Publications by authors named "Nagato Natsume"

33 Publications

Case of feeding disorder due to lymphangioma of the tongue: Importance in developing countries.

Congenit Anom (Kyoto) 2021 Feb 1. Epub 2021 Feb 1.

Cleft Lip and Palate Center, Aichi Gakuin University Dental Hospital, Nagoya, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cga.12410DOI Listing
February 2021

Bone formation potential of collagen type I-based recombinant peptide particles in rat calvaria defects.

Regen Ther 2021 Mar 24;16:12-22. Epub 2020 Dec 24.

Department of Oral Anatomy, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, Aichi, 464-8650, Japan.

Introduction: This study aimed to examine the bone-forming ability of medium-cross-linked recombinant collagen peptide (mRCP) particles developedbased on human collagen type I, contains an arginyl-glycyl-aspartic acid-rich motif, fabricated as bone filling material, compared to that of the autologous bone graft.

Methods: Calvarial bone defects were created in immunodeficient rats though a surgical procedure. The rats were divided into 2 groups: mRCP graft and tibia bone graft (bone graft). The bone formation potential of mRCP was evaluated by micro-computed tomography and hematoxylin-eosin staining at 1, 2, 3, and 4 weeks after surgery, and the data were analyzed and compared to those of the bone graft.

Results: The axial volume-rendered images demonstrated considerable bony bridging with the mRCP graft, but there was no significant difference in the bone volume and bone mineral density between the mRCP graft and bone graft at 4 weeks. The peripheral new bone density was significantly higher than the central new bone density and the bottom side score was significantly higher than the top side score at early stage in the regenerated bone within the bone defects.

Conclusion: These results indicate that mRCP has a high potential of recruiting osteogenic cells, comparable to that of autologous bone chips.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.reth.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773759PMC
March 2021

5,10-Methylenetetrahydrofolate reductase () C677T/A1298C polymorphisms in patients with nonsyndromic cleft lip and palate.

Biomed Rep 2020 Dec 13;13(6):57. Epub 2020 Oct 13.

Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Mibu, Tochigi 321-0293, Japan.

Cleft lip with or without cleft palate (CL/P) is considered a multifactorial genetic disorder. Folic acid metabolism has been suggested to underlie the development of CL/P. The gene for the enzyme 5,10-methylentetrahydrofolate reductase () contributes to folic acid metabolism, and polymorphisms of this gene at C677T (rs1801133) and A1298C (rs1801131) are reported to alter its enzyme activity and are suggested to be involved in CL/P development. We investigated C677T and A1298C polymorphisms of the gene in Japanese patients with nonsyndromic CL/P and cleft palate only (CPO). We examined 240 patients with CL/P, 103 fathers and 153 mothers of the patients, and 68 healthy controls. Restriction fragment length polymorphisms (RFLPs) of C677T and A1298C of were analyzed. We determined the frequencies of the polymorphisms in the patients and controls and performed a transmission equilibrium test and haplotype analysis of both C677T and A1298C. There were no significant differences in the frequencies of C677T and A1298C polymorphisms between the patients and controls. We did not observe transmission equilibrium or linkage equilibrium among the cases. In this experimental condition, we did not detect an association of C677T and/or A1298C polymorphisms with the development of CL/P in this Japanese cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/br.2020.1364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583695PMC
December 2020

SPECC1L regulates palate development downstream of IRF6.

Hum Mol Genet 2020 03;29(5):845-858

Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.

SPECC1L mutations have been identified in patients with rare atypical orofacial clefts and with syndromic cleft lip and/or palate (CL/P). These mutations cluster in the second coiled-coil and calponin homology domains of SPECC1L and severely affect the ability of SPECC1L to associate with microtubules. We previously showed that gene-trap knockout of Specc1l in mouse results in early embryonic lethality. We now present a truncation mutant mouse allele, Specc1lΔC510, that results in perinatal lethality. Specc1lΔC510/ΔC510 homozygotes showed abnormal palate rugae but did not show cleft palate. However, when crossed with a gene-trap allele, Specc1lcGT/ΔC510 compound heterozygotes showed a palate elevation delay with incompletely penetrant cleft palate. Specc1lcGT/ΔC510 embryos exhibit transient oral epithelial adhesions at E13.5, which may delay shelf elevation. Consistent with oral adhesions, we show periderm layer abnormalities, including ectopic apical expression of adherens junction markers, similar to Irf6 hypomorphic mutants and Arhgap29 heterozygotes. Indeed, SPECC1L expression is drastically reduced in Irf6 mutant palatal shelves. Finally, we wanted to determine if SPECC1L deficiency also contributed to non-syndromic (ns) CL/P. We sequenced 62 Caucasian, 89 Filipino, 90 Ethiopian, 90 Nigerian and 95 Japanese patients with nsCL/P and identified three rare coding variants (p.Ala86Thr, p.Met91Iso and p.Arg546Gln) in six individuals. These variants reside outside of SPECC1L coiled-coil domains and result in milder functional defects than variants associated with syndromic clefting. Together, our data indicate that palate elevation is sensitive to deficiency of SPECC1L dosage and function and that SPECC1L cytoskeletal protein functions downstream of IRF6 in palatogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddaa002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104672PMC
March 2020

What we should do for the future of children-A report on the Joint Meeting of the 59th Annual Meeting of the Japanese Teratology Society and the 13th World Congress of the International Cleft Lip and Palate Foundation-CLEFT 2019.

Authors:
Nagato Natsume

Congenit Anom (Kyoto) 2019 Nov;59(6):186-189

Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, School of Dentistry, Nagoya, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cga.12355DOI Listing
November 2019

Rat Palatine Fissure: A Suitable Experimental Model for Evaluating Bone Regeneration.

Tissue Eng Part C Methods 2019 09 11;25(9):513-522. Epub 2019 Sep 11.

Department of Oral Anatomy, Aichi Gakuin University School of Dentistry, Nagoya, Japan.

Impact Statement: The rat palatine fissure is anatomically similar to human alveolar cleft. In this study, we examined potential bone repair by an autologous bone implant and beta-tricalcium phosphate (β-TCP) using rat palatine fissure as a model. Autologous bone chips or β-TCP granules were implanted into the rat palatine fissure. Our model demonstrated that higher bone volume and bone mineral density were achieved with autologous bone graft than with β-TCP. We have provided the first demonstration of the suitability of the rat palatine fissure as the implant site to simulate the transplantation of bone graft materials into human alveolar cleft.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ten.TEC.2019.0143DOI Listing
September 2019

Patients with SATB2-associated syndrome exhibiting multiple odontomas.

Am J Med Genet A 2018 12 21;176(12):2614-2622. Epub 2018 Dec 21.

Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome (SAS) is characterized by alterations of SATB2. Its clinical features include intellectual disability and craniofacial abnormalities, such as cleft palate, dysmorphic features, and dental abnormalities. Here, we describe three previously undiagnosed, unrelated patients with SAS who exhibited dental abnormalities, including multiple odontomas. Although isolated odontomas are common, multiple odontomas are rare. Individuals in families 1 and 3 underwent whole-exome sequencing. Patient 2 and parents underwent targeted amplicon sequencing. On the basis of the hg19/GRCh37 reference and the RefSeq mRNA NM_001172517, respective heterozygous mutations were found and validated in Patients 1, 2, and 3: a splice-site mutation (chr2:g.200137396C > T, c.1741-1G > A), a nonsense mutation (chr2:g.200213750G > A, c.847C > T, p.R283*), and a frame-shift mutations (chr2:g.200188589_200188590del, c.1478_1479del, p.Q493Rfs*19). All mutations occurred de novo. The mutations in Patients 1 and 3 were novel; the mutation in Patient 2 has been described previously. Tooth mesenchymal cells derived from Patient 2 showed diminished SATB2 expression. Multiple odontomas were evident in the patients in this report; however, this has not been recognized previously as a SAS-associated phenotype. We propose that multiple odontomas be considered as an occasional manifestation of SAS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.40670DOI Listing
December 2018

Cleft palate formation after palatal fusion occurs due to the rupture of epithelial basement membranes.

J Craniomaxillofac Surg 2018 Dec 20;46(12):2027-2031. Epub 2018 Sep 20.

Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, School of Dentistry, Aichi-Gakuin University, Japan.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces cleft palate and hydronephrosis in the mouse embryo. Cleft palate occurs due to failure in palatal grow, but the underlying mechanisms are unclear. We investigated the mechanisms of cleft palate development in TCDD-exposed mouse embryos. We administered olive oil (control group) or TCDD diluted in olive oil (40 μg/kg) via gastric tubes to pregnant mice on gestational day (GD) 12. Embryos of control and TCDD-exposed groups were removed from pregnant mice on GD 14 and GD 15, respectively. One mouse embryo from the control group had anteroposterior palatal fusion. Palatal fusion was observed in three TCDD-exposed mouse embryos. Palates of TCDD-exposed mice fused from the interior to the middle of the palates, while the palates were separated in the posterior region. The middle of the embryonic palatal shelves in TCDD-exposed animals was narrow and split at the fusional position. At this position, palatal and blood cells were dispersed from the palatal tissue and the epithelium was split, with a discontinuous basement membrane. The results suggest that decreased intercellular adhesion or insufficient tissue strength of the palatal shelves may be involved in the development of cleft palate following palatal fusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcms.2018.09.016DOI Listing
December 2018

Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes.

Genet Epidemiol 2017 12 10;41(8):887-897. Epub 2017 Nov 10.

Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States of America.

Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes-cleft lip alone (CL) and CL plus cleft palate (CLP)-are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10 ). We also identified significant evidence of gene-gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728176PMC
December 2017

Association of MEOX2 polymorphism with nonsyndromic cleft palate only in a Vietnamese population.

Congenit Anom (Kyoto) 2018 Jul 28;58(4):124-129. Epub 2017 Nov 28.

Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya, Japan.

To evaluate the association between the single nucleotide polymorphism (SNP) rs227493 in the MEOX2 gene and nonsyndromic cleft palate only, this research was conducted as a case-control study by comparing a nonsyndromic cleft palate only group with an independent, healthy, and unaffected control group who were both examined by specialists. Based on clinical examination and medical records, we analyzed a total of 570 DNA samples, including 277 cases and 293 controls, which were extracted from dry blood spot samples collected from both the Odonto and Maxillofacial Hospital in Ho Chi Minh City and Nguyen Dinh Chieu Hospital in Ben Tre province, respectively. The standard procedures of genotyping the specific SNP (rs2237493) for MEOX2 were performed on a StepOne Realtime PCR system with TaqMan SNP Genotyping Assays. Significant statistical differences were observed in allelic frequencies (allele T and allele G) between the non-syndromic cleft palate only and control groups in female subjects, with an allelic odds ratio of 1.455 (95% confidence interval: 1.026-2.064) and P < 0.05. These study findings suggest that nonsyndromic isolated cleft palate might be influenced by variation of MEOX2, especially SNP rs2237493 in Vietnamese females.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cga.12259DOI Listing
July 2018

Outcomes of an international volunteer surgical project for patients with cleft lip and/or cleft palate: A mission in developing Laos.

Congenit Anom (Kyoto) 2018 Jul 3;58(4):112-116. Epub 2017 Nov 3.

Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Cleft lip and/or palate (CL/P) is a common birth defect of complex etiology. CL/P surgery is generally performed in infancy to allow for improvements in esthetics, suckling, and speech disorders as quickly as possible. We have engaged in activities such as free-of-charge surgery for CL/P a total of 12 times from 2001 to 2016 in Lao People's Democratic Republic (Laos). The United Nations has designated Laos as a Least Developed Country; it is one of the poorest countries in Asia. We have carried out our activities for a long time, primarily in CL/P patients who cannot undergo surgery for financial reasons, and we have performed CL/P-related surgeries for 283 patients up to 2016. When we began our activities in 2001, the mean age at first cheiloplasty was 11.6 years, which dropped over time until 2016 when the mean age was 1.8 years. A linear regression analysis showed a significant difference between the age at first lip plasty and the year of first operation (β = -0.35; P < 0.001). This was likely an effect of continuing to train local medical staff in surgical techniques and donating surgical tools and facilities over a period of 16 years while building a good relationship with local staff. However, the healthcare system in Laos is an obstacle to some patients who still cannot undergo CL/P surgery in infancy for financial reasons. We therefore need to support Laos to provide treatment on their own as we continue to carry out our activities for CL/P patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cga.12255DOI Listing
July 2018

Homeobox family Hoxc localization during murine palate formation.

Congenit Anom (Kyoto) 2016 Jul;56(4):172-9

Osaka Medical College, Takatsuki, Osaka, Japan.

Homeobox genes play important roles in craniofacial morphogenesis. However, the characteristics of the transcription factor Hoxc during palate formation remain unclear. We examined the immunolocalization patterns of Hoxc5, Hoxc4, and Hoxc6 in palatogenesis of cleft palate (Eh/Eh) mice. On the other hand, mutations in the FGF/FGFR pathway are exclusively associated with syndromic forms of cleft palate. We also examined the immunolocalization of Fgfr1 and Erk1/2 to clarify their relationships with Hoxc in palatogenesis. Some palatal epithelial cells showed Hoxc5 labeling, while almost no labeling of mesenchymal cells was observed in +/+ mice. As palate formation progressed in +/+ mice, Hoxc5, Hoxc4, and Hoxc6 were observed in medial epithelial seam cells. Hoxc5 and Hoxc6 were detected in the oral epithelium. The palatal mesenchyme also showed intense staining for Fgfr1 and Erk1/2 with progression of palate formation. In contrast, the palatal shelves of Eh/Eh mice exhibited impaired horizontal growth and failed to fuse, resulting in a cleft. Hoxc5 was observed in a few epithelial cells and diffusely in the mesenchyme of Eh/Eh palatal shelves. No or little labeling of Fgfr1 and Erk1/2 was detected in the cleft palate of Eh/Eh mice. These findings suggest that Hoxc genes are involved in palatogenesis. Furthermore, there may be the differences in the localization pattern between Hoxc5, Hoxc4, and Hoxc6. Additionally, Hoxc distribution in palatal cells during palate development may be correlated with FGF signaling. (228/250 words) © 2016 Japanese Teratology Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cga.12153DOI Listing
July 2016

Replication of 13q31.1 association in nonsyndromic cleft lip with cleft palate in Europeans.

Am J Med Genet A 2015 May 18;167A(5):1054-1060. Epub 2015 Mar 18.

Department of Pediatrics, University of Iowa, Iowa City, Iowa.

Genome wide association (GWA) studies have successfully identified at least a dozen loci associated with orofacial clefts. However, these signals may be unique to specific populations and require replication to validate and extend findings as a prelude to etiologic SNP discovery. We attempted to replicate the findings of a recent meta-analysis of orofacial cleft GWA studies using four different ancestral populations. We studied 946 pedigrees (3,436 persons) of European (US white and Danish) and Asian (Japanese and Mongolian) origin. We genotyped six SNPs that represented the most significant P-value associations identified in published studies: rs742071 (1p36), rs7590268 (2p21), rs7632427 (3p11.1), rs12543318 (8q21.3), rs8001641 (13q31.1), and rs7179658 (15q22.2). We directly sequenced three non-coding conserved regions 200 kb downstream of SPRY2 in 713 cases, 438 controls, and 485 trios from the US, Mongolia, and the Philippines. We found rs8001641 to be significantly associated with nonsyndromic cleft lip with cleft palate (NSCLP) in Europeans (P-value = 4 × 10(-5), ORtransmission = 1.86 with 95% confidence interval: 1.38-2.52). We also found several novel sequence variants in the conserved regions in Asian and European samples, which may help to localize common variants contributing directly to the risk for NSCLP. This study confirms the prior association between rs8001641 and NSCLP in European populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402974PMC
May 2015

The hanoi declaration.

Ann Maxillofac Surg 2014 Jul-Dec;4(2):251

International Cleft Lip and Palate Foundation, School of Dentistry, Aichi, Japan E-mail: ; Aichi Gakuin University, Faculty of Psychological and Physical Science, Nisshin, Aichi, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/2231-0746.147171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293860PMC
January 2015

Diagnostic/genetic sreening - approach for genetic diagnoses and prevention of cleft lip and/or palate.

Chin J Dent Res 2013 ;16(2):95-100

The treatment, research and volunteer work for cleft lip and/or palate (CL/P) has been led for over 30 years by our team. Within this period, more than 4,000 cases of CL/P were treated and at the same time, and approximately 400 papers were published as the first or partner researcher in Nature Genetics, New England Journal of Medicine and others. In addition, with $20 million that was donated from companies and laypeople, and the grant from the Japanese government, CL/P centres in many countries and in Japan, the oral and craniofacial congenital anomaly gene bank in our CL/P centre was established by our leadership. In the bank there are genes from approximately more than 8,000 cases. The genes were mapped with Professor Jeffery Murray of Iowa University in the United States, the findings about genetic syndromes such as Van der Woude Syndrome and basal cell nevus syndrome were applied in clinical settings. The genetic counselling section that specialises in the oral and maxillofacial field was established by our effort for the first time in Japan. In this review, our clinical experience and approach for genetic diagnoses and prevention of cleft lip and/or palate will be discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2014

The effect of sevoflurane on developing A/J strain mouse embryos using a whole-embryo culture system--the incidence of cleft lip in culture embryos.

In Vitro Cell Dev Biol Anim 2014 Mar 21;50(3):237-42. Epub 2013 Nov 21.

Department of Anesthesiology, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan,

A/J strain mice have a high spontaneous incidence of cleft lip (ICL) and/or palate. The primary palate-related effects of sevoflurane on developing A/J strain mouse embryos (embryos) were studied using a whole-embryo culture (WEC) system. This system could separate the direct effects of sevoflurane from those that are maternally mediated. A total of 205 10.5-d embryos were cultured for 24 h in either a control group (control gas: 95% O2 and 5% CO2) or sevoflurane-administered groups (1/4, 1/2, and 1 minimum alveolar concentration (MAC) with control gas) for 8 h. After 16 h, 11.5-d culture embryos were examined in terms of crown-rump length, number of somites, and protein content. Crown-rump length in the 1 MAC was significantly shorter than in the control group (p < 0.05). Protein content in the 1/2 MAC (p < 0.05) and 1 MAC (p < 0.001) was significantly lower than in the control group. The ICL showed no significant differences between each group. (The ICL rose with an increase in the sevoflurane concentration, but this was not significant). The positive findings in this study indicate that a WEC system is useful for studying the mechanisms of ICL (teratogenicity) associated with sevoflurane.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11626-013-9697-yDOI Listing
March 2014

Mutations in extracellular matrix genes NID1 and LAMC1 cause autosomal dominant Dandy-Walker malformation and occipital cephaloceles.

Hum Mutat 2013 Aug 28;34(8):1075-9. Epub 2013 May 28.

Department of Pediatrics, The University of Iowa, Iowa City, Iowa52242, USA.

We performed whole-exome sequencing of a family with autosomal dominant Dandy-Walker malformation and occipital cephaloceles and detected a mutation in the extracellular matrix (ECM) protein-encoding gene NID1. In a second family, protein interaction network analysis identified a mutation in LAMC1, which encodes a NID1-binding partner. Structural modeling of the NID1-LAMC1 complex demonstrated that each mutation disrupts the interaction. These findings implicate the ECM in the pathogenesis of Dandy-Walker spectrum disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714376PMC
August 2013

Heparanase localization during palatogenesis in mice.

Biomed Res Int 2013 12;2013:760236. Epub 2013 Feb 12.

Department of Anatomy and Cell Biology, Faculty of Medicine, Osaka Medical College, Takatsuki 569-8686, Japan.

Palatogenesis is directed by epithelial-mesenchymal interactions and results partly from remodeling of the extracellular matrix (ECM) of the palatal shelves. Here, we assessed heparanase distribution in developing mouse palates. No heparanase was observed in the vertically oriented palatal shelves in early stages of palate formation. As palate formation progressed, the palatal shelves were reorganized and arranged horizontally above the tongue, and heparanase localized to the epithelial cells of these shelves. When the palatal bilateral shelves first made contact, the heparanase localized to epithelial cells at the tips of shelves. Later in fusing palatal shelves, the cells of the medial epithelial seam (MES) were labeled with intense heparanase signal. In contrast, the basement membrane heparan sulfate (HS) was scarcely observed in the palatal shelves in contact. Moreover, perlecan labeling was sparse in the basement membrane of the MES, on which laminin and type IV collagen were observed. Moreover, we assessed the distribution of matrix metalloproteinase- (MMP-) 9, MMP-2, and MMP-3 in developing mouse palates and these MMPs were observed in the MES. Our findings indicated that heparanase was important for palate formation because it mediated degradation of the ECM of palatal shelves. Heparanase may, in concert with other proteases, participate in the regression of the MES.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2013/760236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583076PMC
November 2013

Replication of genome wide association identified candidate genes confirm the role of common and rare variants in PAX7 and VAX1 in the etiology of nonsyndromic CL(P).

Am J Med Genet A 2013 May 5;161A(5):965-72. Epub 2013 Mar 5.

Department of Pediatrics, University of Iowa, Iowa City, IA 52242-1181, USA.

Following recent genome wide association studies (GWAS), significant genetic associations have been identified for several genes with nonsyndromic cleft lip with or without cleft palate (CL(P)). To replicate two of these GWAS signals, we investigated the role of common and rare variants in the PAX7 and VAX1 genes. TaqMan genotyping was carried out for SNPs in VAX1 and PAX7 and transmission disequilibrium test (TDT) was performed to test for linkage and association in each population. Direct sequencing in and around the PAX7 and VAX1 genes in 1,326 individuals of European and Asian ancestry was done. The TDT analysis showed strong associations with markers in VAX1 (rs7078160, P = 2.7E-06 and rs475202, P = 0.0002) in a combined sample of Mongolian and Japanese CL(P) case-parent triads. Analyses using parent-of-origin effects showed significant excess transmission of the minor allele from both parents with the effect in the mothers (P = 6.5E-05, OR (transmission) = 1.91) more striking than in the fathers (P = 0.004, OR (transmission) = 1.67) for VAX1 marker rs7078160 in the combined Mongolian and Japanese samples when all cleft types were combined. The rs6659735 trinucleotide marker in PAX7 was significantly associated with all the US cleft groups combined (P = 0.007 in all clefts and P = 0.02 in CL(P)). Eight rare missense mutations found in PAX7 and two rare missense mutations in VAX1. Our study replicated previous GWAS findings for markers in VAX1 in the Asian population, and identified rare variants in PAX7 and VAX1 that may contribute to the etiology of CL(P). Determining the role of rare variants clearly warrants further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.35749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634899PMC
May 2013

Epidemiological Analysis of Cleft Lip and/or Palate by Cleft Pattern.

J Maxillofac Oral Surg 2010 Dec 11;9(4):389-95. Epub 2011 Mar 11.

Objectives: To analyze gender differences in cleft pattern by the clinical statistical study of Japanese patients with cleft lip and/or cleft palate.

Study Design: Cleft pattern modeling was used to analyze 782 patients with cleft lip and/or cleft palate (417 males and 365 females) who had been examined at the Cleft Lip and Palate Center, Aichi-Gakuin University Hospital, and whose details could be confirmed. Relationships between gender and cleft type were analyzed with chi-squared test.

Results: A comparison of gender differences by cleft type revealed that a greater percentage of males had milder cleft lip, cleft lip and palate, or cleft palate, whereas the percentage of females tended to be greater as cleft severity increased.

Conclusions: Modeling of cleft patterns enables more detailed classification of cleft lip and palate, and can lead to a greater understanding of pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12663-010-0132-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177484PMC
December 2010

Perception of Cleft Palate Speech by Japanese Listeners-an Assessment of Palatalized Articulations.

J Maxillofac Oral Surg 2010 Sep 30;9(3):251-5. Epub 2010 Oct 30.

To examine how people react to palatalized articulation, we used one cleft palate speech (CPS) sample of palatalized articulation that was purchased in Japan and one recorded sample of speech from a non-cleft palate individual. Study design The two speech samples were rated by 137 native listeners. Each participant rated the set of speech samples for 10 features using a 10-point scale. Alpha factor analysis was performed. Results Two factors were extracted from the entire set of features with alpha factor analysis. Conclusions Although native listeners could not distinguish between CPS and non-CPS using the psychometrical measurements applied in this study, this method of analyzing speech represents a useful technique for planning treatments in cleft disorder patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12663-010-0036-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177440PMC
September 2010

Mutations in BMP4 are associated with subepithelial, microform, and overt cleft lip.

Am J Hum Genet 2009 Mar 26;84(3):406-11. Epub 2009 Feb 26.

Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, School of Dentistry, Aichi-Gakuin University, Chikusa-Ku, Nagoya, Japan.

Cleft lip with or without cleft palate (CL/P) is a complex trait with evidence that the clinical spectrum includes both microform and subepithelial lip defects. We identified missense and nonsense mutations in the BMP4 gene in 1 of 30 cases of microform clefts, 2 of 87 cases with subepithelial defects in the orbicularis oris muscle (OOM), 5 of 968 cases of overt CL/P, and 0 of 529 controls. These results provide confirmation that microforms and subepithelial OOM defects are part of the spectrum of CL/P and should be considered during clinical evaluation of families with clefts. Furthermore, we suggest a role for BMP4 in wound healing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2009.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667991PMC
March 2009

Cellular localization and functional characterization of the equilibrative nucleoside transporters of antitumor nucleosides.

Cancer Sci 2007 Oct 16;98(10):1633-7. Epub 2007 Aug 16.

Department of Experimental Therapeutics, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.

Nucleoside transporters play an important role in the disposition of nucleosides and their analogs. To elucidate the relationship between chemosensitivity to antitumor nucleosides and the functional expression of equilibrative nucleoside transporters (ENT), we established stable cell lines of human fibrosarcoma HT-1080 and gastric carcinoma TMK-1 that constitutively overexpressed green fluorescent protein-tagged hENT1, hENT2, hENT3 and hENT4. Both hENT1 and hENT2 were predictably localized to the plasma membrane, whereas hENT3 and hENT4 were localized to the intracellular organelles. The chemosensitivity of TMK-1 cells expressing hENT1 and hENT2 to cytarabine and 1-(3-C-ethynyl-beta-D-ribopentofuranosyl) cytosine increased markedly in comparison to that of mock cells. However, no remarkable changes in sensitivity to antitumor nucleosides were observed in cell lines that expressed both hENT3 and hENT4. These data suggest that hENT3 and hENT4, which are mainly located in the intracellular organelles, are not prominent nucleoside transporters like hENT1 and hENT2, which are responsible for antitumor nucleoside uptake.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1349-7006.2007.00581.xDOI Listing
October 2007

Effects of a long-term volunteer surgical program in a developing country: the case in Vietnam from 1993 to 2003.

Cleft Palate Craniofac J 2006 Sep;43(5):616-9

Research Institute of Advanced Oral Science, Aichi-Gakuin University, Nagoya, Japan.

Objective: This study evaluates the activities of the Japanese Cleft Palate Foundation from 1993 to 2003 in southern Vietnam.

Design: We assessed trends associated with patient age at first operation for primary lip repair and palate repair by using medical records of the patients.

Participants: This study consisted of 790 patients with nonsyndromic cleft lip and/or palate (CL/P).

Results: The median patient age for lip repair was reduced from 14.0 years in 1993 to 1.3 years by 2003. For palate repair, the median age was reduced from 13.5 years in 1993 to 5.0 years in 1999 through 2003. The age distributions of both lip and palate repair in the later years became smaller than the age distributions in 1993. The number of adult patients declined throughout the period.

Conclusions: The Japanese Cleft Palate Foundation contributed to lowering the age at first operation for CL/P and to reducing the number of adult patients in Ben Tre province, southern Vietnam. However, appropriate supports will be necessary to maintain CL/P treatment and to improve locally supported health care for patients with CL/P.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1597/05-120DOI Listing
September 2006

A mutation in RYK is a genetic factor for nonsyndromic cleft lip and palate.

Cleft Palate Craniofac J 2006 May;43(3):310-6

The Second Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Chiba, Japan.

Objective: The RYK, EPHB2, and EPHB3 genes are attractive candidates for cleft lip and/or palate and cleft palate only pathogenesis. Both the Ryk-deficient mouse and Ephb2/Ephb3 (genes for interaction molecules with RYK) double-mutant mouse show cleft palate.

Setting: Mutation searches for RYK, EPHB2, and EPHB3 were carried out in a large number of Japanese and Vietnamese patients with cleft lip and/or palate and cleft palate only. Case-control study and transmission disequilibrium tests were performed also, using three single nucleotide polymorphisms within a linkage disequilibrium block in RYK. Seven haplotypes were constructed from the single nucleotide polymorphisms.

Results: A missense mutation, 1355G>A (Y452C), in RYK was identified in one Vietnamese patient with cleft lip and/or palate. This mutation was not found among 1646 Vietnamese, Japanese, and Caucasians, including 354 cleft lip and/ or palate and cleft palate only patients. Colony formation assay using NIH3T3 cells transfected with mutant cDNA revealed that mutant RYK had significantly reduced protein activity, compared with those with wild-type RYK, implying that the transformation ability of RYK is depleted by this mutation. Although a case-control study and transmission disequilibrium tests on three individual single nucleotide polymorphisms provided no evidence for association with oral clefts, a case-control study on one rare haplotype suggested a positive association in Japanese patients with cleft lip and/or palate and cleft palate only. No mutations in EPHB2 and EPHB3 were found in any patients examined.

Conclusion: The findings suggested that a missense mutation, 1355G>A, and one rare single nucleotide polymorphisms haplotype may play a role in the development of cleft lip and/or palate in the Vietnamese, and cleft lip and/ or palate and cleft palate only in the Japanese.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1597/04-145.1DOI Listing
May 2006

A SNP in the ABCC11 gene is the determinant of human earwax type.

Nat Genet 2006 Mar 29;38(3):324-30. Epub 2006 Jan 29.

Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Human earwax consists of wet and dry types. Dry earwax is frequent in East Asians, whereas wet earwax is common in other populations. Here we show that a SNP, 538G --> A (rs17822931), in the ABCC11 gene is responsible for determination of earwax type. The AA genotype corresponds to dry earwax, and GA and GG to wet type. A 27-bp deletion in ABCC11 exon 29 was also found in a few individuals of Asian ancestry. A functional assay demonstrated that cells with allele A show a lower excretory activity for cGMP than those with allele G. The allele A frequency shows a north-south and east-west downward geographical gradient; worldwide, it is highest in Chinese and Koreans, and a common dry-type haplotype is retained among various ethnic populations. These suggest that the allele A arose in northeast Asia and thereafter spread through the world. The 538G --> A SNP is the first example of DNA polymorphism determining a visible genetic trait.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng1733DOI Listing
March 2006

Two missense mutations in the IRF6 gene in two Japanese families with Van der Woude syndrome.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004 Oct;98(4):414-7

Department of Oral and Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Japan.

Van der Woude syndrome (VWS) is a common autosomal dominant disorder with cleft lip and/or palate and lower lip pits. Its prevalence is estimated to be 1/33,600 in the Finnish Population, and 1/47,813 in the Japanese. We performed mutation analysis of the IRF6 gene by direct sequencing in 2 unrelated Japanese families that consist of a total of 3 affected members with cleft lip and palate associated with lower lip pits. Consequently, we found novel base substitutions, 25C>T, in IRF6-exon 3 in a boy, his mother, and his phenotypically normal maternal grandmother in one of the families. A known mutation, 250C>T, was identified in exon 4 of a girl and her unaffected father in the other family. The same mutations were never observed among 190 healthy Japanese. The results indicate incomplete penetrance and variable expressivity in the families. Because 25C>T and 250C>T predict to lead to R9W and R84C substitutions, respectively, at the most conserved DNA binding domain of IRF6, and because arginine at positions 9 and 84 is highly conserved among IRFs, the 2 mutations may lead to abolish the DNA binding activity in the developing craniofacial region. To our knowledge, this is the first report of IRF6 mutations observed in Japanese VWS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tripleo.2003.12.034DOI Listing
October 2004

In a Vietnamese population, MSX1 variants contribute to cleft lip and palate.

Genet Med 2004 May-Jun;6(3):117-25

Second Department of Oral and Maxillofacial Surgery, School of Dentistry Aichi-Gakuin University, Nagoya, Japan.

Purpose: To identify causes of nonsyndromic cleft lip and palate in a Vietnamese population.

Methods: In this study, 175 families with at least one case of cleft lip and/or palate were studied using the candidate genes TGFA, MSX1, and TGFB3.

Results: Transmission distortion for alleles of MSX1 were demonstrated for the whole population and two missense mutations were identified, including one (P147Q) that is found in approximately 2% of the population. The P147Q appears to arise from a founder individual based on shared haplotypes in unrelated families.

Conclusions: MSX1 contributes to nonsyndromic clefting in a Vietnamese population, and consistent with other studies, identifiable mutations in this gene cause about 2% of cases of nonsyndromic clefting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.gim.0000127275.52925.05DOI Listing
February 2005