MafB-dependent neurotransmitter signaling promotes ß cell migration in the developing pancreas.

Hormone secretion from pancreatic islets is essential for glucose homeostasis, and loss or dysfunction of islet cells is a hallmark of type 2 diabetes. Maf transcription factors are crucial for establishing and maintaining adult endocrine cell function. However, during pancreas development, MafB is not only expressed in insulin- and glucagon-producing cells, but also in Neurog3+ endocrine progenitor cells, suggesting additional functions in cell differentiation and islet formation. Here, we report that MafB deficiency impairs ß cell clustering and islet formation, but also coincides with loss of neurotransmitter and axon guidance receptor gene expression. Moreover, the observed loss of nicotinic receptor gene expression in human and mouse ß cells implied that signaling through these receptors contributes to islet cell migration/formation. Inhibition of nicotinic receptor activity resulted in reduced ß cell migration towards autonomic nerves and impaired ß cell clustering. These findings highlight a novel function of MafB in controlling neuronal-directed signaling events required for islet formation.

Aryl Hydrocarbon Receptor Controls Monocyte Differentiation into Dendritic Cells versus Macrophages.

After entering tissues, monocytes differentiate into cells that share functional features with either macrophages or dendritic cells (DCs). How monocyte fate is directed toward monocyte-derived macrophages (mo-Macs) or monocyte-derived DCs (mo-DCs) and which transcription factors control these differentiation pathways remains unknown. Using an in vitro culture model yielding human mo-DCs and mo-Macs closely resembling those found in vivo in ascites, we show that IRF4 and MAFB were critical regulators of monocyte differentiation into mo-DCs and mo-Macs, respectively. Activation of the aryl hydrocarbon receptor (AHR) promoted mo-DC differentiation through the induction of BLIMP-1, while impairing differentiation into mo-Macs. AhR deficiency also impaired the in vivo differentiation of mouse mo-DCs. Finally, AHR activation correlated with mo-DC infiltration in leprosy lesions. These results establish that mo-DCs and mo-Macs are controlled by distinct transcription factors and show that AHR acts as a molecular switch for monocyte fate specification in response to micro-environmental factors.

Polymorphic Toxins and Their Immunity Proteins: Diversity, Evolution, and Mechanisms of Delivery.

All bacteria must compete for growth niches and other limited environmental resources. These existential battles are waged at several levels, but one common strategy entails the transfer of growth-inhibitory protein toxins between competing cells. These antibacterial effectors are invariably encoded with immunity proteins that protect cells from intoxication by neighboring siblings. Several effector classes have been described, each designed to breach the cell envelope of target bacteria. Although effector architectures and export pathways tend to be clade specific, phylogenetically distant species often deploy closely related toxin domains. Thus, diverse competition systems are linked through a common reservoir of toxin-immunity pairs that is shared via horizontal gene transfer. These toxin-immunity protein pairs are extraordinarily diverse in sequence, and this polymorphism underpins an important mechanism of self/nonself discrimination in bacteria. This review focuses on the structures, functions, and delivery mechanisms of polymorphic toxin effectors that mediate bacterial competition.

Macrophage re-programming by JAK inhibitors relies on MAFB.

Monocyte-derived macrophages play a key pathogenic role in inflammatory diseases. In the case of rheumatoid arthritis (RA), the presence of specific synovial tissue-infiltrating macrophage subsets is associated with either active disease or inflammation resolution. JAK inhibitors (JAKi) are the first targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) approved for treatment of RA with comparable efficacy to biologics. However, the effects of JAKi on macrophage specification and differentiation are currently unknown. We have analyzed the transcriptional and functional effects of JAKi on human peripheral blood monocyte subsets from RA patients and on the differentiation of monocyte-derived macrophages promoted by granulocyte-macrophage colony-stimulating factor (GM-CSF), a factor that drives the development and pathogenesis of RA. We now report that JAKi Upadacitinib restores the balance of peripheral blood monocyte subsets in RA patients and skewed macrophages towards the acquisition of an anti-inflammatory transcriptional and functional profile in a dose-dependent manner. Upadacitinib-treated macrophages showed a strong positive enrichment of the genes that define synovial macrophages associated to homeostasis/inflammation resolution. Specifically, Upadacitinib-treated macrophages exhibited significantly elevated expression of MAFB and MAFB-regulated genes, elevated inhibitory phosphorylation of GSK3ß, and higher phagocytic activity and showed an anti-inflammatory cytokine profile upon activation by pathogenic stimuli. These outcomes were also shared by macrophages exposed to other JAKi (baricitinib, tofacitinib), but not in the presence of the TYK2 inhibitor deucravacitinib. As a whole, our results indicate that JAKi promote macrophage re-programming towards the acquisition of a more anti-inflammatory/pro-resolution profile, an effect that correlates with the ability of JAKi to enhance MAFB expression.

Mafba and Mafbb regulate microglial colonization of zebrafish brain via controlling chemotaxis receptor expression.

Microglia are the central nervous system (CNS)-resident macrophages involved in neural inflammation, neurogenesis, and neural activity regulation. Previous studies have shown that naturally occurring neuronal apoptosis plays a critical role in regulating microglial colonization of the brain in zebrafish. However, the molecular signaling cascades underlying neuronal apoptosis-mediated microglial colonization and the regulation of these cascades remain undefined. Here, we show that basic leucine zipper (b-Zip) transcription factors, Mafba and Mafbb, two zebrafish orthologs of mammalian MAFB, are key regulators in neuronal apoptosis-mediated microglial colonization of the brain in zebrafish. We document that the loss of Mafba and Mafbb function perturbs microglial colonization of the brain. We further demonstrate that Mafba and Mafbb act cell-autonomously and cooperatively to orchestrate microglial colonization, at least in part, by regulating the expression of G protein-coupled receptor 34a (Gpr34a), which directs peripheral macrophage recruitment into the brain through sensing the lysophosphatidylserine (lysoPS) released by the apoptotic neurons. Our study reveals that Mafba and Mafbb regulate neuronal apoptosis-mediated microglial colonization of the brain in zebrafish via the lysoPS-Gpr34a pathway.

The cardiac neural crest gene MafB ectopically directs CXCR4 expression in the trunk neural crest.

The cardiac neural crest is a subpopulation of cells arising from the caudal hindbrain. The delaminated cardiac neural crest cells migrate to the heart using the CXCR/SDF1 chemokine signaling system. These cells contribute to the formation of the cardiovascular system, including the septation of the outflow tract, which is unique to these cells. Here, we investigated the effect of ectopic expression of the cardiac neural crest gene MafB on trunk neural crest cells. First, we found that MafB has the potential to activate its own cis-regulatory element in enteric and trunk neural crest cells but not in cranial neural crest cells. Forced expression of two cardiac neural crest genes, Ets1 and Sox8, together with or without MafB, induced ectopic Sox10E2 enhancer activity in the trunk region. Finally, we uncovered that the expression of MafB, Ets1 and Sox8 can induce ectopic CXCR4 expression in the trunk neural crest cells, resulting in acquisition of responsiveness to the SDF1 signal. These results demonstrate that MafB, Ets1 and Sox8 are critical components for generation of the identity of the cardiac neural crest, especially the cell migration property.

A case report of multicentric carpotarsal osteolysis syndrome: Depiction of a debilitating disease course.

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by progressive osteolysis involving the carpal and tarsal bones, and often associated with nephropathy. It is caused by heterozygous mutation in the MAF bZIP transcription factor B (MAFB) gene. Heterogeneous clinical manifestation and wide spectrum of disease severity have been observed in patients with MCTO. Here, we report a case of a male patient who presented with kidney failure in childhood with progressive disabling skeletal deformity. He was diagnosed with MCTO at 31-years-old, where a de novo pathogenic heterozygous variant in NM_005461.5:c.212C>A: p.(Pro71His) of the MAFB gene was identified. While there has been little data on the long-term prognosis and life expectancy of this disease, this case report sheds light on the debilitating disease course with multiple significant morbidities of a patient with MCTO throughout his lifetime of 33 years.

Developmental regulation of the male urogenital papilla in the male marine teleost black rockfish, Sebastes schlegelii (Hilgendorf, 1880)†.

The male external genitalia of the black rockfish (Sebastes schlegelii Hilgendorf, 1880) is a fleshy protrusion known as the urogenital papilla (UGP), which functions to deliver sperm into the female reproductive tract for internal fertilization. It is not known which genes regulate the development of the UGP. The aim of this study was to identify key genes that regulate the development of the UGP in black rockfish and to determine the distribution of androgen receptor gene (ar) in the UGP. A total of 26 adult males and 560 juvenile fish were used in the experiment, in which we divided all normally developing juveniles into normal development and androgen groups. We added methyltestosterone solution (100 µg/l) to the androgen group-treated fish tank, soaked for 2 h per day for 38 days, and sampled 5~10 samples each time every 5 days during the culture process. Gene expression changes related to UGP were analyzed with tissue specificity between control and androgen groups during sex differentiation, adult male maturation, and the copulation stage (September to December) using real-time quantitative polymerase chain reaction. The expression of ar was also localized by two-color in situ hybridization in the UGP region of juvenile fish. Androgen treatment enhanced ar expression levels and the ar signal was stronger in the UGP region of both adult breeding fish and androgen-treated juvenile fish. This study provides insights into the regulation of the external genitalia of black rockfish and presents vital information for the artificial breeding of viviparous fish.

MAFB promotes the malignant phenotypes by IGFBP6 in esophageal squamous cell carcinomas.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant diseases in the world. Although the somatic alterations have been fully identified, there are still no targeted drugs at present. Our previous studies revealed that loss of grand H3K27me3 domains mediated transcriptional activation of a series of genes in ESCC. Among them, we focus on the investigation of MAFB, as its high expression is associated with a poor prognosis in ESCC. Functional assays show that knockdown of MAFB significantly suppresses cell growth, migration and invasion. Mechanistic investigation demonstrates that MAFB exerts its function by upregulating IGFBP6. Our findings suggest that MAFB may play a tumor-promoting role and may act as a potential therapeutic target for ESCC.

Multicentric Carpotarsal Osteolysis: a Contemporary Perspective on the Unique Skeletal Phenotype.

PURPOSE OF REVIEW: Multicentric carpotarsal osteolysis (MCTO) is an ultra-rare disorder characterized by osteolysis of the carpal and tarsal bones, subtle craniofacial deformities, and nephropathy. The molecular pathways underlying the pathophysiology are not well understood. RECENT FINDINGS: MCTO is caused by heterozygous mutations in MAFB, which encodes the widely expressed transcription factor MafB. All MAFB mutations in patients with MCTO result in replacement of amino acids that cluster in a phosphorylation region of the MafB transactivation domain and account for a presumed gain-of-function for the variant protein. Since 2012, fewer than 60 patients with MCTO have been described with 20 missense mutations in MAFB. The clinical presentations are variable, and a genotype-phenotype correlation is lacking. Osteolysis, via excessive osteoclast activity, has been regarded as the primary mechanism, although anti-resorptive agents demonstrate little therapeutic benefit. This paper appraises current perspectives of MafB protein action, inflammation, and dysfunctional bone formation on the pathogenesis of the skeletal phenotype in MCTO. More research is needed to understand the pathogenesis of MCTO to develop rational therapies.

mafba is a downstream transcriptional effector of Vegfc signaling essential for embryonic lymphangiogenesis in zebrafish.

The lymphatic vasculature plays roles in tissue fluid balance, immune cell trafficking, fatty acid absorption, cancer metastasis, and cardiovascular disease. Lymphatic vessels form by lymphangiogenesis, the sprouting of new lymphatics from pre-existing vessels, in both development and disease contexts. The apical signaling pathway in lymphangiogenesis is the VEGFC/VEGFR3 pathway, yet how signaling controls cellular transcriptional output remains unknown. We used a forward genetic screen in zebrafish to identify the transcription factor mafba as essential for lymphatic vessel development. We found that mafba is required for the migration of lymphatic precursors after their initial sprouting from the posterior cardinal vein. mafba expression is enriched in sprouts emerging from veins, and we show that mafba functions cell-autonomously during lymphatic vessel development. Mechanistically, Vegfc signaling increases mafba expression to control downstream transcription, and this regulatory relationship is dependent on the activity of SoxF transcription factors, which are essential for mafba expression in venous endothelium. Here we identify an indispensable Vegfc-SoxF-Mafba pathway in lymphatic development.

Spatial and transcriptional heterogeneity of pancreatic beta cell neogenesis revealed by a time-resolved reporter system.

AIMS/HYPOTHESIS: While pancreatic beta cells have been shown to originate from endocrine progenitors in ductal regions, it remains unclear precisely where beta cells emerge from and which transcripts define newborn beta cells. We therefore investigated characteristics of newborn beta cells extracted by a time-resolved reporter system. METHODS: We established a mouse model, 'Ins1-GFP; Timer', which provides spatial information during beta cell neogenesis with high temporal resolution. Single-cell RNA-sequencing (scRNA-seq) was performed on mouse beta cells sorted by fluorescent reporter to uncover transcriptomic profiles of newborn beta cells. scRNA-seq of human embryonic stem cell (hESC)-derived beta-like cells was also performed to compare newborn beta cell features between mouse and human. RESULTS: Fluorescence imaging of Ins1-GFP; Timer mouse pancreas successfully dissected newly generated beta cells as green fluorescence-dominant cells. This reporter system revealed that, as expected, some newborn beta cells arise close to the ducts (ßduct); unexpectedly, the others arise away from the ducts and adjacent to blood vessels (ßvessel). Single-cell transcriptomic analyses demonstrated five distinct populations among newborn beta cells, confirming spatial heterogeneity of beta cell neogenesis such as high probability of glucagon-positive ßduct, musculoaponeurotic fibrosarcoma oncogene family B (MafB)-positive ßduct and musculoaponeurotic fibrosarcoma oncogene family A (MafA)-positive ßvessel cells. Comparative analysis with scRNA-seq data of mouse newborn beta cells and hESC-derived beta-like cells uncovered transcriptional similarity between mouse and human beta cell neogenesis including microsomal glutathione S-transferase 1 (MGST1)- and synaptotagmin 13 (SYT13)-highly-expressing state. CONCLUSIONS/INTERPRETATION: The combination of time-resolved histological imaging with single-cell transcriptional mapping demonstrated novel features of spatial and transcriptional heterogeneity in beta cell neogenesis, which will lead to a better understanding of beta cell differentiation for future cell therapy. DATA AVAILABILITY: Raw and processed single-cell RNA-sequencing data for this study has been deposited in the Gene Expression Omnibus under accession number GSE155742.

Hypomorphic expression of parathyroid Bmal1 disrupts the internal parathyroid circadian clock and increases parathyroid cell proliferation in response to uremia.

The molecular circadian clock is an evolutionary adaptation to anticipate recurring changes in the environment and to coordinate variations in activity, metabolism and hormone secretion. Parathyroid hyperplasia in uremia is a significant clinical challenge. Here, we examined changes in the transcriptome of the murine parathyroid gland over 24 hours and found a rhythmic expression of parathyroid signature genes, such as Casr, Vdr, Fgfr1 and Gcm2. Overall, 1455 genes corresponding to 6.9% of all expressed genes had significant circadian rhythmicity. Biological pathway analysis indicated that the circadian clock system is essential for the regulation of parathyroid cell function. To study this, a novel mouse strain with parathyroid gland-specific knockdown of the core clock gene Bmal1 (PTHcre;Bmal1flox/flox) was created. Dampening of the parathyroid circadian clock rhythmicity was found in these knockdown mice, resulting in abrogated rhythmicity of regulators of parathyroid cell proliferation such as Sp1, Mafb, Gcm2 and Gata3, indicating circadian clock regulation of these genes. Furthermore, the knockdown resulted in downregulation of genes involved in mitochondrial function and synthesis of ATP. When superimposed by uremia, these PTHcre;Bmal1flox/flox mice had an increased parathyroid cell proliferative response, compared to wild type mice. Thus, our findings indicate a role of the internal parathyroid circadian clock in the development of parathyroid gland hyperplasia in uremia.

What's happening where when SARS-CoV-2 infects: are TLR7 and MAFB sufficient to explain patient vulnerability?

The present COVID-19 pandemic has revealed that several characteristics render patients especially prone to developing severe COVID-19 disease, i.e., the male sex, obesity, and old age. An explanation for the observed pattern of vulnerability has been proposed which is based on the concept of low sensitivity of the TLR7-signaling pathway at the time of infection as a common denominator of vulnerable patient groups.We will discuss whether the concept of established TLR-tolerance in macrophages and dendritic cells of the obese and elderly prior to infection can explain not only the vulnerability of these two demographic groups towards development of a severe infection with SARS-CoV-2, but also the observed cytokine response in these vulnerable patients, which is skewed towards pro-inflammatory cytokines with a missing interferon signature.

Repression of Mafb promotes foreskin fibroblast proliferation through upregulation of CDK2, cyclin E and PCNA.

Mafb plays a significant role in the development and differentiation of various organs, tissues and cells. Nevertheless, its role in the control of external genital cell proliferation and function in the mechanism of hypospadias remains unknown. In this study, the expression of Mafb in foreskin fibroblasts was inhibited by siRNA. The Cell Count Kit-8 (CCK-8) assay showed cell proliferation increased after transfection, and the number of cells entered the S phase significantly increased via flow cytometry. Both mRNA and protein levels of cyclin E, cyclin-dependent kinase 2 (CDK2) and proliferating cell nuclear antigen (PCNA) were significantly upregulated in the siRNA group. Meanwhile, twenty-five prepuce tissue samples were collected from hypospadias repair surgery. These samples were divided into two groups: the severe and mild groups. Normal prepuce tissue specimens were obtained during circumcision as the normal control. The upregulated expression of cyclin E, CDK2 and PCNA and downregulated Mafb expression were observed in the hypospadias group. This study reveals for the first time that the reduction in Mafb promotes the foreskin fibroblast proliferation. Thus, downregulated Mafb expression may cause hypospadias by upregulating CDK2, cyclin E and PCNA. These findings can shed new light on the embryonic development of the urethra.

Role of the Transcription Factor MAFA in the Maintenance of Pancreatic ß-Cells.

Pancreatic ß-cells are specialized to properly regulate blood glucose. Maintenance of the mature ß-cell phenotype is critical for glucose metabolism, and ß-cell failure results in diabetes mellitus. Recent studies provide strong evidence that the mature phenotype of ß-cells is maintained by several transcription factors. These factors are also required for ß-cell differentiation from endocrine precursors or maturation from immature ß-cells during pancreatic development. Because the reduction or loss of these factors leads to ß-cell failure and diabetes, inducing the upregulation or inhibiting downregulation of these transcription factors would be beneficial for studies in both diabetes and stem cell biology. Here, we discuss one such factor, i.e., the transcription factor MAFA. MAFA is a basic leucine zipper family transcription factor that can activate the expression of insulin in ß-cells with PDX1 and NEUROD1. MAFA is indeed indispensable for the maintenance of not only insulin expression but also function of adult ß-cells. With loss of MAFA in type 2 diabetes, ß-cells cannot maintain their mature phenotype and are dedifferentiated. In this review, we first briefly summarize the functional roles of MAFA in ß-cells and then mainly focus on the molecular mechanism of cell fate conversion regulated by MAFA.

Macrophage-Specific, Mafb-Deficient Mice Showed Delayed Skin Wound Healing.

Macrophages play essential roles throughout the wound repair process. Nevertheless, mechanisms regulating the process are poorly understood. MAFB is specifically expressed in the macrophages in hematopoietic tissue and is vital to homeostatic function. Comparison of the skin wound repair rates in macrophage-specific, MAFB-deficient mice (Mafbf/f::LysM-Cre) and control mice (Mafbf/f) showed that wound healing was significantly delayed in the former. For wounded GFP knock-in mice with GFP inserts in the Mafb locus, flow cytometry revealed that their GFP-positive cells expressed macrophage markers. Thus, macrophages express Mafb at wound sites. Immunohistochemical (IHC) staining, proteome analysis, and RT-qPCR of the wound tissue showed relative downregulation of Arg1, Ccl12, and Ccl2 in Mafbf/f::LysM-Cre mice. The aforementioned genes were also downregulated in the bone marrow-derived, M2-type macrophages of Mafbf/f::LysM-Cre mice. Published single-cell RNA-Seq analyses showed that Arg1, Ccl2, Ccl12, and Il-10 were expressed in distinct populations of MAFB-expressing cells. Hence, the MAFB-expressing macrophage population is heterogeneous. MAFB plays the vital role of regulating multiple genes implicated in wound healing, which suggests that MAFB is a potential therapeutic target in wound healing.

Transcription Factor MAFB as a Prognostic Biomarker for the Lung Adenocarcinoma.

MAFB is a basic leucine zipper (bZIP) transcription factor specifically expressed in macrophages. We have previously identified MAFB as a candidate marker for tumor-associated macrophages (TAMs) in human and mouse models. Here, we analyzed single-cell sequencing data of patients with lung adenocarcinoma obtained from the GEO database (GSE131907). Analyzed data showed that general macrophage marker CD68 and macrophage scavenger receptor 1 (CD204) were expressed in TAM and lung tissue macrophage clusters, while transcription factor MAFB was expressed specifically in TAM clusters. Clinical records of 120 patients with lung adenocarcinoma stage I (n = 57), II (n = 21), and III (n = 42) were retrieved from Tsukuba Human Tissue Biobank Center (THB) in the University of Tsukuba Hospital, Japan. Tumor tissues from these patients were extracted and stained with anti-human MAFB antibody, and then MAFB-positive cells relative to the tissue area (MAFB+ cells/tissue area) were morphometrically quantified. Our results indicated that higher numbers of MAFB+ cells significantly correlated to increased local lymph node metastasis (nodal involvement), high recurrence rate, poor pathological stage, increased lymphatic permeation, higher vascular invasion, and pleural infiltration. Moreover, increased amounts of MAFB+ cells were related to poor overall survival and disease-free survival, especially in smokers. These data indicate that MAFB may be a suitable prognostic biomarker for smoker lung cancer patients.

The Mafb cleft-associated variant H131Q is not required for palatogenesis in the mouse.

BACKGROUND: Orofacial clefts (OFCs) are common birth defects with complex etiology. Genome wide association studies for OFC have identified SNPs in and near MAFB. MAFB is a transcription factor critical for structural development of digits, kidneys, skin, and brain. MAFB is also expressed in the craniofacial region. Previous sequencing of MAFB in a Filipino population revealed a novel missense variant significantly associated with an increased risk for OFC. This MAFB variant, leading to the amino acid change H131Q, was knocked into the mouse Mafb, resulting in the MafbH131Q allele. The MafbH131Q construct was engineered to allow for deletion of Mafb ("Mafbdel "). RESULTS: Mafbdel/del animals died shortly after birth. Conversely, MafbH131Q/H131Q mice survived into adulthood at Mendelian ratios. Mafbdel/del and MafbH131Q/H131Q heads exhibited normal macroscopic and histological appearance at all embryonic time points evaluated. The periderm was intact based on expression of keratin 6, p63, and E-cadherin. Despite no effect on craniofacial morphogenesis, H131Q inhibited the Mafb-dependent promoter activation of Arhgap29 in palatal mesenchymal, but not ectodermal-derived epithelial cells in a luciferase assay. CONCLUSIONS: Mafb is dispensable for murine palatogenesis in vivo, and the cleft-associated variant H131Q, despite its lack of morphogenic effect, altered the expression of Arhgap29 in a cell-dependent context.

Association of Single-Nucleotide Polymorphisms of MAFB Gene with Nonsyndromic Cleft Lip with or without Cleft Palate in Kinh Vietnamese Patients.

Background Cleft lip with or without palate (CL/P) is the most common orofacial birth defect. Single-nucleotide polymorphisms (SNPs) in MAFB gene (V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog B) were identified as susceptible to this defect in a genome-wide association study. To further evaluate its role in this birth defect, we conducted this study with the aim of identifying allele frequencies, genotype frequencies, and association of SNPs rs13041247, rs6065259, and rs6072081 of MAFB gene with nonsyndromic cleft lip/palate (NCL/P) in Kinh Vietnamese patients. Methods We performed case-control study involved 79 patients with NCL/P and 77 healthy controls. DNAs were extracted from participants' saliva and tetra-amplification refractory mutation system polymerase chain reaction (tetra-ARMS PCR) was used for genotyping SNPs. Results SNPs of MAFB gene were genotyped using the Tetra-ARMS PCR method. We found that genotype CT of rs13041247 was associated with an increased risk of NCL/P in Kinh Vietnamese (odds ratio TCTT [OR TC/TT ] = 1.63, 95% confidence interval [CI] = 0.83-3.19, p = 0.17). The G allele genotypes of SNP rs6072081 increase high risk for the malformation, statistically significant result (OR GG/AA = 7.06, 95% CI = 2.13-23.42, p < 0.001). There is no clear association between rs6065259 and CL/P (OR AA/GG = 0.75, 95% CI = 0.22-2.50, p = 0.32; OR AG/GG = 1.53, 95% CI = 0.79-2.97, p = 0.32). When the patients were divided into the phenotypic subgroups, there was a similar significant trend between the patients and controls for all SNPs. Conclusions Our study provides further evidence of role of MAFB gene variations with NCL/P defect in Kinh Vietnamese.