PAX9基因与非综合征型多数牙先天缺失的关系及研究进展

先天性缺牙是人类牙列中最常见的发育异常,包括个别牙先天缺失,多数牙先天缺失和先天无牙症。多数牙先天缺失按照其表现型不同通常可分为综合征型和非综合征型,表现为常染色体的显性或隐性遗传、X-连锁遗传特性,有的具有家族遗传史,有的则是无家族史的散发病例。本文就近年来非综合征型牙齿发育不全研究中的热点基因PAX9的研究进展作一综述。     

HED伴多数牙先天缺失1例的临床研究

目的:对1例少汗型外胚叶发育不全综合征(hypohidrotic ectodermal dysplasia,HED)伴多数牙先天缺失的患儿及其孪生姐姐进行临床研究,探讨该病的临床特点和病因.方法:首先从常规口腔检查、全口曲面断层X线片和系谱分析等三个方面研究其临床特点.然后从染色体分析(常染色体数、性染色体数、核型、数目畸变率、结构畸变率等)、血清微量元素(铜、锌、铁、镁、钙)和血清碱性磷酸酶(ALP)检测等方面进行研究.结果:HED患儿先天缺失26颗牙齿,其中包括12颗前牙、8颗前磨牙和6颗磨牙.患儿和其孪生姐姐的染色体分析未见数目畸变和结构畸变;血清微量元素铜、锌、铁、镁、钙均在正常参考值之内;血清碱性磷酸酶(ALP)患儿为250μmol/L(正常参考范围为35～130 μmol/L),其值稍偏高;其孪生姐姐的ALP为92μmol/L,在正常参考范围之内.结论:该患儿HED伴多数牙先天缺失的发病原因不是由于染色体出现异常或微量元素缺少所致,可能与ALP浓度过高相关.     

中国先天性缺失牙患者PAX9基因的新突变

目的 探讨我国先天性缺失牙患者PAX9基因突变的特点，为该病发病的分子机制研究提供依据。方法 应用聚合酶链反应．单链构象多态性(PCR-SSCP)分析方法，对4个常染色体显性遗传少牙畸形家系(共45名成员，22例患者)中的13例患者和9名健康成员、16例散发性牙齿发育不全患者以及196名健康对照者的PAX9基因进行研究。结合DNA序列分析方法，对发现异常SSCP条带的患者进行突变分析。结果 2个少牙畸形家系(家系A和家系B)的先证者出现异常SSCP条带，家系A和家系B内患者均出现与各自先证者相同的异常SSCP条带。经过DNA序列分析，发现PAX9基因第2外显子的2个新突变：碱基插入(109InsG)导致的移码突变，碱基置换(c139T)导致的错义突变。其余家系患者、散发性患者均未发现异常SSCP条带。结论 109InsG和C139T突变扩大了先天性缺失牙患者的PAX9基因突变谱，为我国先天性缺失牙的基因诊断提供依据。     

2例多数牙先天缺失患儿及其父母的Pax9基因突变检测

目的:探讨多数牙先天缺失患者的基因突变位点.方法:从两例多数牙先天缺失患者与家庭成员的静脉血中提取DNA,在Pax9基因内设计引物,采用PCR方法扩增Pax9基因的外显子2、3、4,而后通过对分段PCR纯化产物的测序,并结合系谱进行单核甘酸多态性分析.结果:外显子3的第88、89位点上发现两个单核甘酸多态性位点(single nucleotide polymorphisms,SNPs),其中第88位为C变为T,第99位为G变为C,前者是同义突变,后者是错义突变,由丙氨酸变为脯氨酸.结论:多数牙先天缺失可能与Pax9基因外显子3的第88、89位点上的两个SNPs有关.     

先天性多数恒牙缺失3例报告及文献复习

多数恒牙先天性缺失较为少见,作者报告3例多数先天性恒牙缺失,观察缺牙情况,追溯其家族史,并结合文献复习,对其治疗及相关病因进行初步总结,为临床诊治提供参考。     

PAX9基因上新近发现的一个单核苷酸多态性位点的SNP分析

目的:研究位于PAX9基因外显子3的第89位点上的SNP与多数牙先天缺失的相关性.方法:分别从11名多数牙先天缺失病人,5名少数牙先天缺失病人和38名正常对照者的静脉血样品中提取DNA.采用TaqMan-MGB探针技术对该SNP位点进行单核苷酸多态性研究,利用软件对实验结果进行SNP分型,并行统计分析.结果:突变为纯合子C/C的绝大多数表现为先天缺牙(多数牙先天缺失5例,少数牙先天缺失2例,正常1例).但31例杂合子中只有7例表现为先天缺牙(多数牙先天缺失6例,少数牙先天缺失1例).13例野生型纯合子只有2例表现为少数牙先天缺失,11例完全正常.统计结果表明该位点与多数牙先天缺失相关(P<0.001).结论:多数牙先天缺失可能与PAX9基因外显子3的第89位点上的SNP有关.     

先天性多数牙缺失家系1例

1临床资料患者男,7岁,因多数牙缺失要求修复治疗前来就诊。查体:体格发育较同龄人迟缓、偏瘦,皮肤偏黑,毛发及智力发育正常。口腔及颌面部检查:双侧面部对称,面下1/3缩短,张闭口运动正常。混合牙列,多数牙缺失,牙列稀疏,缺     

多数牙先天缺失可能与MSX1上的3个SNPs相关

目的:探讨多数牙先天缺失患者的MSXl基因突变位点.方法:从4个多数牙先天缺失患者与家庭部分成员、1个唇腭裂并发少数牙先天缺失的患者、1个牙列完整的对照儿童共14人的静脉血中提取DNA,在MSXl基因内设计引物,采用PCR方法扩增MSXl基因外显子1、2的编码区,而后对外显子1、2的PCR纯化产物测序,结合系游进行序列比对分析.结果:发现3个可能的单核苷酸多态性位点(single nucleotide pol-ymorphisms,SNPs).这3个SNPs均位于外显子1中,且来自不同家系的3个患者在这3个位点上同时出现杂合突变.其中,311位点由G变A,对应的密码子由编码甘氨酸的GGC变为编码天门冬氨酸的GAC,发生了错义突变;402位点由C变A,对应的密码子由CCC变为CCA,但仍编码脯氨酸,属同义突变;458位点由C变T,对应的密码子由编码丙氨酸的GCC变为编码缬氨酸的GTC,发生了错义突变.结论:多数牙先天缺失可能与MSX1基因上该3个单核苷酸多态性位点有关.     

先天性12颗恒牙缺失伴乳恒牙形态异常1例

多数恒牙先天性缺失较少见,笔者在临床中诊治先天性恒牙缺失伴乳恒牙形态异常1例。患者12岁,自幼身体健康,家族内其他成员未发现类似缺牙史,体型消瘦,指(趾)无发育不良,毛囊发育正常,智力正常,听力、视力、B超、心电图检查均未见异常。经口腔及X线检查:15、17、18、25、27、28、31、37、38、42、47、48先天性缺失;71、72融合牙;12、22过小牙;未发现颌骨发育异常,骨密度无异常。该例患者属于非综合征性多颗恒牙先天性缺失。由于年龄原因,综合、序列治疗效果尚待追踪观察。     

Identification of a novel mutation in the PAX9 gene in a family affected by oligodontia and other dental anomalies

The objective of the present work was to study the phenotype and the genotype of three generations of a family affected by oligodontia and other dental anomalies. These family members also presented systemic conditions such as hypercholesterolemia, hypothyroidism, diabetes mellitus, scoliosis, and congenital cardiovascular anomalies. Clinical evaluation, panoramic radiographs, and anamnestic data were used for dental analysis. DNA extraction was carried out from gum samples or buccal swabs. A mutation was identified in six subjects across three generations affected by oligodontia, as well as different phenotypical manifestations, both systemic and oral. The previously undescribed PAX9 mutation was observed in the paired box (exon 2); this was a heterozygote transition of C175 to T, implying the change of arginine 59 for a termination codon. These results strongly suggested that the identified mutation was the etiological cause of the oligodontia. However, in two family members affected by both hypodontia and peg-shaped upper lateral incisors, no mutations in the PAX9 and MSX1 genes were identified. This fact underscores the importance that other presently unknown genes and developmental factors have in tooth development and in the etiology of dental anomalies.     

A novel PAX9 mutation causing oligodontia

IntroductionAn extended family presenting with several members affected by developmentally missing teeth was investigated by analysis of the MSX1 and PAX9 genes.Materials and methodsSaliva samples were collected and DNA extracted. Primers were designed to span the exons and intron-exon junctions of the MSX1 and PAX9 genes. These primers were optimised using gradient Polymerase Chain Reaction. The amplified fragments were sent for Sanger sequencingResultsa novel heterozygote missense mutation in exon 3 of PAX9 (c.296G > C, p.A99P), was found in two severely affected members of the family as well as a potentially pathogenic heterozygote variant (c.119C > G, p.A40G) in exon 1 of the MSX1 gene.ConclusionThe PAX9 A99P mutation is in the DNA binding domain and is predicted to be pathogenic.     

A novel mutation in human PAX9 causes molar oligodontia

Experimental and animal studies, as well as genetic mutations in man, have indicated that the development of dentition is under the control of several genes. So far, mutations in MSX1 and PAX9 have been associated with dominantly inherited forms of human tooth agenesis that mainly involve posterior teeth. We identified a large kindred with several individuals affected with molar oligodontia that was transmitted as an isolated autosomal-dominant trait. Two-point linkage analysis using DNA from the family and polymorphic marker D14S288 in chromosome 14q12 produced a maximum lod score of 2.29 at theta = 0.1. Direct sequencing of exons 2 to 4 of PAX9 revealed a cytosine insertion mutation at nucleotide 793, leading to a premature termination of translation at aa 315. Our results support the conclusion that molar oligodontia is due to allelic heterogeneity in PAX9, and these data further corroborate the role of PAX9 as an important regulator of molar development.     

A screen of a large Czech cohort of oligodontia patients implicates a novel mutation in the PAX9 gene

Tooth agenesis is one of the most common developmental anomalies in humans. To date, many mutations involving paired box 9 (PAX9), msh homeobox 1 (MSX1), and axin 2 (AXIN2) genes have been identified. The aim of the present study was to perform screening for mutations and/or polymorphisms using the capillary sequencing method in the critical regions of PAX9 and MSX1 genes in a group of 270 individuals with tooth agenesis and in 30 healthy subjects of Czech origin. This screening revealed a previously unknown heterozygous g.9527G>T mutation in the PAX9 gene in monozygotic twins with oligodontia and three additional affected family members. The same variant was not found in healthy relatives. This mutation is located in intron 2, in the region recognized as the splice site between exon 2 and intron 2. We hypothesize that the error in pre‐mRNA splicing may lead to lower expression of PAX9 protein and could have contributed to the development of tooth agenesis in the affected subjects.     

Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia

Tooth development is regulated through a series of reciprocal interactions between the dental epithelium and mesenchyme and requires protein products of a number of genes. It has been reported that selective tooth agenesis is associated with mutations in human MSX and PAX9 genes. Mutational analysis of the two genes was performed in 25 individuals with familial or sporadic form of permanent tooth agenesis. Single-stranded conformational polymorphism analysis revealed no mutations in the entire coding sequence of the MSX1 gene. In PAX9, a novel, heterozygous G151A transition in the sequence encoding the paired domain of the PAX9 protein was detected in a patient with agenesis of third molars, second premolars and incisors, but not in her parents, the remaining patients or 162 individuals with normal dentition. This is the first de novo mutation described in PAX9. Our results support the view that mutations in PAX9 could constitute a causative factor of oligodontia. We hypothesize that the G151A transition in PAX9 might be responsible for the sporadic form of tooth agenesis in this patient.     

Identification of a novel missense mutation of MSX1 gene in Chinese family with autosomal-dominant oligodontia

OBJECTIVES: Oligodontia is defined as the congenital absence of 6 or more permanent teeth excluding the third molar. The occurrence of non-syndromic still remains poorly understood, but in recent years some cases have been reported where mutations or polymorphisms of PAX9 and MSX1 had been associated with non-syndromic oligodontia. The objective of the present work was to study the phenotype and genotype of three generations of a Han Chinese family affected by non-syndromic autosomal-dominant oligodontia. DESIGN: We examined all individuals of the oligodontia family by clinical and radiographic examinations. Based on clinical manifestations, candidate genes MSX1 and PAX9 were picked up to analyse and screen mutations. RESULTS: Dental evaluation showed that the most commonly missing teeth are the mandibular second premolars, followed by the maxillary second premolars and maxillary lateral incisors, and subsequently the maxillary first premolars. The probability of missing a particular type of tooth is not always bilaterally symmetrical, and differences exist between maxilla and mandible. PCR-SSCP analysis and DNA sequencing revealed a novel missense mutation c.662C>A in a highly conserved homeobox sequence of MSX1 and a known polymorphisms c.347C>G. CONCLUSION: Our finding suggests the missense transversion (c.662C>A) and the polymorphisms (c.347C>G) may be responsible for oligodontia phenotype in this Chinese family.     

Novel mutation of the initiation codon of PAX9 causes oligodontia

Tooth development is under strict genetic control. Oligodontia is defined as the congenital absence of 6 or more permanent teeth, excluding the third molar. The occurrence of non-syndromic oligodontia is poorly understood, but in recent years several cases have been described where a single gene mutation is associated with oligodontia. Several studies have shown that MSX1 and PAX9 play a role in early tooth development. We screened one family with non-syndromic oligodontia for mutations in MSX1 and PAX9. The pedigree showed an autosomal-dominant pattern of inheritance. Direct sequencing and restriction enzyme analysis revealed a novel heterozygous A to G transition mutation in the AUG initiation codon of PAX9 in exon 1 in the affected members of the family. This is the first mutation found in the initiation codon of PAX9, and we suggest that it causes haploinsufficiency.