Abstract：
BACKGROUND: MSX1 sequence variants have been known to cause human tooth agenesis (TA) with or without orofacial clefts. However, their roles during the whole processes of tooth development are not fully understood. This study aimed to characterize a 4-membered family with TA carrying a novel MSX1 pathogenic variant and investigate the disease mechanism.
METHODS: The authors conducted whole exome analysis to define the disease-causing sequence variant. They performed microcomputed tomography, morphometric analyses, transcriptome profiling, and molecular characterization to study the affected teeth and the gene variant.
RESULTS: The authors identified an MSX1 pathogenic variant, p.Glu232∗, in affected family members with TA and concomitant orodental anomalies, namely, prominent maxillary labial frenum, central incisor diastema, median maxillary anterior alveolar cleft, tooth fusion, mandibular molar dysmorphology, thin dentin layer, and slender dental roots. MSX1-defective teeth were not apparently microdontic but had thin dentin layers. The mandibular molars showed a homeotic transformation to maxillary counterparts. Genes involved in extracellular matrix organization and dentinogenesis, such as DMP1 and MMP20, were downregulated in dental pulp tissues of MSX1-defective teeth. The p.Glu232∗-truncated MSX1 properly localized to the nucleus but partially lost its transactivation ability. Analyzing reported cases indicated that truncation sequence variants within the homeobox domain of MSX1 caused a more severe TA phenotype than those outside of the homeobox domain, probably due to dominant negativity compared with haploinsufficiency.
CONCLUSIONS: This study provides in vivo evidence that MSX1 contributes to developmental processes of various orodental tissues in humans.
CONCLUSIONS: Clinically, hypertrophic labial frenum, incisor diastema, and median maxillary anterior alveolar cleft might be considered diagnostic for MSX1-associated TA.
METHODS: The authors conducted whole exome analysis to define the disease-causing sequence variant. They performed microcomputed tomography, morphometric analyses, transcriptome profiling, and molecular characterization to study the affected teeth and the gene variant.
RESULTS: The authors identified an MSX1 pathogenic variant, p.Glu232∗, in affected family members with TA and concomitant orodental anomalies, namely, prominent maxillary labial frenum, central incisor diastema, median maxillary anterior alveolar cleft, tooth fusion, mandibular molar dysmorphology, thin dentin layer, and slender dental roots. MSX1-defective teeth were not apparently microdontic but had thin dentin layers. The mandibular molars showed a homeotic transformation to maxillary counterparts. Genes involved in extracellular matrix organization and dentinogenesis, such as DMP1 and MMP20, were downregulated in dental pulp tissues of MSX1-defective teeth. The p.Glu232∗-truncated MSX1 properly localized to the nucleus but partially lost its transactivation ability. Analyzing reported cases indicated that truncation sequence variants within the homeobox domain of MSX1 caused a more severe TA phenotype than those outside of the homeobox domain, probably due to dominant negativity compared with haploinsufficiency.
CONCLUSIONS: This study provides in vivo evidence that MSX1 contributes to developmental processes of various orodental tissues in humans.
CONCLUSIONS: Clinically, hypertrophic labial frenum, incisor diastema, and median maxillary anterior alveolar cleft might be considered diagnostic for MSX1-associated TA.
摘要：
背景:已知MSX1序列变体引起具有或不具有口面裂痕的人牙齿发育不全(TA)。然而,它们在牙齿发育的整个过程中的作用还没有完全理解。这项研究旨在表征带有新型MSX1致病变体的TA的4元家族，并研究其疾病机制。
方法：作者进行了全外显子组分析以定义致病序列变异。他们做了显微计算机断层扫描,形态计量学分析，转录组分析，和分子表征来研究受影响的牙齿和基因变异。
结果：作者确定了MSX1致病变种，p.Glu232＊，在患有TA和伴随的牙齿异常的受影响家庭成员中，即,突出的上颌唇缘，中切牙舒张，上颌正中前牙槽裂，牙齿融合,下颌磨牙形态学,薄牙本质层，和细长的牙根。MSX1缺陷牙齿显然不是微牙本质，但牙本质层很薄。下颌磨牙显示出与上颌对应物的同源转化。参与细胞外基质组织和牙本质生成的基因，如DMP1和MMP20在MSX1缺陷牙齿的牙髓组织中下调。p.Glu232*截断的MSX1正确定位到细胞核，但部分失去了其反式激活能力。分析报道的病例表明，MSX1同源异型盒结构域内的截短序列变体比同源异型盒结构域外的截短序列变体引起更严重的TA表型，可能是由于与单倍功能不全相比的显性负性。
结论：这项研究提供了体内证据，表明MSX1有助于人类各种牙组织的发育过程。
结论：临床上，肥大的唇缘,切牙舒张，和正中上颌前牙槽裂可能被认为是MSX1相关TA的诊断。
方法：作者进行了全外显子组分析以定义致病序列变异。他们做了显微计算机断层扫描,形态计量学分析，转录组分析，和分子表征来研究受影响的牙齿和基因变异。
结果：作者确定了MSX1致病变种，p.Glu232＊，在患有TA和伴随的牙齿异常的受影响家庭成员中，即,突出的上颌唇缘，中切牙舒张，上颌正中前牙槽裂，牙齿融合,下颌磨牙形态学,薄牙本质层，和细长的牙根。MSX1缺陷牙齿显然不是微牙本质，但牙本质层很薄。下颌磨牙显示出与上颌对应物的同源转化。参与细胞外基质组织和牙本质生成的基因，如DMP1和MMP20在MSX1缺陷牙齿的牙髓组织中下调。p.Glu232*截断的MSX1正确定位到细胞核，但部分失去了其反式激活能力。分析报道的病例表明，MSX1同源异型盒结构域内的截短序列变体比同源异型盒结构域外的截短序列变体引起更严重的TA表型，可能是由于与单倍功能不全相比的显性负性。
结论：这项研究提供了体内证据，表明MSX1有助于人类各种牙组织的发育过程。
结论：临床上，肥大的唇缘,切牙舒张，和正中上颌前牙槽裂可能被认为是MSX1相关TA的诊断。
