遗传性釉质发育不全家系的临床分析一例

釉质发育不全(amelogenesis imperfecta,AI)是一组影响釉质发育的遗传性疾病,由于釉质形成时造釉器的某些功能障碍,导致釉质在厚度、结构和组织上的改变[1].AI的临床表现多种多样,并有种族差异;遗传方式有3种:常染色体显性、常染色体隐性及x性连锁遗传.国外已有研究证实有5个候选基因与AI相关.现将一例遗传性釉质发育不全家系及其临床表现报道如下.     

釉质发育不全临床表型与基因变异

釉质发育不全为一组引起釉质在数量、结构和组成上发生改变的遗传性疾病,临床表型多样,遗传方式有X-连锁、常染色体显性及隐性等多种形式,存在明显的临床和遗传异质性。本文就其临床分型、基因定位、致病基因以及候选基因的研究作一综述。     

釉质发育不全临床表型与基因变异

釉质发育不全为一组引起釉质在数量、结构和组成上发生改变的遗传性疾病，临床表型多样，遗传方式有X-连锁、常染色体显性及隐性等多种形式，存在明显的临床和遗传异质性。本文就其临床分型、基因定位、致病基因以及候选基因的研究作一综述。     

一个中国汉族遗传性出血性毛细血管扩张症家系致病基因的定位研究

目的定位一个中国汉族遗传性出血性毛细血管扩张症家系的致病基因。方法选择基因ALK-1及endoglin作为该HHT家系致病基因的候选基因，在候选基因染色体区域进行定位。结果连锁分析结果发现ALK-1染色体区域微卫星遗传标记D12s1586LODZMAX为1．82，D12s1677LODZMAX为1．74，D12s1635LODZMAX为1．65，D12s368 LODZMAX为1．87，支持连锁。构建单体型发现家系内所有患者在ALK-1染色体区域都连锁，无交换重组现象。而endoglin染色体区域微卫星遗传标记连锁分析结果不支持连锁。结论这个中国汉族HHT家系的致病基因定位在ALK-1染色体区域。     

一个中国汉族痣样基底细胞癌综合征家系致病基因的定位研究

目的定位一个中国汉族痣样基底细胞癌综合征(NBCCS)家系的致病基因.方法选择SHH信号系统的基因作为该NBCCS家系致病基因的候选基因,用微卫星遗传标记在候选基因染色体区域定位致病基因.结果连锁分析结果发现,PTCH2基因所在染色体区域微卫星遗传标记D1 s2797 LODZMAX为1.31(平均遗传距离73.81)、D1 s2802 LODZMAX为1.26(平均遗传距离73.81),支持连锁.构建单体型发现家系内所有病变表型的个体D1s2797和D1 s2802的基因型一致,无交换重组现象.而SHH,PTCH,SMO基因染色体区域微卫星遗传标记连锁分析结果不支持连锁.结论这个中国汉族NBCCS家系的致病基因定位在PTCH2基因染色体区域1p32.3,遗传距离为1.85cM.     

釉原蛋白基因突变与X-连锁釉质发育不全

釉质发育不全是一类牙釉质发育异常的疾病.釉质发育期,包括釉原蛋白在内的多种基质蛋白参与釉质的正常发育,除局部性形成不全型釉质发育不全外,几乎所有的釉质发育不全都涉及釉原蛋白的异常表达.釉原蛋白基因定位于X、Y染色体上,而人釉原蛋白基因的转录本主要来自X染色体,故作者对釉原蛋白基因突变及其引起的X-连锁釉质发育不全进行综述.     

一个遗传性釉质发育不全家系的临床及致病基因研究

目的:探讨一个遗传性釉质发育不全(amelogenesis imperfecta, AI)家系的临床表型和致病基因,为该病的临床诊断和遗传咨询提供依据。方法:收集先证者及其家系成员的临床资料,同时采集家系成员的外周血,提取全基因组DNA,全外显子组测序检测可能的致病基因,进一步对候选变异进行Sanger测序验证。结果:该家系患病成员的临床表现为全口牙呈黄褐色,釉质质地较软,剥脱磨损,牙面粗糙不规则,釉质密度接近牙本质,符合AI中的亚型钙化不全型的临床表型;同时该家系患病成员在FAM83H基因第5外显子上均存在c.1366C>T(p.Gln456~*)的无义突变,已有该变异致病性的相关报道,且未患病的家系成员未发现上述突变。结论:该家系患有常染色体显性遗传钙化不全型AI,FAM83H基因第5外显子c.1366C>T(p.Gln456~*)的无义突变是该家系的致病原因,本研究为该家系的诊断和遗传咨询提供依据。     

釉基质非成釉蛋白研究进展

非成釉蛋白含量不足发育时期釉基质蛋白的10％,包括釉丛蛋白、釉蛋白、釉鞘蛋白、牙本质涎磷蛋白。以往人们对其认识较少。近年来,随着分子生物学的发展,非成釉蛋白的基因结构、mRNA转录及蛋白表达逐渐被人们认识,并初步证实,非成釉蛋白基因突变与常染色体遗传性釉质发育不全关系密切。     

釉基质非成釉蛋白研究进展

非成釉蛋白含量不足发育时期釉基质蛋白的10％,包括釉丛蛋白、釉蛋白、釉鞘蛋白、牙本质涎磷蛋白。以往人们对其认识较少。近年来,随着分子生物学的发展,非成釉蛋白的基因结构、mRNA转录及蛋白表达逐渐被人们认识,并初步证实,非成釉蛋白基因突变与常染色体遗传性釉质发育不全关系密切。     

遗传性釉质发育不全研究现状

遗传性釉质发育不全（amelogenesis imperfecta, AI）通常是指不伴有系统性疾病的一类单基因遗传病,乳牙、恒牙均可累及。目前已知的AI致病基因众多,且临床表型和基因型之间存在一定相关性。AI治疗计划的制定及预后评估与早期确诊息息相关。     

Exclusion of candidate genes in two families with autosomal dominant hypocalcified amelogenesis imperfecta

The amelogenesis imperfectas (AI) are a group of hereditary enamel defects characterized by clinical and genetic diversity. The most common AI types are inherited as autosomal traits. Three mutations of the enamelin (ENAM) gene have been found in cases of autosomal dominant hypoplastic AI. The gene(s) responsible for hypocalcified forms of AI have not been identified, although a number of autosomal genes have been proposed as candidates for AI based on their expression by ameloblasts, including ameloblastin and enamelin (chromosome 4q13.3), tuftelin (chromosome 1q21), enamelysin (chromosome 11q22.3-q23) and kallikrein 4 (chromosome 19q13.3-q13.4). To localize the gene(s) responsible for autosomal dominant hypocalcified AI, we evaluated support for/against linkage of AI to genetic markers spanning five AI candidate genes in two extended families. Our data excluded all proposed candidate gene regions as causal for autosomal dominant hypocalcified AI in these families. These linkage findings provide further evidence for genetic heterogeneity among families with autosomal dominant AI and indicate that, at least, some forms of autosomal dominant hypocalcified AI are not caused by a gene in the five most commonly reported AI candidate genes.     

Enamelin/ameloblastin gene polymorphisms in autosomal amelogenesis imperfecta among Syrian families

Aim: This study was undertaken to investigate whether a single G deletion within a series of seven G residues (codon 196) at the exon 9–intron 9 boundary of the enamelin gene ENAM and a tri‐nucleotide deletion at codon 180 in exon 7 (GGA vs deletion) of ameloblastin gene AMBN could have a role in autosomal amelogenesis imperfecta among affected Syrian families. Methods: A new technique – size‐dependent, deletion screening – was developed to detect nucleotide deletion in ENAM and AMBN genes. Twelve Syrian families with autosomal‐dominant or ‐recessive amelogenesis imperfecta were included. Results: A homozygous/heterozygous mutation in the ENAM gene (152/152, 152/153) was identified in affected members of three families with autosomal‐dominant amelogenesis imperfecta and one family with autosomal‐recessive amelogenesis imperfecta. A heterozygous mutation (222/225) in the AMBN gene was identified. However, no disease causing mutations was found. The present findings provide useful information for the implication of ENAM gene polymorphism in autosomal‐dominant/‐recessive amelogenesis imperfecta. Conclusion: Further investigations are required to identify other genes responsible for the various clinical phenotypes.     

Molecular-based phenotype variations in amelogenesis imperfecta

Amelogenesis imperfecta (AI) is one of the typical dental genetic diseases in human. It can occur isolatedly or as part of a syndrome. Previous reports have mainly clarified the types and mechanisms of nonsyndromic AI. This review aimed to compare the phenotypic differences among the hereditary enamel defects with or without syndromes and their underlying pathogenic genes. We searched the articles in PubMed with different strategies or keywords including but not limited to amelogenesis imperfecta, enamel defects, hypoplastic/hypomaturation/hypocalcified, syndrome, or specific syndrome name. The articles with detailed clinical information about the enamel and other phenotypes and clear genetic background were used for the analysis. We totally summarized and compared enamel phenotypes of 18 nonsyndromic AI with 17 causative genes and 19 syndromic AI with 26 causative genes. According to the clinical features, radiographic or ultrastructural changes in enamel, the enamel defects were basically divided into hypoplastic and hypomineralized (hypomaturated and hypocalcified) and presented a higher heterogeneity which were closely related to the involved pathogenic genes, types of mutation, hereditary pattern, X chromosome inactivation, incomplete penetrance, and other mechanisms.The gene-specific enamel phenotypes could be an important indicator for diagnosing nonsyndromic and syndromic AI.     

Phenotypic diversity and revision of the nomenclature for autosomal recessive amelogenesis imperfecta

PURPOSE: The purpose of this study was to characterize the phenotype in 9 families with autosomal recessive amelogenesis imperfecta (ARAI), and to propose a classification system allowing inclusion and delineation of diverse ARAI phenotypes. STUDY DESIGN: Nine families with ARAI were evaluated clinically and radiographically. Exfoliated and extracted teeth were examined via light and scanning electron microscopy, with the enamel in one case evaluated by amino acid analysis. RESULTS: The 9 families demonstrated diverse ARAI phenotypes including localized hypoplastic, generalized thin hypoplastic, hypocalcified and hypomaturation AI types. CONCLUSIONS: Some ARAI phenotypes observed in this study and reported in the literature cannot be classified using currently accepted ARAI nomenclature. Therefore, we propose a revised nomenclature permitting both classification of all ARAI clinical forms and inclusion of anticipated molecular-based nomenclature, such as now exists for some X-linked and autosomal dominant AI subtypes.     

Phenotype of ENAM mutations is dosage-dependent

Five mutations in the ENAM gene have been found to cause hypoplastic amelogenesis imperfecta (AI), with phenotypes ranging from localized enamel pitting in carriers to severe hypoplastic AI. To determine the generality of ENAM mutations in hypoplastic AI, we sequenced the ENAM gene in ten Turkish families segregating autosomal hypoplastic AI. In two families, ENAM mutations were found. A novel nonsense mutation (g.12663C>A; p.S246X) was identified in one family segregating local hypoplastic AI as a dominant trait. Affected individuals in a second family segregating autosomal-recessive AI were compound heterozygotes for a novel insertion mutation (g.12946_12947insAGTCAGTACCAGTACTGTGTC) and a previously described insertion (g.13185_13186insAG) mutation. Heterozygous carriers of either insertion had a localized enamel-pitting phenotype. These findings substantiate that enamel phenotypes of ENAM mutations may be dose-dependent, with generalized hypoplastic AI segregating as a recessive trait and localized enamel pitting segregating as a dominant trait.     

Amelogenesis imperfecta among Israeli Jews and the description of a new type of local hypoplastic autosomal recessive amelogenesis imperfecta.

Amelogenesis imperfecta (AI) was detected in nine of 70,359 school children surveyed, a prevalence approximating 1:8,000. Of these cases, eight were the hypoplastic type and one the snow-capped hypomaturation type. Family studies demonstrated that hypoplastic AI was an autosomal dominant trait in two children and an autosomal recessive in six. Of three additional families referred to our clinic, two had autosomal recessive hypoplastic AI and one the hypocalcified type, inherited as an autosomal dominant trait. In four families, a new type of local hypoplastic autosomal recessive AI was observed, characterized by horizontal pitting and grooving more pronounced in the middle third of the crowns of most teeth in both dentitions.     

Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a Danish five-generation family with a novel FAM83H nonsense mutation

BACKGROUND. Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) is a disease with severe dental manifestations. OBJECTIVES. The aims were by means of a genome-wide linkage scan to search for the gene underlying the ADHCAI phenotype in a Danish five-generation family and to study the phenotypic variation of the enamel in affected family members. RESULTS. Significant linkage was found to a locus at chromosome 8q24.3 comprising the gene FAM83H identified to be responsible for ADHCAI in other families. Subsequent sequencing of FAM83H in affected family members revealed a novel nonsense mutation, p.Y302X. Limited phenotypic variation was found among affected family members with loss of translucency and discoloration of the enamel. Extensive posteruptive loss of enamel was found in all teeth of affected subjects. The tip of the cusps on the premolars and molars and a zone along the gingival margin seemed resistant to posteruptive loss of enamel. We have screened FAM83H in another five unrelated Danish patients with a phenotype of ADHCAI similar to that in the five-generation family, and identified a de novo FAM83H nonsense mutation, p.Q452X in one of these patients. CONCLUSION. We have identified a FAM83H mutation in two of six unrelated families with ADHCAI and found limited phenotypic variation of the enamel in these patients.     

Cloning, characterization and immunolocalization of human ameloblastin

Amelogenesis imperfecta is a broad classification of hereditary enamel defects, exhibiting both genetic and clinical diversity. Most amelogenesis imperfecta cases are autosomal dominant disorders, yet only the local hypoplastic form has been mapped to human chromosome 4q between D4S242 1 and the albumin gene. An enamel protein cDNA, termed ameloblastin (also known as amelin and sheathlin), has been isolated from rat, mouse and pig. Its human homolog has been mapped to chromosome 4q21 between markers D4S409 and D4S400, flanking the local hypoplastic amelogenesis imperfecta critical region. Therefore, ameloblastin is a strong candidate gene for this form of amelogenesis imperfecta. To facilitate genetic studies related to this dental disease, we isolated and characterized a human ameloblastin cDNA. A human third molar cDNA library was screened and two ameloblastin clones identified. Nucleotide sequencing of these cDNAs indicated alternative splicing of the putative open reading frame, use of different polyadenylation signals, and a high degree of similarity to reported rat, mouse and porcine cDNAs. Immunohistochemistry studies on embryonic human teeth using an antibody to recombinant ameloblastin indicated ameloblastin expression by ameloblasts with localization in the enamel matrix associated with the sheath structures.     

Dentine structure and mineralization in hypocalcified amelogenesis imperfecta: a quantitative X-ray histochemical study

OBJECTIVE: This study was undertaken in order to establish the structural and mineralization pattern of the response of dentine to alterations in enamel in hypocalcified amelogenesis imperfecta (AI). DESIGN: The images and data obtained with scanning electron microscopy and electron probe X-ray microanalysis in enamel and dentine specimens from control and affected teeth were compared in this study. PATIENTS AND METHODS: We compared 46 fragments of permanent teeth from patients with clinically diagnosed hypocalcified AI and 20 normal permanent teeth. All specimens were prepared for electron probe X-ray microanalysis. RESULTS: Dentine is characterized by thickening of the peritubular dentine and partial obliteration of the dentinal tubules that does not give rise to a compact sclerotic cast. In dentine, calcium levels were significantly higher in teeth with clinically hypocalcified AI in relation with control teeth (P < 0.001). CONCLUSIONS: Dentine is affected in hypocalcified AI increasing mineralization (narrower tubules and higher content of calcium) in response to enamel disorder.