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DLX3 Mutation in a New Family and Its Phenotypic Variations
1 Department of Cell and Developmental Biology & Dental Research Institute, Correspondence: * corresponding author, pedoman{at}snu.ac.kr
Tricho-dento-osseous syndrome (TDO) is an autosomal-dominant disease characterized by curly hair at birth, enamel hypoplasia, taurodontism, and a thick cortical bone. A common DLX3 gene mutation (c.571_574delGGGG) has been identified in multiple families with variable clinical phenotypes. Recently, another DLX3 gene mutation (c.561_562delCT) was reported to cause amelogenesis imperfecta with taurodontism (AIHHT). We identified a Korean family with overlapping phenotypes of TDO and AIHHT. We performed mutational analysis to discover its genetic etiology. The identified mutation was c.561_562delCT mutation in the DLX3 gene. The enamel was hypomature and hypoplastic. The characteristic taurodontic features were not identified. Increased bone density or thickness could not be revealed by cephalometric, hand-wrist, and panoramic radiographs. Affected individuals reported that their nails were brittle, and they had curly hair at birth. This study clearly showed that the c.561_562delCT mutation had not only enamel defects, but also other clinical phenotypes resembling those of TDO syndrome.
Key Words: tricho-dento-osseous syndrome • TDO • DLX3 • amelogenesis imperfecta • mutational hot spot
Tricho-dento-osseous syndrome (TDO; OMIM 190320) is a rare autosomal-dominant disease affecting mainly the hair, teeth, and bones. The main clinical features are curly hair at birth, enamel hypoplasia, and thick cortical bone, along with minor symptoms, such as multiple dental abscesses and nail involvement (Wright et al., 1997). In contrast, the autosomal-dominant form of hypoplastic-hypomaturation-type amelogenesis imperfecta with taurodontism (AIHHT; OMIM 104510) demonstrates only enamel defects with enlarged pulp chambers resembling taurodontic teeth (Crawford et al., 1988). Taurodontism and enamel hypoplasia have been reported as fully penetrating features, while kinky/curly hair at birth, osseous changes, and fingernail involvement are variably expressed (Wright et al., 1997). These phenotypic variations make the differential diagnosis of TDO and AIHHT difficult in many cases. With the identification of the underlying mutation (c.571_574delGGGG) in the DLX3 gene causing TDO (Price et al., 1998a), and several reports on the phenotypic variation between and/or within TDO families (Hart et al., 1997; Price et al., 1998b), controversies on the definition of and necessity for subtyping (Price et al., 1999; Aldred et al., 2002) seemed to be settled. However, recent findings of another mutation (c.561_562delCT) in the DLX3 gene causing AIHHT (Dong et al., 2005) have provoked a new round of debate on the molecular genetic etiology, pathogenesis, and definition of TDO and AIHHT. We identified a Korean family with overlapping phenotype of TDO and AIHHT. We performed mutational analysis to discover its genetic etiology. Here, we report the identification of the mutation in this family and its unique and overlapping clinical phenotype for establishment of the genotype-phenotype correlation and the correct definition of TDO and AIHHT.
Enrollment of Human Participants The study protocol and participant consents were independently reviewed and approved by the Institution Review Board at the Seoul National University Dental Hospital. Informed consent was obtained according to the Declaration of Helsinki. Available family members received a complete oral examination, including dental radiographs.
PCR & Sequencing
Mutation Results The identified mutation was a deletion of CT at the 3' end of the conserved homeodomain (c.561_562delCT and g.3179_3180delCT based on NM_005220.2 and NT_010783.14) (Fig. 1  ). This deletion resulted in a frameshift with an in-frame termination codon at nucleotide 3216 in the deletion allele and a mutant protein which is 88 amino acids shorter than the normal DLX3 protein (287 amino acids). A frameshift mutation after Leu187 introduced 12 extraneous amino acids before terminating translation (p.Tyr188GlnfsX13) with the truncation of the last 2 amino acids in the distal-less-like homeodomain.
Clinical Findings The 12-year-old proband (III:6) had interdental spacing in his dentition (Fig. 2A ). Hypoplastic and hypomature enamel had a brown discoloration. Excessive wear resulted in spontaneous pulp exposures in several teeth (maxillary right lateral incisor and canine) before root growth was completed (Figs. 2B, 2C). Taurodontic features were absent in all molar teeth; however, maxillary central incisors had an extension of the pulp chamber with a slightly slender root (Figs. 2D, 2E). Nail involvement was not identified in this individual, but his hair was curly at birth. No bone-related abnormality was identified in his radiographs (Fig. 2F).
The other affected individuals (II:3 and II:9) reported that they also had curly hair at birth and that their nails were brittle, prone to peeling and breaking. Characteristic taurodontic features were not identified among the remaining teeth. No bone-related abnormality was identified by cephalometric, hand-wrist, and panoramic radiographs (Figs. 3 , 4).
Unaffected members (III:2, III:7) had neither curly hair at birth nor nail involvement.
Increased bone density has been reported as a feature of TDO (Haldeman et al., 2004). From extensive study of the TDO phenotype, increased thickening of cortical bone (65%), obliterated diploe (68%), lack of frontal sinus pneumatization (49%), and lack of mastoid pneumatization (81%) were reported as variable, age-dependent features related to osseous changes in TDO-affected individuals (Hart et al., 1997). In contrast, enamel hypoplasia and taurodontism have been reported as a clinical phenotype related to AIHHT (Price et al., 1999). Bony changes as well as hair and nail involvement have been excluded from the AIHHT definition. In this study, there was no evidence of increased bone density in accordance with the previous DLX3 (c.561_562delCT) mutation underlying AIHHT (Dong et al., 2005). Taurodontism is one of the main diagnostic features of both TDO and AIHHT. Almost all affected individuals have been reported as having taurodontic molar teeth. However, mild cases with only a slight increase in the pulp chamber length in molar teeth (hypotaurodontism) have been reported in TDO families (Wright et al., 1997; Aldred et al., 2002). There was no definitive evidence of taurodontic molars in this study. The only change observed in our proband was the extension of the pulp chamber with a slightly slender root in the maxillary central incisors. The other affected individuals in our study showed no or, if any, minimal taurodontic features. In this study, we could not confirm this phenotypic variation because of the limited number of affected individuals and the incompleteness of the remaining dentition. However, this could be attributed to modifying gene effects or different genetic backgrounds from the previous reports. All the affected individuals in this family had curly hair at birth. Characteristic kinky/curly hair at birth has been related to TDO in about 85% of the TDO-affected individuals (Wright et al., 1997). Investigation of hair samples of TDO revealed no difference from normal samples in hair shaft morphology, diameter, and cuticular pattern and periodicity (Wright et al., 1994). In our 12-year-old proband, though he had curly hair at birth, he did not retain this hair-type. Older affected individuals in our study also showed nail involvement. It is not surprising that the defects in the DLX3 gene resulted in hair and nail phenotypes, because DLX3 involvement in epidermal appendage development is well-known (Merlo et al., 2000; Radoja et al., 2007). These two features in our family had similarities to the TDO that resulted from the DLX3 mutation (c.571_574delGGGG), but not to AIHHT with the same mutation (c.561_562delCT). It is believed that multiple families with TDO in North Carolina and Virginia originated from a common ancestor (Price et al., 1998b). However, the c.561_562delCT mutation was first identified in an Australian AIHHT family (Dong et al., 2005). The same mutation was identified in a Swiss family, showing a reduced hair shaft diameter in addition to enamel hypoplasia and taurodontism (Wright, 2006). In this study, we identified a third family with the same mutation, but with different ethnicity. These findings suggest that this mutation site could be a mutational ’hot spot’ in the DLX3 gene. The effects of environment and modifying gene on gene expression are well-known (Peters and Breuning, 2001; Kelada et al., 2003), and different genetic backgrounds can modify the mutant gene’s effect, which results in variable clinical expression (Zimbalist and Plumer, 1995; Badhwar et al., 2004). The variations in the clinical phenotype with the same DLX3 mutation (c.561_562delCT) can be attributed to these factors and to minor clinical changes that could not be detected readily. Further study is needed to clarify the effect of this mutation, to gain a better understanding of the molecular genetic pathogenesis, and to establish the correct genotype-phenotype correlation.
We thank all the family members involved in this study for their cooperation. This work was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A060010), and by the Korea Science and Engineering Foundation (KOSEF) through the Biotechnology R&D program (#2006-05229). Received for publication June 26, 2007. Revision received December 28, 2007. Accepted for publication January 14, 2008.
Journal of Dental Research, Vol. 87, No. 4,
354-357 (2008) This article has been cited by other articles:
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