一个常染色体显性钙化不全型釉质发育不全家系的致病基因研究及多学科治疗

doi:10.19439/j.sjos.2025.01.011

上海口腔医学 ›› 2025, Vol. 34 ›› Issue (1): 59-67.doi: 10.19439/j.sjos.2025.01.011

一个常染色体显性钙化不全型釉质发育不全家系的致病基因研究及多学科治疗

崔梦娟¹, 柴利², 翟蔷岚¹, 汪政良¹, 许彤³, 陈洁仪^4,*, 刘超^1,*

1.上海交通大学医学院附属第九人民医院口腔正畸科, 上海交通大学口腔医学院, 国家口腔医学中心, 国家口腔疾病临床医学研究中心, 上海市口腔医学重点实验室, 上海市口腔医学研究所, 上海 200011;
2.济南二机床集团有限公司医院口腔科, 山东济南 250000;
3.山东省耳鼻喉医院耳鼻咽喉科, 山东济南 250022;
4.复旦大学附属儿科医院分子医学中心, 上海 201102

收稿日期:2024-06-25 修回日期:2024-08-20 发布日期:2025-03-05
通讯作者: 刘超,E-mail: ibuliuchao@gmail.com;陈洁仪,E-mail: chenjieyi@fudan.edu.cn。^*共同通信作者
作者简介:崔梦娟（1998-）,女,在读硕士研究生,E-mail: cui_mengjuan@163.com
基金资助:
上海交通大学医学院附属第九人民医院生物样本库项目（YBKA202202）;2022年九院优秀研究型医师培育项目（2022yxyjxys-lc）;上海交通大学医学院附属第九人民医院临床研究助推计划（JYLJ202114）

Genetic analysis and multidisciplinary treatment of a pedigree affected with autosomal dominant hypocalcified amelogenesis imperfecta

CUI Meng-juan¹, CHAI Li², ZHAI Qiang-lan¹, WANG Zheng-liang¹, XU Tong³, CHEN Jie-yi⁴, LIU Chao¹

1. Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology. Shanghai 200011;
2. Department of Stomatology, Hospital of JIER Machine-Tool Group Co., Ltd.. Jinan 250000, Shandong Province;
3. Department of Otorhinolaryngology, Shandong Provincial ENT Hospital. Jinan 250000, Shandong Province;
4. Center for Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University. Shanghai 201102, China

Received:2024-06-25 Revised:2024-08-20 Published:2025-03-05

摘要/Abstract

摘要： 目的: 研究一个中国常染色体显性钙化不全型釉质发育不全家系的致病基因,并报道该家系2例患者的多学科联合治疗过程,为遗传性釉质发育不全的遗传咨询和临床治疗提供指导。方法: 收集先证者及其家系成员的临床资料及外周血,进行全外显子组测序,通过数据分析,筛选出可能的致病基因;通过Sanger测序和蛋白质三维结构预测进行验证。结果: 该遗传家系中患病成员全口牙冠呈黄褐色,牙面粗糙,釉质剥脱磨损,符合钙化不全型釉质发育不全。在先证者及其母亲、妹妹的测序结果中发现了FAM83H基因第5外显子存在c.1363C>T无义突变,该突变预测会导致FAM83H蛋白发生截断突变（p.Gln455*）,家系中未患病成员未发现上述突变。先证者及其妹妹接受以正畸为基础的多学科治疗,口腔功能和美观恢复。结论: 本研究首次在一个中国家系中发现了导致常染色体显性钙化不全型釉质发育不全的FAM83H 基因无义突变位点c.1363C>T（p.Gln455*）,进一步验证和补充了导致釉质发育不全的FAM83H 突变位点。釉质发育不全患者可以通过多种正畸和修复治疗方式,恢复口腔功能及美观。

关键词: 常染色体显性钙化不全型釉质发育不全, FAM83H基因, 全外显子组测序, 多学科治疗

Abstract: PURPOSE: To investigate the pathogenic gene of one Chinese family with autosomal dominant hypocalcified amelogenesis imperfecta and to report multidisciplinary treatment process for two patients from this family, so as to provide guidance for genetic counseling and clinical treatment of hereditary amelogenesis imperfecta. METHODS: The clinical data and peripheral blood of the family members were collected. Whole-exome sequencing was performed, and candidate variants were filtered out by data analysis. The identified variant was confirmed by Sanger sequencing and protein three-dimensional structure prediction. RESULTS: Affected members of this hereditary family exhibited yellow-brown discoloration of the dental crowns, rough tooth surfaces, and enamel erosion, consistent with hypocalcified amelogenesis imperfecta. A nonsense mutation c.1363C>T(p.Gln455*) in exon 5 of the FAM83H gene was identified in the proband, her mother, and her sister; this mutation was predicted to cause a truncation of the FAM83H protein. This variant was not found in unaffected family members. After receiving multidisciplinary treatment based on orthodontics, the proband and her sister restored oral function and aesthetics. CONCLUSIONS: The nonsense variant of FAM83H caused hypocalcified amelogenesis imperfecta in this study is detected for the first time in a Chinese family. The results further validate the pathogenic variant involved in FAM83H leading to amelogenesis imperfecta. Patients with amelogenesis imperfecta can restore oral function and aesthetics through various orthodontic and restorative treatments.

Key words: Autosomal dominant hypocalcified amelogenesis imperfecta, FAM83H gene, Whole exome sequencing, Multidisciplinary treatment

中图分类号:

R782.1

崔梦娟, 柴利, 翟蔷岚, 汪政良, 许彤, 陈洁仪, 刘超. 一个常染色体显性钙化不全型釉质发育不全家系的致病基因研究及多学科治疗[J]. 上海口腔医学, 2025, 34(1): 59-67.

CUI Meng-juan, CHAI Li, ZHAI Qiang-lan, WANG Zheng-liang, XU Tong, CHEN Jie-yi, LIU Chao. Genetic analysis and multidisciplinary treatment of a pedigree affected with autosomal dominant hypocalcified amelogenesis imperfecta[J]. Shanghai Journal of Stomatology, 2025, 34(1): 59-67.

参考文献

[1] Crawford PJ, Aldred M, Bloch-Zupan A.Amelogenesis imperfecta[J]. Orphanet J Rare Dis, 2007, 2: 17.
[2] Bäckman B, Holm AK.Amelogenesis imperfecta: prevalence and incidence in a northern Swedish county[J]. Community Dent Oral Epidemiol, 1986, 14(1): 43-47.
[3] Witkop CJ Jr.Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: problems in classification[J]. J Oral Pathol, 1988, 17(9-10): 547-553.
[4] Gadhia K, McDonald S, Arkutu N, et al. Amelogenesis imperfecta: an introduction[J]. Br Dent J, 2012, 212(8): 377-379.
[5] Kim JW, Lee SK, Lee ZH, et al.FAM83H mutations in families with autosomal-dominant hypocalcified amelogenesis imperfecta[J]. Am J Hum Genet, 2008, 82(2): 489-494.
[6] Xin W, Wenjun W, Man Q, et al.Novel FAM83H mutations in patients with amelogenesis imperfecta[J]. Sci Rep, 2017, 7(1): 6075.
[7] Wright JT, Frazier-Bowers S, Simmons D, et al.Phenotypic variation in FAM83H-associated amelogenesis imperfecta[J]. J Dent Res, 2009, 88(4): 356-360.
[8] Wang SK, Zhang H, Hu CY, et al.FAM83H and autosomal dominant hypocalcified amelogenesis imperfecta[J]. J Dent Res, 2021, 100(3): 293-301.
[9] Chen S, Zhou Y, Chen Y, et al.fastp: an ultra-fast all-in-one FASTQ preprocessor[J]. Bioinformatics, 2018, 34(17): i884-i890.
[10] Li H, Durbin R.Fast and accurate short read alignment with Burrows-Wheeler transform[J]. Bioinformatics, 2009, 25(14): 1754-1760.
[11] Li H, Handsaker B, Wysoker A, et al.The sequence alignment/map format and SAMtools[J]. Bioinformatics, 2009, 25(16): 2078-2079.
[12] McKenna A, Hanna M, Banks E, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data[J]. Genome Res, 2010, 20(9): 1297-1303.
[13] Wang K, Li M, Hakonarson H.ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data[J]. Nucleic Acids Res, 2010, 38(16): e164.
[14] Talevich E, Shain AH, Botton T, et al.CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing[J]. PLoS Comput Biol, 2016, 12(4): e1004873.
[15] Richards S, Aziz N, Bale S, et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424.
[16] Yang J, Zhang Y.I-TASSER server: new development for protein structure and function predictions[J]. Nucleic Acids Res, 2015, 43(W1): W174-W181.
[17] Song JS, Lee Y, Shin TJ, et al.Identification of a Novel FAM83H mutation and management of hypocalcified amelogenesis imperfecta in early childhood[J]. Children (Basel), 2022, 9(3): 429.
[18] 段小红. 口腔罕见病名录(第一版)[J]. 中华口腔医学杂志, 2020, 55(7): 494-500.
[19] Nusier M, Yassin O, Hart TC, et al.Phenotypic diversity and revision of the nomenclature for autosomal recessive amelogenesis imperfecta[J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2004, 97(2): 220-230.
[20] 毛颂雅,段小红. FAM83H突变导致牙釉质发育不全伴牙萌出异常的特征分析[J]. 中华口腔医学杂志, 2023, 58(9): 933-937.
[21] de La Dure-Molla M, Philippe Fournier B, Berdal A. Isolated dentinogenesis imperfecta and dentin dysplasia: revision of the classification[J]. Eur J Hum Genet, 2015, 23(4): 445-451.
[22] Barron MJ, McDonnell ST, Mackie I, et al. Hereditary dentine disorders: dentinogenesis imperfecta and dentine dysplasia[J]. Orphanet J Rare Dis, 2008, 3: 31.
[23] Smith CEL, Poulter JA, Antanaviciute A, et al.Amelogenesis imperfecta: genes, proteins, and pathways[J]. Front Physiol, 2017, 8: 435.
[24] Dong J, Ruan W, Duan X.Molecular-based phenotype variations in amelogenesis imperfecta[J]. Oral Dis, 2023, 29(6): 2334-2365.
[25] Mendoza G, Pemberton TJ, Lee K, et al.A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.3[J]. Hum Genet, 2007, 120(5): 653-662.
[26] 郭思敏, 陈婷. 常染色体显性钙化不全型釉质发育不全相关基因序列相似性83蛋白质家族成员H及其突变的研究进展[J]. 国际口腔医学杂志, 2022, 49(5): 600-606.
[27] Kuga T, Kume H, Adachi J, et al.Casein kinase 1 is recruited to nuclear speckles by FAM83H and SON[J]. Sci Rep, 2016, 6: 34472.
[28] Kim KM, Park SH, Bae JS, et al.FAM83H is involved in the progression of hepatocellular carcinoma and is regulated by MYC[J]. Sci Rep, 2017, 7(1): 3274.
[29] Wang B, Li R, Cai Y, et al.Alteration of DNA methylation induced by PM(2.5) in human bronchial epithelial cells[J]. Toxicol Res (Camb), 2020, 9(4): 552-560.
[30] Lee SK, Hu JC, Bartlett JD, et al.Mutational spectrum of FAM83H: the C-terminal portion is required for tooth enamel calcification[J]. Hum Mutat, 2008, 29(8): E95-E99.
[31] Haubek D, Gjϕrup H, Jensen LG, et al.Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a Danish five-generation family with a novel FAM83H nonsense mutation[J]. Int J Paediatr Dent, 2011, 21(6): 407-412.
[32] Song YL, Wang CN, Zhang CZ, et al.Molecular characterization of amelogenesis imperfecta in Chinese patients[J]. Cells Tissues Organs, 2012, 196(3): 271-279.
[33] Hart PS, Becerik S, Cogulu D, et al.Novel FAM83H mutations in Turkish families with autosomal dominant hypocalcified amelogenesis imperfecta[J]. Clin Genet, 2009, 75(4): 401-404.
[34] Ding Y, Estrella MR, Hu YY, et al.Fam83h is associated with intracellular vesicles and ADHCAI[J]. J Dent Res, 2009, 88(11): 991-996.
[35] Wright JT, Torain M, Long K, et al.Amelogenesis imperfecta: genotype-phenotype studies in 71 families[J]. Cells Tissues Organs, 2011, 194(2-4): 279-283.
[36] Pourhashemi SJ, Ghandehari Motlagh M, Meighani G, et al.Missense mutation in Fam83H gene in iranian patients with amelogenesis imperfecta[J]. Iran J Public Health, 2014, 43(12): 1680-1687.
[37] Yu S, Quan J, Wang X, et al.A novel FAM83H mutation in one Chinese family with autosomal-dominant hypocalcification amelogenesis imperfecta[J]. Mutagenesis, 2018, 33(4): 333-340.
[38] Nowwarote N, Theerapanon T, Osathanon T, et al.Amelogenesis imperfecta: a novel FAM83H mutation and characteristics of periodontal ligament cells[J]. Oral Dis, 2018, 24(8): 1522-1531.
[39] Prasad MK, Geoffroy V, Vicaire S, et al.A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement[J]. J Med Genet, 2016, 53(2): 98-110.
[40] Hyun HK, Lee SK, Lee KE, et al.Identification of a novel FAM83H mutation and microhardness of an affected molar in autosomal dominant hypocalcified amelogenesis imperfecta[J]. Int Endod J, 2009, 42(11): 1039-1043.
[41] Chan HC, Estrella NM, Milkovich RN, et al.Target gene analyses of 39 amelogenesis imperfecta kindreds[J]. Eur J Oral Sci, 2011, 119(Suppl 1): 311-323.
[42] Wang SK, Hu Y, Yang J, et al.Fam83h null mice support a neomorphic mechanism for human ADHCAI[J]. Mol Genet Genomic Med, 2016, 4(1): 46-67.
[43] El-Sayed W, Shore RC, Parry DA, et al.Ultrastructural analyses of deciduous teeth affected by hypocalcified amelogenesis imperfecta from a family with a novel Y458X FAM83H nonsense mutation[J]. Cells Tissues Organs, 2010, 191(3): 235-239.
[44] Kantaputra PN, Intachai W, Auychai P.All enamel is not created equal: supports from a novel FAM83H mutation[J]. Am J Med Genet A, 2016, 170A(1): 273-276.
[45] Sriwattanapong K, Nitayavardhana I, Theerapanon T, et al.Age-related dental phenotypes and tooth characteristics of FAM83H-associated hypocalcified amelogenesis imperfecta[J]. Oral Dis, 2022, 28(3): 734-744.
[46] Urzúa B, Martínez C, Ortega-Pinto A, et al.Novel missense mutation of the FAM83H gene causes retention of amelogenin and a mild clinical phenotype of hypocalcified enamel[J]. Arch Oral Biol, 2015, 60(9): 1356-1367.
[47] Zheng Y, Lu T, Chen J, et al.The gain-of-function FAM83H mutation caused hypocalcification amelogenesis imperfecta in a Chinese family[J]. Clin Oral Investig, 2021, 25(5): 2915-2923.
[48] Lee SK, Lee KE, Jeong TS, et al.FAM83H mutations cause ADHCAI and alter intracellular protein localization[J]. J Dent Res, 2011, 90(3): 377-381.
[49] Arkutu N, Gadhia K, McDonald S, et al. Amelogenesis imperfecta: the orthodontic perspective[J]. Br Dent J, 2012, 212(10): 485-489.
[50] Abd Alraheam I, Donovan T.Management of amelogenesis imperfecta in an adult patient: a short review and clinical report[J]. Br Dent J, 2020, 229(4): 239-243.
[51] Malik K, Gadhia K, Arkutu N, et al.The interdisciplinary management of patients with amelogenesis imperfecta-restorative dentistry[J]. Br Dent J, 2012, 212(11): 537-542.
[52] Leung VW, Low B, Yang Y, et al.Oral rehabilitation of young adult with amelogenesis imperfecta[J]. J Contemp Dent Pract, 2018, 19(5): 599-604.

一个常染色体显性钙化不全型釉质发育不全家系的致病基因研究及多学科治疗

Genetic analysis and multidisciplinary treatment of a pedigree affected with autosomal dominant hypocalcified amelogenesis imperfecta

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