PAX9 and MSX1 transcription factor genes in non-syndromic dental agenesis Vane ssa R odri gues Paix a ˜ o-Co ˆ rtes a,1 , Tatiana Braga b,1 , Francisco Mauro Salzano a , Karina Mundstock b , Carlos Alberto Mundstock b , Maria Ca ´tira Bortolini a, *a Departamento de Gene ´tica, Instituto de B iocie ˆ ncias, Universidade Federal do Rio Grande do Sul, Caixa Postal 15053, 91501-97 0 Porto Alegre , RS, Brazil b Faculdade de Odontologia, Universidade Federal do Rio Grande do Sul, Caixa Postal 1118, 90035-003 Porto Alegre, RS, Brazil 1. In trod uction Therole of hete rod ontyfor themammal ianevolu tion aryhistor y is well-recognized. 1,2 For humans, teeth have also a prominen t relevance to socio-cultural interactions and at an individual level can represen t a bad or g ood life quality . 3,4 Agenesis of one or more teeth is the most common anomaly observed in the human craniofacial development. 1,3,5–7 Amongst all non-syn- dromic (familial or sporadic) agenesis conditions detected in huma ns, th e most common is the abs ence of third molar(s) – in avera ge about20% ofthe individuals ina populatio n donot ha ve at least one third molar. Upper lateral incisors and second premola r ageneses are also common, being second in frequen- cies (2.2% and 3.4%, respectively). 8–10 archives of oral biology 56 (2011) 337–344 a r t i c l e i n f o Article history: Accepte d 27 Octob er 2010 Keywords: PAX9 gene MSX1 gene Dental agenesis Developmental genes a b s t r a c t Objective: The molecular variation of paired domain box gene 9 (PAX9) was previously inv esti gate d by ourresearc h group anda hig h degr ee of evolution ary conserv ation incodi ngand non-coding regions was observed except in exon 3. PAX9 is a transcription factor imp ort antin too th develop ment, andwe wan ted to veri fy itsrole in dentalagenes is in det ail. Since dental development is a complex trait we also decided to examine the influence ofanother transcription factor, muscle segment homeodomain-homeobox 1 (MSX1) on it. Design: A total of 360 consecutively ascertained patients seeking orthodontic treatment were scre enedfor too th agen esi s and 33% of the m wer e found to haveit. Thirty- five of those with agenesis and 15 controls had their DNA studied for PAX9 exons 2, 3, 4 and adjacent regi ons (t ot alof 1476basepair s,bp) aswellas MSX1exon2 (6 98 bp).A tr io(a pr oband and her parents) was also studied. Results: Six polymorphic sites were found, three in PAX9 exon 3 and three in MSX1 exon2. MSX1 rs1095 derived allele occurred in individuals with agenesis only, and two other mutations in this gene had been earlier associated with tooth agenesis. Homozygosity for the PAX9 Ala240Pro mutation was studied in a family (proband and her parents), suggesting recessive inheritance with variable expressivity for the dental agenesis found. Conclusion: Common variants located out of the DNA binding domain of the two PAX9 and MSX1 genes can also be related to tooth agenesis. # 2010 Elsevier Ltd. All rights reserved . * Corresponding author . Tel.: +55 51 3308 9844. E-mail address: [email protected](M.C. Bortolini). 1 These two authors contributed equally to this work. available at www.sciencedirect.com journal homepage: http://www.elsevier.com/locate/aob 0003–99 69/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.archoralbio.2010.10.020
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8/6/2019 Paixao-Cortes_2011_PAX9 and MSX1 Transcription Factor Genes in Non-syndromic
PAX9 and MSX1 transcription factor genes in non-syndromic
dental agenesis
Vanessa Rodrigues Paixao-Cortes a,1, Tatiana Braga b,1, Francisco Mauro Salzano a,Karina Mundstock b, Carlos Alberto Mundstock b, Maria Ca tira Bortolini a,* a Departamento de Gene tica, Instituto de Biociencias, Universidade Federal do Rio Grande do Sul,
Caixa Postal 15053, 91501-970 Porto Alegre, RS, BrazilbFaculdade de Odontologia, Universidade Federal do Rio Grande do Sul, Caixa Postal 1118, 90035-003 Porto Alegre, RS, Brazil
1. Introduction
Therole of heterodontyfor themammalianevolutionaryhistory
is well-recognized.1,2 For humans, teeth have also a prominent
relevance to socio-cultural interactions and at an individual
level can represent a bad or good life quality.3,4 Agenesis of one
or more teeth is the most common anomaly observed in the
human craniofacial development.1,3,5–7 Amongst all non-syn-
dromic (familial or sporadic) agenesis conditions detected in
humans, the most common is the absence of third molar(s) – in
average about20% ofthe individuals ina population donot have
at least one third molar. Upper lateral incisors and second
premolar ageneses are also common, being second in frequen-
cies (2.2% and 3.4%, respectively).8–10
a r c h i v e s o f o r a l b i o l o g y 5 6 ( 2 0 1 1 ) 3 3 7 – 3 4 4
a r t i c l e i n f o
Article history:
Accepted 27 October 2010
Keywords:
PAX9 gene
MSX1 gene
Dental agenesis
Developmental genes
a b s t r a c t
Objective: The molecular variation of paired domain box gene 9 (PAX9) was previously
investigated by ourresearch group and a high degree of evolutionary conservation in coding
and non-coding regions was observed except in exon 3. PAX9 is a transcription factor
importantin tooth development, andwe wanted to verify itsrole in dentalagenesis in detail.
Since dental development is a complex trait we also decided to examine the influence of
another transcription factor, muscle segment homeodomain-homeobox 1 (MSX1) on it.
Design: A total of 360 consecutively ascertained patients seeking orthodontic treatment
were screenedfor tooth agenesis and 33% of them were found to haveit. Thirty-five of those
with agenesis and 15 controls had their DNA studied for PAX9 exons 2, 3, 4 and adjacent
regions (totalof 1476basepairs,bp) aswellas MSX1 exon2 (698 bp).A trio(a proband and her
parents) was also studied.Results: Six polymorphic sites were found, three in PAX9 exon 3 and three in MSX1 exon2.
MSX1 rs1095 derived allele occurred in individuals with agenesis only, and two other
mutations in this gene had been earlier associated with tooth agenesis. Homozygosity
for the PAX9 Ala240Pro mutation was studied in a family (proband and her parents),
suggesting recessive inheritance with variable expressivity for the dental agenesis found.
Conclusion: Common variants located out of the DNA binding domain of the two PAX9 and
ND: No data. All were classified as White.a BCA: Code for patient identification.b Agenesis was characterized by panoramic radiographs and clinical examination. The universal numbering system, which is adopted by the
American Dental Association, was used to identify each tooth (http://www.ada.org/).c 50 flanking intronic segment of PAX9 exon3.d BSA: Code for control identification.
a r c h i v e s o f o r a l b i o l o g y 5 6 ( 2 0 1 1 ) 3 3 7 – 3 4 4340
since the number of missing third molars is different for each
patient. Our results also indicate a possible role of this
polymorphism for lateral incisor development but in this case
other factors may be involved, since one 240Pro homozygote
studied here presents all lateral incisors (the father in Fig. 2).
Finally, it should be stressed that non-syndromic congeni-
tal missing tooth is a complex and heterogeneous trait.7 Fig. 3
shows a network involving 42 teeth development genes,
including the two studied here. Table S3 give details of each
gene of this network, their interconnections, and the wide
range of their functions. In this context, and based in ourresults, MSX1 and PAX9 appear to influence different agenesis
phenotypes, with other known and unknown genes as well as
epigenetic factors having an influence in tooth development.
For instance, nine Ala240Pro G/C heterozygote patients
present third molar agenesis, whilst the trio’s mother and
other four controls with thissame condition showno agenesis
(Table 2 and Fig. 2). These results illustrate the importance of
these other factors in tooth development and agenesis.
5. Conclusion
Our results support an earlier finding that the derived 240Proallele (PAX9 exon 3) is related with third molar agenesis and
that it may have a recessive pattern of inheritance with
variable expressivity. On the other hand, MSX1 rs1095 derived
allele appeared in agenesis affected individuals only. These
results suggest that common variants located out of the DNA
binding domain of these two transcription factor genes can
also be related to tooth agenesis.
Acknowledgement
We would like to thank the patients and controls who made
this study possible.
Funding: Thisresearchwas supportedby Conselho Nacional
de Desenvolvimento Cientıfico e Tecnologico and Fundaca ˜ o de
Amparo a Pesquisa do Estado do Rio Grande do Sul.
Competing interest: None declared.
Ethical approval: Informed consent was obtained from all of
the participants, andthe project wasapprovedby theResearch
and Ethics Committee of the Federal University of Rio Grande
do Sul. In the case of children under 15 years of age, consentwas requested from their parents or from the individual
legally in charge of the child.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.archoral-
bio.2010.10.020.
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