites for transcription factors involved in craniofacial development or bone morphogenesis. Variants enriched in more than one trio and predicted to be damaging to gene function are prioritized for functional studies.

Asunto(s)

RESUMEN

SEC24 is mainly involved in cargo sorting during COPII vesicle assembly. There are four SEC24 paralogs (A-D) in vertebrates, which are classified into two subgroups (SEC24A/B and SEC24C/D). Pathological mutations in SEC24D cause osteogenesis imperfecta with craniofacial dysplasia in humans. sec24d mutant fish also recapitulate the phenotypes. Consistent with the skeletal phenotypes, the secretion of collagen was severely defective in mutant fish, emphasizing the importance of SEC24D in collagen secretion. However, SEC24D patient-derived fibroblasts show only a mild secretion phenotype, suggesting tissue-specificity in the secretion process. Using Sec24d KO mice and cultured cells, we show that SEC24A and SEC24B also contribute to endoplasmic reticulum (ER) export of procollagen. In contrast, fibronectin 1 requires either SEC24C or SEC24D for ER export. On the basis of our results, we propose that procollagen interacts with multiple SEC24 paralogs for efficient export from the ER, and that this is the basis for tissue-specific phenotypes resulting from SEC24 paralog deficiency.

Asunto(s)

RESUMEN

OBJECTIVE: Systemic hypertension remains an important risk factors for cardiovascular diseases and a major global public health problem. Left ventricular hypertrophy (LVH) is a recognized complication of hypertension and strongly predicts cardiovascular morbidity and mortality. In Nigeria, few studies evaluated the role of echocardiography in the diagnosis of LVHs among hypertensives. This study sets out to determine the prevalence of LVH among hypertensives as determined by echocardiography.MATERIAL AND METHODS: One hundred and seventy-eight hypertensives and eighty-nine age and sex-matched controls were recruited consecutively into the study. They all had echocardiography done to determine which among had LVH. The partition value for LVH for hypertensives was determined using the 97th percentile of the left ventricular mass for controls as a cutoff point. RESULTS:Echocardiographic determined the prevalence of LVH among hypertensives was 32.4%.CONCLUSION:The echocardiographic prevalence of LVH was 32.4% in the study population. This is a significant proportion among the study population considering the clinical impact of LVH among patients with hypertension.

Asunto(s)

RESUMEN

Background: Asthma accounts for 1 out of every 250 deaths worldwide. Many of these deaths are preventable as they occur as a result of suboptimal long-term medical care and delay in seeking help during severe exacerbation. It is believed that increased concentrations of dust, high winds, low temperatures, and low humidity may cause exacerbation of asthma. Objective: The aim of this study is to assess seasonal variation in asthma exacerbation among patients attending Usmanu Danfodiyo University Teaching Hospital, Sokoto. Materials and Methods: Eighty-seven patients aged 16 years and above with physician-diagnosed asthma were selected by systematic random sampling. Clinical information was obtained from each participant about history of asthma exacerbation and health-care utilization. Meteorological data were obtained from the Nigerian Meteorological Agency corresponding to period of patient's recruitment. Results: Eighty-seven patients comprising 60 females and 27 males aged 32.1 ± 10.8 years participated in the study. Among the study participants, 50.6%, 28.7%, and 20.7% had exacerbation during harmattan, rainy, and dry (hot) seasons, respectively. Correlation analysis shows a significant negative relationship between temperature and asthma exacerbation (r = -0.372, P < 0.01). Conclusion: This study shows that asthma exacerbation is most frequent during the harmattan season and low temperature is associated with its exacerbation.

RésuméContexte: L'asthme est responsable de 1 décès sur 250 dans le monde. Beaucoup de ces décès sont évitables car ils surviennent à la suite de soins médicaux à long terme sous-optimaux et retard dans la recherche d'aide en cas d'exacerbation grave. On pense que l'augmentation des concentrations de poussière, les vents, les basses températures et une faible humidité peuvent provoquer une exacerbation de l'asthme. Objectif: Le but de cette étude est d'évaluer la variation saisonnière exacerbation de l'asthme chez les patients fréquentant l'hôpital universitaire Usmanu Danfodiyo, Sokoto. Matériel et méthodes: quatre-vingt-sept les patients âgés de 16 ans et plus souffrant d'asthme diagnostiqué par un médecin ont été sélectionnés par échantillonnage aléatoire systématique. L'information clinique était obtenu de chaque participant sur les antécédents d'exacerbation de l'asthme et l'utilisation des soins de santé. Les données météorologiques ont été obtenues à partir du Agence météorologique nigériane correspondant à la période de recrutement des patients. Résultats: quatre-vingt-sept patients dont 60 femmes et 27 hommes âgés de 32,1 ± 10,8 ans ont participé à l'étude. Parmi les participants à l'étude, 50,6%, 28,7% et 20,7% ont eu une exacerbation pendant les saisons harmattan, pluvieuse et sèche (chaude), respectivement. L'analyse de corrélation montre une relation négative significative entre la température et exacerbation de l'asthme (r = −0,372, p <0,01). Conclusion: Cette étude montre que l'exacerbation de l'asthme est la plus fréquente pendant l'harmattan la saison et les basses températures sont associées à son exacerbation. Mots-clés: asthme, exacerbation, saison.

Asunto(s)

RESUMEN

PURPOSE: Nonsyndromic craniosynostosis (NCS), the premature fusion of cranial sutures, results in an abnormal skull shape and is associated with a significant morbidity. Proteomics is a promising tool for disease characterization and biomarker discovery; we aimed to identify biologically relevant differentially expressed proteins for NCS. EXPERIMENTAL DESIGN: Label-based quantitative proteomic profiling using TMT was performed on protein extracted from mesenchymal stem cells, osteoblasts and bone tissue of five open and five fused sutures of sagittal NCS (sNCS) and analyzed using quantitative LC-MS/MS based bottom-up proteomics. Differential protein abundance between open and fused sutures was determined to identify biologically relevant proteins of interest. Proteins were validated in an independent sample set by western blot and immunohistochemistry. RESULTS: We observed 838 differentially expressed proteins between open and fused sutures of sNCS. Decorin, lumican, and asporin were significantly downregulated while COL4A1 and TGFß1|1 were upregulated in fused compared to open sutures. CONCLUSIONS AND CLINICAL RELEVANCE: The majority of significantly differentially expressed proteins between open and fused sutures were observed in the proteomes of osteoblasts suggesting that protein changes contributing to premature sagittal suture fusion occur predominantly at the osteoblast level. Our findings suggest a possible ineffective ECM deposition at the osteoblast cell stage.

Asunto(s)

RESUMEN

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RESUMEN

PURPOSE: Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. METHODS: We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. RESULTS: We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10-7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. CONCLUSION: Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.

Asunto(s)

RESUMEN

Craniosynostosis (CS), the premature fusion of one or more cranial sutures, is a relatively common congenital anomaly, occurring in 3-5 per 10,000 live births. Nonsyndromic CS (NCS) accounts for up to 80% of all CS cases, yet the genetic factors contributing to the disorder remain largely unknown. The RUNX2 gene, encoding a transcription factor critical for bone and skull development, is a well known CS candidate gene, as copy number variations of this gene locus have been found in patients with syndromic craniosynostosis. In the present study, we aimed to characterize RUNX2 to better understand its role in the genetic etiology and in the molecular mechanisms underlying midline suture ossification in NCS. We report four nonsynonymous variants, one intronic variant and one 18 bp in-frame deletion in RUNX2 not found in our study control population. Significant difference in allele frequency (AF) for the deletion variant RUNX2 p.Ala84-Ala89del (ClinVar 257,095; dbSNP rs11498192) was observed in our sagittal NCS cohort when compared to the general population (P = 1.28 × 10-6), suggesting a possible role in the etiology of NCS. Dual-luciferase assays showed that three of four tested RUNX2 variants conferred a gain-of-function effect on RUNX2, further suggesting their putative pathogenicity in the tested NCS cases. Downregulation of RUNX2 expression was observed in prematurely ossified midline sutures. Metopic sites showed significant downregulation of promoter 1-specific isoforms compared to sagittal sites. Suture-derived mesenchymal stromal cells showed an increased expression of RUNX2 over matched unfused suture derived cells. This demonstrates that RUNX2, and particularly the distal promoter 1-isoform group, are overexpressed in the osteogenic precursors within the pathological suture sites.

Asunto(s)