589957

research-article2015
JDRXXX10.1177/0022034515589957Journal of Dental ResearchThe ADAMTS1 Gene

Research Reports: Clinical

Journal of Dental Research
2015, Vol. 94(9) 1196­–1201
The ADAMTS1 Gene Is Associated with © International & American Associations
for Dental Research 2015

Familial Mandibular Prognathism Reprints and permissions:

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DOI: 10.1177/0022034515589957
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X. Guan1, Y. Song1, J. Ott2, Y. Zhang1, C. Li1, T. Xin1, Z. Li3, Y. Gan4,

J. Li1, S. Zhou1, and Y. Zhou5

Abstract
Mandibular prognathism is a facial skeletal malocclusion. Until now, the genetic mechanism has been unclear. The goal of this study
was to identify candidate genes or genomic regions directly associated with mandibular prognathism development, by employing whole
genome sequencing. A large Chinese family was recruited, composed of 9 affected and 12 unaffected individuals, and the inheritance
pattern of this family tends to be autosomal dominant. A single-nucleotide missense mutation in the ADAMTS1 gene (c. 742I>T) was
found to segregate in the family, given that the affected individuals must be heterozygous for the mutation. For mutation validation, we
screened this candidate mutation and 15 tag single-nucleotide polymorphisms in the coding sequence of ADAMTS1 among 230 unrelated
cases and 196 unrelated controls using Sequenom Massarray and found that 3 in 230 cases carried this mutation and none of the controls
did. Final results suggested that 2 single-nucleotide polymorphisms (rs2738, rs229038) of ADAMTS1 were significantly associated with
mandibular prognathism.

Keywords: whole genome analysis, SNV, craniofacial biology/genetics, orthodontic(s), molecular genetics, bioinformatics

Introduction The trait can occur in association with other systematic disor-
ders, such as Apert syndrome and Crouzon syndrome, but we
In a normal facial skeletal relationship, the upper jaw is in a focus on nonsyndromic MP in this study.
more anterior position than the lower jaw, which is defined as MP is a disorder of bone development, and as indicated by
skeletal class I jaw relationship and results in a normal bite and familial recurrence and ethnic aggregation, a genetic compo-
aesthetic facial appearance. Mandibular prognathism (MP; nent plays an important role in its etiology. The most famous
OMIM:176700; Online Mendelian Inheritance of Man, http:// example is the Habsburg jaw in the Spanish Royal family, in
omim.org/entry/176700) is a dentofacial deformity, which is which MP was transmitted through many generations of the
characterized by overgrowth of the lower jaw with or without
undergrowth of the upper jaw. It leads to more prominence in 1
Department of Orthodontics, Peking University School and Hospital of
the lower jaw than the upper jaw and a frontal teeth negative
Stomatology, Beijing, P.R. China
overjet (van Vuuren 1991). The unpleasant facial profile due to 2
Department of Laboratory of Statistical Genetics, Institute of
MP may decrease patients’ self-confidence in social life and Psychology, Chinese Academy of Sciences, Beijing, P.R. China, and
may lead to a severe psychological handicap. The lower ante- Rockefeller University, New York, NY, USA
3
rior teeth cannot bite with upper teeth, leading to low mastica- Department of Oral and Maxillofacial Surgery, Peking University School
tory efficiency (English et al. 2002), which may result in and Hospital of Stomatology. Beijing, P.R. China
4
digestive disorders and compromised nutritional status. The Department of Laboratory of Molecular Biology and Center for
TMD and Orofacial Pain, Peking University School and Hospital of
discrepancy between upper and lower jaw may also cause the
Stomatology. Beijing, P.R. China
deficiency in speech articulation. In most cases, there is no 5
Department of Orthodontics, Center for Craniofacial Stem Cell
abnormal finding in early childhood. However, with the growth Research, Regeneration, and Translational Medicine, Peking University
of the general skeleton, inappropriate developments of upper School and Hospital of Stomatology, Beijing, P.R. China
and lower jaw emerge gradually and accelerate in puberty
A supplemental appendix to this article is published electronically only at
(Shira and Neuner 1976). The combination of orthognathic http://jdr.sagepub.com/supplemental.
surgery and orthodontic treatment is needed for patients with
severe MP to correct upper and lower jaw discrepancies. The Corresponding Author:
Y. Zhou, Department of Orthodontics, Center for Craniofacial Stem
prevalence of MP is much higher in Asian populations (2.1% to
Cell Research, Regeneration, and Translational Medicine, Peking
19.9%), especially in Chinese and Japanese, than in Caucasian University School and Hospital of Stomatology, #22 Zhongguancun
populations (0.48% to 4.3%; Fukui et al. 1989; Tang 1994; Nandajie, Haidian District, Beijing, 100081. P.R. China.
Coltman et al. 2000; Danaie et al. 2006; Perillo et al. 2010). Email: yanhengzhou@vip.163.com

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The ADAMTS1 Gene 1197

Figure.  The characteristic records of a patient with mandibular prognathism (MP) and the pedigree chart of the MP family, (A) The facial lateral
photograph showing a concave facial profile of an MP patient. (B) The cephalometric radiography of the same patient shows the lower jaw being in an
anterior position of the upper jaw. A, subspinale, point of maximum concavity on maxillary alveolus; B, supramentale, point of maximum concavity on
mandibular alveolus; N, nasion, most anterior point on frontonasal suture. A negative ANB angle indicates that the maxilla is positioned posteriorly
relative to the mandible. (C, D) The intraoral photographs show an anterior teeth crossbite and a mesial molar relationship. (E) The Chinese family
recruited in our study is composed of 9 affected and 12 unaffected individuals; the arrow indicates proband.

Habsburg line as a dominant trait with incomplete penetrance, employing whole genome sequencing of 2 affected individuals
which is the most common inheritance pattern of MP (McCullar from a large Chinese family and a case-control study.
1992). However, the molecular genetic basis of this disease
remains poorly understood. Genome-wide linkage analyses of
MP have been carried out in Korean, Japanese, and Chinese Methods
patients and have identified several putative chromosomal loci
Family Recruitment
for MP, including 1p36, 6q25, 19p13.2, 1p22.1, 3q26.2, 11q22,
12q13.13, 12q23, 14q24.3-31.2, and 4p16.1. Candidate genes The Chinese family recruited in our study is composed of 9
within these loci include IGF, TGFB3, HOXC, COL2A1, and affected and 12 unaffected individuals (Fig. E), with ages rang-
LTBP2 (Xue et al. 2010; Li et al. 2011), and some of them have ing from 12 to 67 y. All affected individuals have concave
been identified to play important roles in bone development facial lateral profile, anterior teeth crossbite, class III molar
and metabolism. The inconsistent results of these genome- relationship, and minus ANB angle (Fig. B). The protocols for
wide linkage analyses in different ethnic groups indicate that this study and participant consent were reviewed and approved
the causative gene of MP may not be unique. Furthermore, the by the Institutional Ethics Committee at Peking University
molecular regulation mechanism of jaw development is not School of Stomatology.
fully understood. Therefore, better understanding the genetic MP diagnosis was based on patients’ facial lateral profile,
basis of MP can help us in terms of not only estimating suscep- anterior teeth overjet, molar relationship, and data from cepha-
tibility to this malformation but also better comprehending the lometric analysis. Cephalograms, study models, and bite regis-
molecular mechanism of jaw development. trations were taken from all 21 participants. The lateral
The goal of the present study was to identify candidate genes cephalometric radiographs were taken in a natural head posi-
or genomic regions directly associated to MP development, by tion with maximum contacted intercuspal occlusion. The

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1198 Journal of Dental Research 94(9)

digital films were immediately uploaded to a radiographic platform that efficiently and precisely measures the amount of
database. A computer-based cephalometric and metacarpal- genetic target material and/or variations and is suitable for a
phalange length appraisal was developed with Dolphin variety of research applications, including somatic mutation
Imaging 9.0 (Dolphin Imaging Systems, Chatsworth, CA, profiling, genotyping, methylation analysis, molecular typing,
USA). The diagnosis criteria were as follows: presence of a and quantitative gene expression. Detection by MALDI-TOF
concave facial lateral profile, anterior teeth crossbite, a class mass spectrometry offers high sensitivity and accuracy. Chi-
III molar relationship, and an ANB angle <0.0 degrees (Fig. square or Fisher exact calculations were used to assess Hardy-
B). There is no other symptom shared by the patients or unaf- Weinberg equilibrium and significance in genotype- and
fected individuals. allele-type frequencies between the case and control groups. A
For further validation of findings, a case-control study was P value <0.05 was considered statistically significant.
performed. For this purpose, 230 unrelated MP patients and
196 unrelated 120 controls (class I jaw relationship) were ana-
lyzed. The diagnosis criteria of MP patients were used as men- Quality Control
tioned before. The diagnosis criteria of control patients were as
The first quality check measure was based on read length, and
follows: presence of a straight facial lateral profile, normal
reads <76 bp were regarded as unquantified. Furthermore, we
anterior teeth overbite and overjet, a class I molar relationship,
also employed coverage percentage as a quality check measure
and an ANB angle from 0 to 5 degrees.
to increase reliability in whole genome sequencing, and the
We performed whole genome sequencing on 2 distantly
coverage of the 2 individuals in the MP family were 92.4% and
related affected individuals with the most severe phenotype
91.8%. Therefore, the filtering reads of whole genome sequenc-
(individuals IV-1 and III-11 in Fig. E).
ing were considered reliable.

Whole Genome Sequencing

Genomic DNA was extracted from peripheral blood lympho-
Results
cytes using the QIAmp Blood mini kit (Qiagen, Venlo, the Whole Genome Sequencing and Mendelian
Netherlands), and 1.5 μg of DNA from each individual was
used for construction of the sequencing library with insert sizes
Linkage Analysis Identified a Candidate Single-
of about 500 base pairs (bp). The whole genome of 2 affected nucleotide Missense Mutation for MP
individuals with MP in the Chinese family was sequenced by A mean 88-Gb sequence was generated per affected individual
pair-end sequencing, which was performed on an Illumina as pair-end 76-bp reads in 2 affected individuals with MP. After
HiSeq 2000 platform (Illumina, San Diego, CA, USA) (Bentley discarding low-quality reads, we achieved ~30-fold coverage
et al. 2008). Shorter reads (reads <76 bp) resulted in ambigu- of the genome. SNP calling based on SAMtools gave us
ous alignments, which can be regarded as unquantified and 3,435,919 and 3,450,352 SNPs, respectively, for affected indi-
discarded from whole data. The sequencing reads were mapped viduals IV-1 and III-11 (Fig. E). After filtering for the known
to the reference human genome (GRCh37.5). SNPs and SNVs (single-nucleotide variants) using dbSNP135
and the 1000 Genome Projects database, we found 83 nonsyn-
Variant Calling onymous and 2 splice site mutations shared by the 2 affected
individuals of the Chinese family (Appendix Fig.).
Single-nucleotide polymorphism (SNP) calling was done by This pipeline was repeated using the GATK and 3,511,134
the Sequence Alignment/Map tools (SAMtools 1.7) and and 3,519,355 SNPs, respectively, for affected individuals IV-1
Genome Analysis Toolkit (GATK 1.0.5083) and then filtered and III-11 (Fig. E). Following the same filtering steps as above,
by dbSNP135 and the 1000 Genome Projects database. the 2 individuals shared 53 nonsynonymous SNVs and 5 splice
Ensemble and SIFT predictions were performed to estimate the site mutations.
function of all the single-nucleotide variants. Calling for short Ensemble and SIFT predictions were performed to estimate
coding insertions or deletions (indels) was done by GATK the function of these variants. We focused on those mutations,
only, and structural variants—including long deletions (>60 bp), which could probably damage the protein structure under
tandem duplications, long insertions, inversions, and replace- Ensemble or SIFT prediction, and finally chose 65 candidate
ments—were called by Pindel (Appendix Fig.). SNVs (Appendix Table 1), which are distributed in different
genes to analyze Mendelian linkage among 21 members in this
family using Sequenom Massarray. As a result, we found 1 novel
Mutation Validation
SNV (chromosome 21, 28210577, 1, T/C), which was predicted
Sequenom mass array was used to confirm the presence of to have damaging influence to ADAMTS1 and was strongly
variants identified via whole genome sequencing in the linked with the disease. In total, 10 individuals with the same
Chinese family and in the case-control study. Haploview 4.2 mutations in the ADAMTS1 gene were found in the family, 9 of
software was employed to construct haplotypes of candidate whom present the MP phenotype; that is, there is 1 exceptional
gene. The Sequenom MassARRAY system is a DNA analysis individual who carries the causal mutation but is unaffected.

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The ADAMTS1 Gene 1199

Haploview 4.2 software was employed to construct haplo- Table.  MP and Class I Groups: Number of Subjects with Each
types of ADAMTS1, with the restrictive standards including r2 Genotype and Number of Alleles Found in Each Group (ADAMTS1
Gene).
value >0.8 and minimum allele frequency >0.05, and all the tag
SNPs in the gene were determined. After function analysis, 15 Subjects, n
tag SNPs in the ADAMTS1 gene—besides the mutation observed
SNP: Genotype MP Class I
in the Chinese family—were selected for genotyping, which
included as much functional SNPs as possible (Appendix Table rs2738  
2). We found that 3 in 230 cases carried the mutation obtained  AA 3 5
 CC 180 119
from the MP family and none of the controls did. The chi-square
 AC 47 71
test was used to compare differences in genotype and allele fre-   P = 0.001  
quencies between the case and control groups. All markers were rs229038  
in Hardy-Weinberg equilibrium in both class I and MP groups.  CC 39 48
Two SNPs in ADAMTS1, rs2738 and rs229038, were found to be  GG 87 51
significantly associated with MP (P = 0.001 and P = 0.019,  CG 102 96
  P = 0.019  
respectively; Table and Appendix Table 3).
SNP: Allele Alleles, n

No Indel Is Strongly Related to MP Deformity rs2738  

 A 53 81
Indel calling was done by GATK and then filtered by dbSNP135  C 407 309
and the 1000 Genome Projects database. The intersection   P = 0.000  
indels in the coding sequence of the 2 siblings were used for rs229038  
 C 190 192
Mendelian analysis; 46 indels were used, but none of them
 G 266 198
showed a strong relationship with MP.   P = 0.028  

MP, mandibular prognathism; SNP, single-nucleotide polymorphism.

Discussion
MP is a bone development disorder. The pattern of bone forma-
tion in the mandible includes intramembranous ossification There are several subtypes of MP, such as mandibular over-
and endochondral ossification, with only intramembranous growth with or without maxillary retrusion. Since there is
ossification in the maxilla (Iwata et al. 2010). Maxilla and extensive clinical heterogeneity, the genetic bases of types of
mandible are both derived from the first branchial arch MP may be different (Xue et al. 2010; Li et al. 2011). There are
(Cobourne and Sharpe 2003). The mandible is ossified in the many genes known to be involved in the process of mandibular
fibrous membrane covering the outer surfaces of Meckel carti- development; however, the mechanism of gene regulation
lages (Shibata and Yokohama-Tamaki 2008). These cartilages leading to mandibular overgrowth is still not clear.
form the cartilaginous bar of the mandibular arch. In the sev- Whole genome sequencing is a powerful tool to explore the
enth week of embryonic development, the mesenchymal cells causal variants of genetic disorders. Compared with genome-
aggregate in the region of the mental foramen (an anatomic wide association studies, whole genome sequencing is opti-
structure of the mandible) and then differentiate to osteocytes, mized to detect the role of causal variants in small samples. In
followed by bone matrix formation and ossification, called this study, we chose 1 pedigree to investigate the genetic mech-
the mandibular corpus ossification center (Wyganowska- anism of MP. The clinical features of all patients are similar,
Swiatkowska and Przystanska 2011). In the 13th week of including maxillary deficiency and MP; therefore, the clinical
embryonic development, the condylar cartilage merges with heterogeneity is minimal. According to the pedigree, there is
the mandibular corpus ossification center to form the mandible no difference in the number of male and female affected by
(Orliaguet et al. 1993). The condylar cartilage forms the con- MP, and the inheritance pattern of this family tends to be auto-
dyle through endochondral ossification. Before 1 y after birth, somal dominant. To eliminate background gene variants, we
mandibular development in the sagittal direction occurs due to chose 2 distantly related affected individuals and then per-
the continuous ossification in symphysial fibrocartilage, and formed whole genome sequencing. Although MP has a relative
bone resorption and deposition occur in the anterior and poste- high prevalence, we try to disregard common variants found in
rior borders of the ramus. MP is mainly due to the overgrowth the dbSNP135 and 1000 Genome Projects databases because
of the mandible in the sagittal direction (Chang et al. 2006). rare large-effect mutations are now recognized as causes of
However, there is no abnormal finding in early childhood. many common medical conditions (McClellan and King 2010).
With the growth of the general skeleton, inappropriate devel- Therefore, a pipeline was subsequently developed to recover
opments of upper and lower jaw emerge gradually and clearly rare variants (i.e., absent or <1% frequency between 2 data-
accelerate in puberty (Noble et al. 2007). Therefore, abnormal bases), for which the affected individuals should be heterozy-
bone remodeling in adolescence may be responsible for the gous. If unsuccessful, we would turn to more common variants.
occurrence of MP. Fortunately, we found 1 rare variant segregating in the family.

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1200 Journal of Dental Research 94(9)

Combined with linkage analysis, a nonsynonymous single- phenotype of ADAMTS1 mutation manifests as mandibular
nucleotide mutation (c. 742I>T) in ADAMTS1 was the only overgrowth and maxillary hypoplasia.
putative causative variant in all cases. With 1 exception, none The result of mutation validation in unrelated MP patients
of the unaffected individuals carry the mutation in the indicates that the mutation in ADAMTS1 can explain only a
ADAMTS1 gene. The single unaffected individual with the small part of MP occurrence in the Chinese population.
mutation has a straight facial lateral profile; however, the posi- Moreover, ADAMTS1 was not identified in previous genome-
tion of the lower anterior teeth presents a little bit forward, wide association studies. This suggests that ADAMTS1 is not
which is caused by mandibular overgrowth. This indicates the only causative gene of MP, which is coincident with con-
incomplete penetrance, which has been suggested in other clusions in previous studies indicating that MP is a polygenetic
studies (El-Gheriani et al. 2003). disorder (Cruz et al. 2008). Thus, locus and allele heterogene-
The damaging effects of ADAMTS1 mutations (c. 742I>T) ity is expected for MP, including differences in the causative
reported in this study are the first to be described in a jaw gene/alleles among different ethnic groups, populations, and
developmental disorder. ADAMTS—a disintegrin and metal- even families. Therefore, there is so much remaining work to
loprotease with thrombospondin type I motifs—is a family of do for a comprehensive understanding of the genetic outline of
extracellular proteases (Apte 2009). The function of ADAMTS MP.
is to cleave proteoglycans, such as aggrecan, versican, and In summary, we performed whole genome sequencing and
brevican, which has been shown to be involved in various linkage analysis with an MP family and found that 1 nonsyn-
human biological processes (normal or pathologic), including onymous single-nucleotide mutation (c. 742I>T) in ADAMTS1
connective tissue structure, cancer, coagulation, arthritis, was the only affected variant in all cases, indicating that
angiogenesis, cell migration, and bone development (Beristain ADAMTS1 is the causative gene in this pedigree. We validated
et al. 2011; Stanton et al. 2011; Kumar et al. 2012). ADAMTS1 the mutation with 230 unrelated MP patients and 196 controls
is the first member of the ADAMTS protein family that is and found that 3 cases carried this mutation and none of the
involved in proteolytic modification of cell surface proteins controls did. Here, we present the first report of ADAMTS1 as
and extracellular matrices (Rehn et al. 2007). The unique struc- a causative gene of familial MP. It is more important that our
ture of ADAMTS1, characterized by the presence of thrombos- finding first focused on 1 nonsynonymous single-nucleotide
pondin type I motifs, is shared by other newly identified mutation (c. 742I>T) associated with dominant inherited MP.
proteins in mammals and in Caenorhabditis elegans, which Functional studies of ADAMTS1 in bone development are nec-
constitute the ADAMTS subfamily that may perform well- essary to better understand the etiology of MP.
conserved biological functions (Shindo et al. 2000). ADAMTS1
is anchored to the extracellular matrix by an interaction Author Contributions
between its carboxyl-terminal spacing region with its thrombo- X. Guan, Y. Song, Y. Zhou, contributed to conception, design,
spondin type I motifs and sulfated glycosaminoglycans, such data acquisition, analysis and interpretation, drafted the manu-
as heparan sulfate (Kuno and Matsushima 1998). Therefore, script; J. Ott, Y. Zhang, C. Li, T. Xin, Z. Li, Y. Gan, J. Li, S. Zhou,
ADAMTS1 may serve as a local factor processing as-yet- contributed to conception and data analysis, critically revised the
unknown substrates by protease activity. manuscript. All authors gave final approval and agree to be
It has been reported that ADAMTS1 is expressed in the rat accountable for all aspects of the work.
mandible during embryonal and early postnatal stages (Mitani
et al. 2006). ADAMTS1 is also expressed in teeth during erup- Acknowledgments
tion (Sone et al. 2005). Some studies have suggested that
We gratefully appreciate the support of the family and the dentists
ADAMTS1 may play an important role in bone growth, and the who participated in this study. We also thank Dr. Cai Tao, Dr. Wei
deletion of ADAMTS1 would result in development retardation Liping, and Dr. Zhang Xue for reading all the experimental data
(Lind et al. 2005). ADAMTS1–/– mice were significantly and giving us advice on their analysis. This research was spon-
smaller than wild-type mice; the reduction in bone growth was sored by the general project of the National Natural Science
already significant at birth and was accentuated thereafter. Foundation of China (81170980). The authors declare no potential
Furthermore, structural abnormalities of adrenal glandular tis- conflicts of interest with respect to the authorship and/or publica-
sue were found in ADAMTS1–/– mice, and only a few capillar- tion of this article.
ies containing blood cells were observed in the adrenal medulla
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