The Society of Craniofacial Genetics and Developmental Biology 34th Annual Meetingстатья из журнала
Аннотация: This article is an introduction to active areas of research in craniofacial genetics and developmental biology as highlighted by Dr. Brian Hall's accompanying article in this issue of AJMG (Hall BK 2012. AJMG XX) and the publication in this issue of the abstracts which were presented as either talks or posters at the 34th annual meeting of the Society of Craniofacial Genetics and Developmental Biology (SCGDB). The meeting hosted by the faculty of Dentistry at McGill University convened in October 2011, in Montreal, Quebec, Canada. The Society met in conjunction with the International Congress of Human Genetics-American Society of Human Genetics meeting. Clinical Craniofacial Dysmorphology was the theme of the scientific sessions given by invited speakers. The SCGDB is an international organization established in 1975 as the Society of Craniofacial Genetics. In 2011, the name of the society was expanded to include developmental biology to reflect the tight yet hierarchical integration between genetics and development/embryogenesis. The objectives of the Society are to promote understanding, research, and interdisciplinary communication concerning craniofacial genetics and developmental biology, and to apply the results of basic and clinical research to the care and management of individuals with craniofacial problems. (http://craniofacialgenetics.org/index.php?section=ABOUT+US for detailed objectives). The society is enormously active in pursuit of its objectives. To bring to attention the work of those who have and are contributing to the advancement of the Society two awards were established in 2011 for graduate students demonstrating research excellence. The first was to recognize the significant contributions to craniofacial genetics, developmental biology and the Society by Dr. Geoffrey Sperber. As befits Geoff's status in the field and role in the Society, the “Geoffrey Sperber Award for Excellence in Craniofacial Research” was presented at the Montreal meeting. Zohreh Khavandgar of the Faculty of Dentistry at McGill University received this award for her research on mechanisms of bone mineralization. A second award, the genesis Award for Excellence in Craniofacial Research, generously funded by the journal genesis was won by Christopher Percival for his research on bone mineral density in a mouse model for Beare–Stevenson Cutis Gyrata Syndrome. The 2012 annual meeting of the SCFDB is scheduled to convene on November 5th in San Francisco in conjunction with the annual meeting of the American Society of Human Genetics (ASHG) to be held November 6–10 (http://www.ashg.org). Mark your calendar and monitor the SCGDB and ASHG web sites for details. Abstracts of the 34th Annual Meeting of the Society of Craniofacial Genetics and Developmental Biology (SCGDB) in Montreal, Quebec on 11 October 2011 Inherited Retinal Disorders: Hope for Treatment Roderick R. McInnes1 1Lady Davis Institute, Jewish General Hospital, Department of Human Genetics, McGill University, Montreal, Quebec, Canada Inherited retinal diseases can be broadly classified into developmental defects and retinal degenerations. I will give a brief overview of these conditions, and focus in particular on our current understanding of the mechanisms that underlie photoreceptor death in the inherited degenerations. In our work on these diseases, we are addressing two fundamental questions: First, why do the neurons die? And second, how is it that they can function perfectly normally for decades, yet still be at risk of death? Are they sick? What are the biochemical changes that result from the mutation, and that eventually kill the cells? Some insight into these difficult questions has been obtained by many groups over the past decade (reviewed in Bramall et al. [2010]). I will also review exciting progress in the treatment of inherited retinal disease, both cell replacement therapy and gene therapy. In Phase 1 clinical trials, gene therapy appears to have been effective in partially correcting the blindness of at least one retinal degeneration, and cell replacement therapy in mouse models of retinal degeneration is very promising. Finally, I will report new findings on the role of one transcription factor gene, Prdm8, in retinal development. Loss of function of this gene leads to a virtual absence of bipolar cells, the major interneurons in the retina, and also to fascinating neuromuscular abnormalities [Ross et al., 2011]. Supported in part by grants from the Canadian Institutes of Health Research and the Macula Vision Research Foundation. References Bramall AN, Wright AF, Jacobson SG, McInnes RR. 2010. The genomic, biochemical, and cellular responses of the retina in inherited photoreceptor degenerations and prospects for the treatment of these disorders. Annu Rev Neurosci 33:441–472. Ross SE, McCord AE, Jung C, Atan D, Mok SI, Hemberg M, Kim TK, Salogiannis J, Hu L, Cohen S, Lin Y, Harrar D, McInnes RR, Greenberg ME. 2012. Bhlhb5 and prdm8 form a repressor complex involved in neuronal circuit assembly. Neuron. Jan 26;73(2):292–303. What Can One Learn From Fetal Facies: Is it a Clue to Diagnosis? Deborah Krakow, MD1 1Department of Orthopaedic Surgery, Human Genetics and Obstetrics and Gynecology, David Geffen School of Medicine, UCLA, Los Angeles, California Improvements in prenatal fetal ultrasound based on technological advancements have yielded superior images of many organ systems throughout gestational ages. This is especially true of the fetal facies. Ultrasound can evaluate both the bony structures as well as the soft tissue contours. Absolute measurements of the orbital diameters, philtrum, and mandible can give definite evidence for hypo- and hypertelorism, abnormal philtrums, and micrognathia. The recognition of well-described craniofacial disorders can be translated into the fetal period, as soon as the early second trimester. Abnormal craniofacial finding can be readily appreciated in the skeletal dysplasia group of disorders, craniosynostosis group of disorders, and cleft/lip palate syndromes. Determining the constellation of abnormal facial findings can help direct the prenatal geneticists toward differential diagnoses, including recognition of novel disorders. These diagnoses can then be refined based on abnormalities in other organ systems and well as using molecular diagnostics to help identify the causative mechanisms. Clinical Approach to the Child With Cleft or Craniofacial Anomalies Marilyn C. Jones1 1Division of Genetics, Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, California Facial clefts and other craniofacial anomalies (CFA) constitute a group of birth defects that are both pathogenically and etiologically heterogeneous. With respect to pathogenesis, CFA's can be classified as malformations, deformations, disruptions, or dysplasias. Malformations do not change over time. Most are due to multifactorial inheritance and the treatment is typically surgical. Deformations have the potential to improve with time and postural intervention. Disruptions do not recur, but the treatment is surgical. The altered growth potential in dysplasias raises concerns about progression and the development of neoplasia over time. With respect to etiology, CFAs are the result of genomic changes (dosage imbalance with gain or loss of groups of genes), genetic changes (at the level of the DNA itself), environmental factors, or the interaction of environmental factors with a specific genetic background that renders an individual at risk for a specific CFA. The clinical approach starts with defining the pathogenesis of the specific craniofacial anomaly (such as failure of formation of the frontonasal process leading to a midline cleft lip) and using the history and physical examination to elucidate etiology (such as parent with a single central incisor might suggest a mutation in SHH where as a history of poorly controlled diabetes and the presence of sacral agenesis might suggest diabetic embryopathy). Genetic Regulation of Bone Extracellular Matrix Mineralization Monzur Murshed1 1Department of Medicine and Faculty of Dentistry, McGill University, Montreal, Quebec, Canada Mineralization of vertebrate bone extracellular matrix (ECM) is a physiologic process. In contrast, soft tissue mineralization is a pathologic condition. Initiation of ECM mineralization requires a scaffold of fibrillar proteins such as collagen or elastin within which critically sized nuclei of salts of calcium and inorganic phosphate precipitate and become stable. These precipitates later grow and mature into hydroxyapatite crystals. Interestingly, although suitable scaffolding proteins are present in many soft tissues, normally, ECMs in these tissues do not mineralize. There are two possibilities that may explain this phenomenon. Firstly, it is possible that an activator of mineralization is missing in these soft tissues, and secondly, that soft tissue mineralization is actively prevented by the presence of mineralization inhibitors. Several key studies now identify the latter as the most likely explanation. In fact, absence or removal of mineralization inhibitors is a prerequisite for the initiation of mineralization in the bone microenvironment. We provided genetic evidence suggesting that bone mineralization can be explained, at least in part, by the matrix composition and by the enzymatic removal of pyrophosphate, a ubiquitously present small-molecule mineralization inhibitor, from the bone ECM. More recently, we demonstrated a local role for Sphingomyelin phosphodiesterase 3 (SMPD3), a lipid metabolizing enzyme, in bone mineralization. A deletion mutation in Smpd3 leads to severe skeletal dysplasia in mice. Our in vivo genetic experiments suggest that SMPD3 enzymatic activity is necessary for normal bone mineralization and skeletal development. Mammalian Mandibular Modules: 20 Years Since the “Atchley–Hall” Model Brian K. Hall1 1Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada It is 20 years since Atchley and Hall [1991] published a model for the development and evolution of complex morphological structures using the mammalian mandible (dentary) as the exemplar anatomical structure. Included in the model was the development of the concept of modularity of morphology, modules consisting of aggregations (condensations) of cells that are the primary resource for the development of individual bones or cartilages. In this first of a series of presentations/papers to review the model, I examine our current understanding of cellular modules of the murine dentary. The 1991 model postulated that the dentary arose from six cell condensations of neural-crest-derived cells. Four were skeletogenic forming the ramus and the three processes of the dentary. Two were odontogenic, forming the incisor and molar teeth and associated alveolar bone. Subsequent studies reveal that a single skeletogenic unit forms the bone of the ramus and the angular, condylar, and coronoid processes. In mice the distal cartilages on these processes are secondary, arising from the periosteum. In rats and humans, these cartilages are sesamoids arising in separate condensations outside the dentary. Thus, the single osteo-chondrogenic condensation in mice is represented in rats and humans by four cell populations; one osteogenic and three sesamoid (chondrogenic) condensations. The significance of these differences for our understanding of the cellular and molecular mechanism underlying mandibular development and for the application of studies from other mammalian species to human craniofacial development will be documented and discussed. Supported by NSERC of Canada (A5056). Reference Atchley WR, Hall BK. 1991. A model for development and evolution of complex morphological structures. Biol Rev Camb Philos Soc 66:101–157. GWAS Follow-Up Mutation Screen and Expression Analysis Implicate ARHGAP29 as a Novel Candidate Gene for Nonsyndromic Cleft Lip/Palate Elizabeth J. Leslie1, M. Adela Mansilla1, Leah C. Biggs1, Kristi Schuette1, Steve Bullard2, Tian-Xiao Zhang3, Margaret Cooper4, Martine Dunnwald1, Andrew C. Lidral2, Mary L. Marazita4, Terri H. Beaty3, Jeffrey C. Murray1 1Department of Pediatrics, University of Iowa, Iowa City, Iowa 2Department of Orthodontics, University of Iowa, Iowa City, Iowa 3Department of Epidemiology, School of Public Health, Johns Hopkins University, Baltimore, Maryland 4Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania Nonsyndromic cleft lip and/or palate (NSCL/P) is a common birth defect with complex etiology. Genome-wide association studies have successfully identified novel loci associated with NSCL/P including one near the ABCA4 gene, mutations in which cause several retinal disorders. Neither expression analysis nor mutation screening support a role for ABCA4 in the etiology of NSCL/P, so we investigated the adjacent gene, ARHGAP29, encoding Rho GTPase activating protein 29. ARHGAP29 has preferential activity toward RhoA, which has many functions related to cellular shape, movement, and proliferation, all critical for craniofacial development. Expression analysis using a mouse demonstrated that Arhgap29 is present in the epithelium and mesenchyme of the medial and lateral nasal processes and the mandibular processes at E10.5, and the oral and medial edge epithelia and palatal mesenchyme at E14.5. Sequencing of ARHGAP29 in 962 individuals with NSCL/P and 972 unrelated controls from the Philippines and the US revealed one nonsense, one frameshift, and 14 missense variants, which are overrepresented in cases (P = 0.03). We tested the most associated SNP (rs560426) near ABCA4 and ARHGAP29 for genetic interaction with other candidate genes, identifying a possible interaction with IRF6 (rs2235371; P = 0.04). This interaction is supported by reduced expression of Arhgap29 in the oral epithelium of an Irf6-null mouse, suggesting a novel pathway for clefting involving the transcription factor IRF6 interacting with the Rho pathway via ARHGAP29. The combination of genome-wide association, rare coding sequence variants, craniofacial expression, and interactions with a known clefting gene support a role for ARHGAP29 in NSCL/P. Supported by NIH DE08559 and DE020057. Autosomal Dominant Multiple Natal Teeth With Selective Tooth Agenesis John M. Graham Jr1, Nancy Kramer1, Vincent Funari1, Ophir Klein2, Kerstin Seidel2, Piranit Kantaputra3, Kent D. Taylor1 1Medical Genetics Institute, Cedars Sinai Medical Center, Los Angeles, California 2Department Orofacial Sciences, University of California, San Francisco, California 3Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand We report a 5-generation family with autosomal dominant multiple natal teeth followed by selective tooth agenesis, which is not associated with any nondental features. Natal teeth are usually a sporadic isolated finding in an otherwise normal infant. Familial occurrence is rare but has been reported to be autosomal dominant. Autosomal dominant agenesis of teeth can be caused by mutations in the homeobox gene MSX1. Other families with autosomal dominant oligodontia have mutations in PAX9, and selective agenesis of only the permanent teeth has been linked to 10q11.2-q21. A family with isolated X-linked selective tooth agenesis resulted from mutations EDA. Mutations in WNT10A have been associated with isolated hypodontia. The genetic basis for isolated natal teeth is unknown. DNA from 28 family members was analyzed on the Illumina OMNI-express chip using 733,120 SNPs and mapped to an approximately 2 Mb segment on chromosome 1q36.11 with LOD score 2.97 at 23.8–25.8 Mb (GRCh37/hg19; MERLIN). By dividing the pedigree into three 3-generation families, a region of association was found located between LOC284632 and GRHL3 (parenTDT, P = 0.005 for rs11249039, rs11249045, or rs7526505). GRHL3 is a gene expressed exclusively in surface ectoderm in drosophila, where it plays an essential role in cuticle formation. Expression of the murine Grhl3 gene is found in ectodermally derived tissues including the oral epithelium. Sequencing of the region of association is underway, and experimental models are being developed to test the hypothesis that variation in the regulation of this gene might play a role in this phenotype. Is the Craniofacial Phenotype Sufficient to Characterize FGFR-Related Craniosynostosis Syndromes? Yann Heuzé1, Neus Martínez-Abadías1, Jennifer M. Stella1, Federico Di Rocco2, Corinne Collet3, Gemma García Fructuoso4, Mariana Alamar4, Lun-Jou Lo5, Simeon A. Boyadjiev6, Joan T. Richtsmeier1 1Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania 2Craniofacial Surgery Unit, Department of Pediatric Neurosurgery, Hôpital Necker–Enfants Malades,University Paris V, Paris, France 3Laboratoire de Biochimie et de Biologie Moléculaire, INSERM U606, Paris, France 4Servei de Neurocirurgia, Hospital Sant Joan de Déu, Barcelona, Spain 5Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan 6Section of Genetics, Department of Pediatrics, University of California Davis, Sacramento, California More than 180 craniosynostosis syndromes (CS) have been described, the more common CS being associated with mutations in fibroblast growth factor receptors (FGFRs). These “FGFR-related CS” show the characteristic premature fusion of one or several cranial sutures along with additional craniofacial, neural, limb, heart, lung, and/or skin anomalies. Despite the potentially high number of causative mutations for some of these FGFR-related CS, clinical diagnoses are quite reliable. However, our morphometric analysis based on landmarks collected from skull CT images of patients with Apert (n = 19), Crouzon (n = 9), Pfeiffer (n = 5), and Muenke (n = 4) syndromes along with those of unaffected children (n = 20) shows that these diagnostic categories are more difficult to establish when skull shape is the only trait considered. Indeed, we observe substantial overlap between craniofacial phenotypes, particularly of Apert, Pfeiffer and Muenke syndromes. The craniofacial phenotype as characterized by CT data is not sufficient to characterize FGFR-related CS. The cases that are most different from the unaffected individuals are the syndromic cases with bicoronal craniosynostosis. When syndromic cases displaying bicoronal craniosynostosis (n = 17) are compared with unaffected individuals (n = 20) and with children presenting with nonsyndromic bicoronal craniosynostosis (n = 14), our data provide a clear separation between craniofacial phenotypes of syndromic and nonsyndromic cases. The syndromic cases with bicoronal craniosynostosis display frontal bossing and severe midfacial hypoplasia. These last results indicate that in the case of bicoronal craniosynostosis the FGFR-related causative mutation and/or the molecular pathway affected by this mutation generates additional cranial dysmorphologies. Supported in part by NIH/NIDCR R01DE018500, 3R01 DE018500-02S1, R01DE016886, and CDC 5R01 DD000350. Understanding Phenotypic Variability in Neurodevelopmental Disorders Santhosh Girirajan1, Jill A. Rosenfeld2, Blake C. Ballif2, Lisa G. Shaffer2, Evan E. Eichler1 1Department of Genome Sciences, University of Washington, Seattle, Washington 2Signature Genomics Laboratory, Spokane, Washington We recently proposed a two-hit model to explain the phenotypic variability associated with a 520-kbp microdeletion on chromosome 16p12.1, wherein, the microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large (>500 kbp) copy number variants (CNVs). We extended our model to include 72 genomic disorders and examined CNV data from 32,587 cases with intellectual disability and congenital malformation for the presence of two large CNVs compared to 8,635 controls. Of the 2,312 cases with a known genomic disorder, 233 (10.2%) cases carried another CNV >500 kbp and 373 carried another CNV >150 kbp elsewhere in the genome. For 45/233 (19%) of these two-hit carriers, the second CNV was also associated with a genomic disorder. While the frequency of second hits was higher in CNVs associated with variable expressivity such as del15q13.3, del16p11.2, dup16p13.11, del16p12.1, and del and dup1q21.1, we found a positive correlation (Spearman correlation, r = 0.64, P < 0.001) between the proportion of inherited cases and the prevalence of the second hit. Analysis of parental DNA shows a combination of inherited and de novo events contributing to the occurrence of two hits in the probands. Pathway analysis of genes within the second hit CNVs shows disruption of genes involved in cellular signaling, neurological, and developmental functions. Our data provide strong support for the two-hit model to explain variable expressivity in genomic disorders and, overall, presents an oligogenic basis for the study of complex diseases. Supported by NIH HD065285 to EEE. Sphingomyelin Phosphodiesterase 3, a Novel Regulator of Skeletal Development and Mineralization Zohreh Khavandgar1, Robert Scott Kiss2, Jingjing Li3, Monzur Murshed1,3 1Faculty of Dentistry, McGill University, Montreal, Quebec, Canada 2Division of Cardiology, McGill University Health Center, Montreal, Quebec, Canada 3Department of Medicine, McGill University, Montreal, Quebec, Canada Mineralization of vertebrate bone and tooth extracellular matrix is a genetically regulated process. One of the latest additions to the growing list of mineralization regulators is Sphingomyelin phosphodiesterase 3 (Smpd3). Smpd3 encodes a neutral sphingomyelinase that cleaves sphingomyelin to generate bioactive lipid metabolites. A deletion mutation called fragilitas ossium (fro) in the murine Smpd3 gene leads to severe skeletal dysplasia and perinatal death. In a recent study, it has been suggested that SMPD3 activity in the brain regulates skeletal development through endocrine factors. To further understand the role of SMPD3 in skeletal development, we examined endochondral ossification during early skeletogenesis in fro/fro mice. We observed an impaired apoptosis of the hypertrophic chondrocytes and severely under-mineralized cortical bones in E15.5 fro/fro embryos. To investigate whether SMPD3 plays a cell-autonomous role in these tissues, we generated fro/fro;Col1a1-Smpd3 mice, in which osteoblast-specific expression of Smpd3 corrected the fro/fro skeletal abnormalities and prevented perinatal deaths. Although the bone mineralization defects were fully corrected in fro/fro;Col1a1-Smpd3 embryos, their cartilage phenotype was largely unaffected. In the current study, we demonstrate a critical role for SMPD3 metabolites during in vitro mineral deposition by MC3T3-E1 pre-osteoblasts. Our data identify SMPD3 as a novel regulator of skeletal development and mineralization. Supported by Canadian Institute of Health Research and Osteogenesis Imperfecta Foundation, USA. A Rare DNA Variant in a cis-Overlapping Motif (COM) in an IRF6 Enhancer Element is Associated With Van der Woude Syndrome Walid D. Fakhouri1, Fedik Rahimov2, Huiqing Zhou3, Tianli Du1, Evelyn N. Kouwenhoven3, Hans van Bokhoven3,4, Jeffrey C. Murray2, Brian C. Schutte1,5 1Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan 2Department of Pediatrics, The University of Iowa, Iowa City, Iowa 3Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands 4Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 5Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan Cleft lip and palate (CLP) is one of the most common birth defects in humans. Mutations in interferon regulatory factor 6 (IRF6) cause Van der Woude syndrome (VWS), an autosomal dominant form of CLP, and contribute risk for isolated CLP, including a common DNA variant rs642961. Rs642961 is located in MCS9.7, a multi-species conserved sequence that is near IRF6. MCS9.7 element was shown to possess enhancer activity that mimicked the expression of endogenous Irf6. In order to identify possible etiologic DNA variants, we sequenced MCS9.7 in DNA samples obtained from individuals with VWS. We screened 48 DNA samples for which no disease-causing mutation was detected in IRF6 exons. We observed one new DNA variant that is an A insertion and is predicted to disrupt the DNA binding for both p63 and for bHLH transcription factors. We focused on four members of bHLH family whose expression pattern appeared to overlap with Irf6. Using a DNA binding assay, we observed that this DNA variant abrogated binding by p63 and reduced the binding affinity for the bHLH trans factors. In a transient transactivation assay, we observed strong enhancer activity by the MCS9.7 element. This activation was highly dependent on p63, and the activation was abrogated by the A insertion mutation. In conclusion, these data are consistent with the hypothesis that the rare DNA variant at the cis-overlapping motif in MCS9.7 is etiologic for VWS, and supports the rationale for additional mutation screening of the MCS9.7 enhancer element in patients with CLP. Supported in part by NIH-DE13513. A Systems Biology Approach to Cleft Lip and Palate Evelyn J. Bowers1 1Department of Anthropology, Ball State University, Muncie, Indiana The etiology of clefts may follow a multifactorial-threshold model. That model, however, fits poorly. Some clefts are teratogenic; others, genetic, occasionally following a Mendelian pattern. Although human sibships are usually too small for testing, the recurrence frequency may approximate what would be expected for a double recessive in a two factor cross, 1/16 or 6.25%. About 25% of CLP is attributable to known genetic pathways. It appears that CLPs result from alleles or teratogens which slow neural crest cell migration as the known pathways may. My group (Bowers) have found that CLPs are systematic disorders, not alterations of the head and face alone. Affected children sometimes have reduced heights and delayed maturation, and frequently have reduced elbow breadths, with normal triceps skinfolds and arm circumferences. We found significantly negative standard deviation scores (Zs) for elbow breadth in a sample of 209 children, ages 2–18:11, divided by sex, age group, and whether the cleft was unilateral or bilateral. Average Zs ranged from −0.40 (P < 0.05) to −1.27 (P < 0.001). Only boys above age 7:7 with bilateral CLP had non-significant average Zs, and these too were negative. This suggests that one of the molecules contributing to the formation of both membranous and endochondral bone, such as the transcription factor RUNX2, may be involved. Here, I start to trace the regulatory circuitry which may link Runx2 to the pathways with known involvement. References Bowers EJ, Mayro RF, Whitaker LA, Pasquariello PS, LaRossa D, Randall P. 1987. General body growth in children with clefts of the lip, palate and craniofacial structure. Scand J Plastic Reconstr Surg 21:7–14. Bowers EJ, Mayro RF, Whitaker LA, Pasquariello PS, LaRossa D, Randall P. 1988. General body growth in children with cleft palate and related disorders: Age differences. Am J Phys Anth 75:503–515. Bowers EJ. 2011. Growth in children with clefts: Serial hand-wrist X-ray evidence. Cleft Palate Craniofacial J 48(6):762–772. Alterations in Postnatal Craniofacial Bone Mineral Density and Volume in the Fgfr2Y394C/+ Beare–Stevenson Cutis Gyrata Syndrome Mouse Model Christopher Percival1, Yingli Wang2, Xueyan Zhou2, Ethylin Jabs2, Joan Richtsmeier1 1Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania 2Department of Genetics and Genomic Sciences, Mt. Sinai School of Medicine, New York, New York A novel technique is used to quantify individual cranial bone volume and relative bone mineral density across the murine skull from micro-computed tomography images and, in doing so, highlights the association between low bone density, low bone volume, and craniosynostosis in the Fgfr2Y394C/+ mouse model of Beare–Stevenson cutis gyrata syndrome at P0 and at P8. While landmark based morphometric analysis indicates that the severity of dysmorphology in craniofacial form varies across the skull, the influence of the Fgfr2 Y394C mutation on rates of bone volume increase appear standard for all bones measured. These results suggest that this mutation influences bone cell activity across the skull, even at sites quite distant from the prematurely fused sutures that define craniosynostosis syndromes. The net volume reduction of high-density material in some mutant bones suggests that osteoclast activity, in addition to that of osteoblast, is affected during this early postnatal period. This novel study provides important information on the effect of the Fgfr2 Y394C mutation on endochondral and intramembranous bone development across the skull, complementing the results of morphometric analyses, and providing the basis for hypotheses that can be tested with more in depth histological, molecular, and cellular studies. Supported in part by NIH/NIDCR R01-DE018500 (JTR), 3R01 DE018500-02S1 (JTR and EWJ), and NSF BCS-0725227. Assessing the Oral Microbiota of Healthy and Alcohol-Treated Rats Using Whole-Genome DNA Probes From Human Bacteria Zaher Jabbour1, Cássio do Nascimento2, Michel El-Hakim3, Janet E. Henderson4, Rubens Albuquerque1 1Faculty of Dentistry, Division of Restorative Dentistry, McGill University, Montreal, Quebec, Canada 2Faculty of Dentistry of Ribeirao Preto, Department of Dental Materials and Pros
Год издания: 2012
Авторы: Dwight R. Cordero
Издательство: Wiley
Источник: American Journal of Medical Genetics Part A
Ключевые слова: Medical and Biological Sciences
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