Subscribe to RSS
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/s-0041-1726162
Clinical and Molecular Study of the NOG Gene in Families with Mandibular Micrognathism
Funding This project was financed by Pontificia Javeriana University, grant no: 4397 and 9217.![](https://www.thieme-connect.de/media/10.1055-s-00042133/202104/lookinside/thumbnails/10-1055-s-0041-1726162-1.jpg)
Abstract
Objectives Previous studies showed that noggin gene (NOG) sequence alterations, as well as epigenetic factors, could influence mandibular development. The aim of this study was to analyze clinical characteristics, NOG gene sequences, and promoter methylation sites in patients with mandibular micrognathism.
Materials and Methods A total of 35 individuals of five Colombian families were subject to clinical and cephalometric analysis for mandibular micrognathism. One nonaffected individual of each family was included as a control. DNA was isolated from whole blood sample from all individuals by salting out method. Nine NOG gene fragments were amplified by polymerase chain reaction (PCR) and sequenced. Identification of CpG islands for methylation analysis at the NOG gene promoter was performed by MSP-PCR kit (Qiagen R).
Statistical Analysis A descriptive statistical analysis was carried out evaluating the presence or absence of genetics variants and the methylation sites in the NOG gene.
Results NOG sequence results of affected individuals with mandibular micrognathism for one of the families studied demonstrated that they were heterozygous for 672 C/A (new mutation). For a second family, individuals were heterozygous for 567 G/C (single nucleotide polymorphism [SNP] RS116716909). For DNA analyzed from all patients studied, no methylations were observed at the NOG gene promoter region.
Conclusion Our results suggested that 672 C/A and 567 G/C variants could be involved in the presence of mandibular micrognathism. Moreover, lack of methylation sites at the NOG gene promoter region of all individuals studied suggests possibly other epigenetic factors could modulate mandibular growth. The search of genetic variants related with mandibular micrognathism will allow to predict in an integral way the development patterns of the patients and therefore establish a better clinical treatment.
Publication History
Article published online:
30 September 2021
© 2021. European Journal of Dentistry. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Thieme Medical and Scientific Publishers Pvt. Ltd.
Thieme Medical and Scientific Publishers Pvt. Ltd.
-
References
- 1 Mossey PA, Modell B. Epidemiology of oral cleft: an international perspective. In: Wyszynski DF, ed. Cleft lip and palate. From Origin to Treatment. New York, NY: Oxford University Press 2002
- 2 Holder-Espinasse M, Abadie V, Cormier-Daire V. et al Pierre Robin sequence: a series of 117 consecutive cases. J Pediatr 2001; 139 (04) 588-590
- 3 Pruzinsky T. Social and psychological effects of major craniofacial deformity. Cleft Palate Craniofac J 1992; 29 (06) 578-584 discussion 570
- 4 Chigurupati R, Massie J, Dargaville P, Heggie A. Internal mandibular distraction to relieve airway obstruction in infants and young children with micrognathia. Pediatr Pulmonol 2004; 37 (03) 230-235
- 5 Martínez-Plaza A, Martínez-Lara I, García-Medina B, Fernández- Valadés R. Distracción ósea: tratamiento de la apnea obstructiva en neonatos con micrognatia. Rev Esp Cir Oral Maxilofac 2011; 33 (02) 67-74
- 6 Yu S, Tang Q, Xie M. et al Circadian BMAL1 regulates mandibular condyle development by hedgehog pathway. Cell Prolif 2020; 53 (01) e12727
- 7 Mina M, Wang YH, Ivanisevic AM, Upholt WB, Rodgers B. Region- and stage-specific effects of FGFs and BMPs in chick mandibular morphogenesis. Dev Dyn 2002; 223 (03) 333-352
- 8 Tucker AS, Yamada G, Grigoriou M, Pachnis V, Sharpe PT. Fgf-8 determines rostral-caudal polarity in the first branchial arch. Development 1999; 126 (01) 51-61
- 9 Shigetani Y, Nobusada Y, Kuratani S. Ectodermally derived FGF8 defines the maxillomandibular region in the early chick embryo: epithelial-mesenchymal interactions in the specification of the craniofacial ectomesenchyme. Dev Biol 2000; 228 (01) 73-85
- 10 Ferguson CA, Tucker AS, Sharpe PT. Temporospatial cell interactions regulating mandibular and maxillary arch patterning. Development 2000; 127 (02) 403-412
- 11 Ekanayake S, Hall BK. The in vivo and in vitro effects of bone morphogenetic protein-2 on the development of the chick mandible. Int J Dev Biol 1997; 41 (01) 67-81
- 12 Kanzler B, Foreman RK, Labosky PA, Mallo M. BMP signaling is essential for development of skeletogenic and neurogenic cranial neural crest. Development 2000; 127 (05) 1095-1104
- 13 Bonilla-Claudio M, Wang J, Bai Y, Klysik E, Selever J, Martin JF. Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development. Development 2012; 139 (04) 709-719
- 14 Brunet LJ, McMahon JA, McMahon AP, Harland RM. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 1998; 280 (5368) 1455-1457
- 15 McMahon JA, Takada S, Zimmerman LB, Fan CM, Harland RM, McMahon AP. Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev 1998; 12 (10) 1438-1452
- 16 Zimmerman LB, De Jesús-Escobar JM, Harland RM. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 1996; 86 (04) 599-606
- 17 Valenzuela DM, Economides AN, Rojas E. et al Identification of mammalian noggin and its expression in the adult nervous system. J Neurosci 1995; 15 (09) 6077-6084
- 18 Potti TA, Petty EM, Lesperance MM. A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD). Hum Mutat 2011; 32 (08) 877-886
- 19 Gong Y, Krakow D, Marcelino J. et al Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet 1999; 21 (03) 302-304
- 20 Masuda S, Namba K, Mutai H. et al A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss. Biochem Biophys Res Commun 2014; 447 (03) 496-502
- 21 Sémonin O, Fontaine K, Daviaud C, Ayuso C, Lucotte G. Identification of three novel mutations of the noggin gene in patients with fibrodysplasia ossificans progressiva. Am J Med Genet 2001; 102 (04) 314-317
- 22 Anderson RM, Lawrence AR, Stottmann RW, Bachiller D, Klingensmith J. Chordin and noggin promote organizing centers of forebrain development in the mouse. Development 2002; 129 (21) 4975-4987
- 23 Gutiérrez SJ, Gómez M, Rey JA, Ochoa M, Gutiérrez SM, Prieto JC. Polymorphisms of the noggin gene and mandibular micrognathia: a first approximation. Acta Odontol Latinoam 2010; 23 (01) 13-19
- 24 Song T, Shi J, Guo Q. et al Association between NOGGIN and SPRY2 polymorphisms and nonsyndromic cleft lip with or without cleft palate. Am J Med Genet A 2015; 167A (01) 137-141
- 25 Mangold E, Ludwig KU, Birnbaum S. et al Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genet 2010; 42 (01) 24-26
- 26 Setó-Salvia N, Stanier P. Genetics of cleft lip and/or cleft palate: association with other common anomalies. Eur J Med Genet 2014; 57 (08) 381-393
- 27 Gudbjartsson DF, Walters GB, Thorleifsson G. et al Many sequence variants affecting diversity of adult human height. Nat Genet 2008; 40 (05) 609-615
- 28 Nimmagadda S, Buchtová M, Fu K. et al Identification and functional analysis of novel facial patterning genes in the duplicated beak chicken embryo. Dev Biol 2015; 407 (02) 275-288
- 29 Garrick D, Fiering S, Martin DI, Whitelaw E. Repeat-induced gene silencing in mammals. Nat Genet 1998; 18 (01) 56-59
- 30 Xu J, Wang AH, Oses-Prieto J. et al Arginine methylation initiates BMP-induced Smad signaling. Mol Cell 2013; 51 (01) 5-19
- 31 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16 (03) 1215
- 32 Zody MC, Garber M, Adams DJ. et al DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage. Nature 2006; 440 (7087) 1045-1049
- 33 Marcelino J, Sciortino CM, Romero MF. et al Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding. Proc Natl Acad Sci U S A 2001; 98 (20) 11353-11358
- 34 Takano K, Ogasawara N, Matsunaga T. et al A novel nonsense mutation in the NOG gene causes familial NOG-related symphalangism spectrum disorder. Hum Genome Var 2016; 3: 16023
- 35 Sha Y, Ma D, Zhang N, Wei X, Liu W, Wang X. Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family. BMC Med Genet 2019; 20 (01) 133
- 36 Liu WD, Feng XL, Ren CP. et al Critical role of Cys168 in noggin protein’s biological function. Acta Biochim Biophys Sin (Shanghai) 2005; 37 (03) 181-185
- 37 Higashi K, Inoue S. Conductive deafness, symphalangism, and facial abnormalities: the WL syndrome in a Japanese family. Am J Med Genet 1983; 16 (01) 105-109
- 38 Dąbrowska M, Dąbrowski P, Tabarkiewicz J. Fibrodysplasia Ossificans Progressiva – a presentation of cases and literature review. European J of Clin and Experim Med. 2019; 2: 184-191
- 39 Moffett SP, Dillon KA, Yerges LM. et al Identification and association analysis of single nucleotide polymorphisms in the human noggin (NOG) gene and osteoporosis phenotypes. Bone 2009; 44 (05) 999-1002
- 40 Angov E. Codon usage: nature’s roadmap to expression and folding of proteins. Biotechnol J 2011; 6 (06) 650-659
- 41 Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. 4th ed. New York, NY: Garland Science 2007
- 42 Yerges LM, Klei L, Cauley JA. et al High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men. J Bone Miner Res 2009; 24 (12) 2039-2049