Novel FAM83H mutations in patients with amelogenesis imperfecta

Wang, Xin; Wang, Wenjun; Qin, Man; Zhao, Yuming

doi:10.1038/s41598-017-05208-0

Cited by 17 publications

(13 citation statements)

References 32 publications

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“…To date, 27 different FAM83H autosomal dominant truncation mutations have been associated with ADHCAI (Chan et al, ; Ding et al, ; El‐Sayed, Shore, Parry, Inglehearn, & Mighell, ; Hart et al, ; Haubek et al, ; Hyun et al, ; Kantaputra, Intachai, & Auychai, ; Kim et al, ; Lee et al, , ; Prasad et al, ; Song, Wang, Zhang, Yang, & Bian, ; Wang, Hu, Yang, Smith, Richardson, et al, ; Wright et al, , ; Xin, Wenjun, Man, & Yuming, ; Zhang, Song, & Bian, ). Seven of these mutations have been found in multiple families.…”

Section: Introductionmentioning

confidence: 99%

The Enamel Phenotype in Homozygous Fam83h Truncation Mice

Wang

Smith

et al. 2019

Molec Gen & Gen Med

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Background Truncation FAM83H mutations cause human autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI), an inherited disorder characterized by severe hardness defects in dental enamel. No enamel defects were observed in Fam83h null mice suggesting that Fam83h truncation mice would better replicate human mutations. Methods We generated and characterized a mouse model (Fam83hTr/Tr) expressing a truncated FAM83H protein (amino acids 1–296), which recapitulated the ADHCAI‐causing human FAM83H p.Tyr297* mutation. Results Day 14 and 7‐week Fam83hTr/Tr molars exhibited rough enamel surfaces and slender cusps resulting from hypoplastic enamel defects. The lateral third of the Fam83hTr/Tr incisor enamel layer was thinner, with surface roughness and altered enamel rod orientation, suggesting disturbed enamel matrix secretion. Regular electron density in mandibular incisor enamel indicated normal enamel maturation. Only mildly increased posteruption attrition of Fam83hTr/Tr molar enamel was observed at 7‐weeks. Histologically, the Fam83hTr/Tr enamel organ, including ameloblasts, and enamel matrices at sequential stages of amelogenesis exhibited comparable morphology without overt abnormalities, except irregular and less evident ameloblast Tomes' processes in specific areas. Conclusions Considering Fam83h−/− mice showed no enamel phenotype, while Fam83hTr/Tr (p.Tyr297*) mice displayed obvious enamel malformations, we conclude that FAM83H truncation mutations causing ADHCAI in humans disturb amelogenesis through a neomorphic mechanism, rather than haploinsufficiency.

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Section: Introductionmentioning

confidence: 99%

The Enamel Phenotype in Homozygous Fam83h Truncation Mice

Wang

Smith

et al. 2019

Molec Gen & Gen Med

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“…9 But the relationship of FAM83H gene with the nonsense, missense, and deletion mutations that lead to the production of a truncated protein has been reported. [10][11][12] Although mutational studies of the human FAM83H indicate a role for FAM83H in AI, its actual functions, pathogenesis, and association with enamel defects are generally unknown. 4 However, the detailed function and mechanism of FAM83H have yet to be fully discovered.…”

Section: Introductionmentioning

confidence: 99%

“…Also, mutation in this domain might prevent them from binding to CK1 and, subsequently, prevent proper subcellular localization and cellular functions of both the FAM83H protein and CK1 . But the relationship of FAM83H gene with the nonsense, missense, and deletion mutations that lead to the production of a truncated protein has been reported . Although mutational studies of the human FAM83H indicate a role for FAM83H in AI, its actual functions, pathogenesis, and association with enamel defects are generally unknown .…”

Section: Introductionmentioning

confidence: 99%

Generation of Fam83h knockout mice by CRISPR/Cas9‐mediated gene engineering

Nasseri

Nikkho

Parsa

et al. 2019

J of Cellular Biochemistry

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Family with sequence similarity 83 member H (FAM83H) protein-coding geneplay an essential role in the structural organization, calcification of developing enamel, and keratin cytoskeleton disassembly by recruiting Casein kinase 1 alpha (CSNK1A1) to keratin filaments. In this study, we have applied CRISPR Cas9 nickase (D10A) to knockout (KO) the Fam83h gene in NMRI outbred mice. We generated homozygous Fam83h KO mice (Fam83h Ko/Ko ) through a premature termination codon, which was validated by Sanger sequencing in F0 generation. Next, we also bred the FAM83H KO for two generations. Reverse-transcription polymerase chain reaction and Western blot analysis approved the Fam83h KO mice. The Fam83h KO mice had evidence of normal morphology at the cervical loops, secretory and maturation stages, and mandibular molars. In comparison with the normal wild-type mice (Fam83h W/W ), the F2 homozygous KO (Fam83h Ko/Ko ) had sparse, scruffy coats with small body size and decreased general activity. Also, they had the natural reproductive ability and natural lifespan. In addition, delay in opening the eyes and dry eyes among infant mice were seen. The F1 heterozygous mice looked comparable to the normal wild-type mice (Fam83h W/W ), which showed autosomal recessive inheritance of these phenotypes. The KO of FAM83H had controversial effects on the development of teeth and the formation of enamel.The phenotype defect in dental development and the enamel formation were seen in three mice among four generations. It can be concluded that null FAM83H in outbred mice not only showed the reported phenotypes in null inbred mouse but also showed normal lifespan and reproductive ability; dental deficiency in three homozygous mice; and the symptoms that were similar to the symptoms of dry eye syndrome and curly coat dog syndrome in all four evaluated KO generations. K E Y W O R D Samelogenesis imperfecta, CRISPR-Cas system, family with sequence similarity 83 member H protein, knockout mice, outbred mice

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“…FAM20A encodes a secreted glycoprotein [ 34 ]. The most severe type, the hypocalcified amelogenesis imperfecta, is mostly caused by nonsense mutations in the FAM83H gene [ 35 ]. Nonetheless, the clinically normal crown morphology in this patient set enamel malformations very low to the differential diagnosis list.…”

Section: Discussionmentioning

confidence: 99%

Orthodontic Treatment of a Patient with Dentin Dysplasia Type I and Bilateral Maxillary Canine Impaction: Case Presentation and a Family-Based Genetic Analysis

et al. 2021

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Dentin dysplasia is a rare hereditary disorder, transmitted by autosomal dominant mode, affecting both dentin and pulp. In Type I crown morphology is normal, but root dentin organization loss leads to shorter roots. Mutations in the SSUH2, VPS4B and SMOC2 genes have been reported as responsible for this condition. Orthodontic treatment was conducted on an 11-year-old female patient presenting the disorder along with bilaterally impacted permanent maxillary canines, in close proximity to the roots of the lateral and central incisors. Treatment plan included lateral incisors extraction, surgical exposure and traction of the impacted canines. Light forces were applied from a custom-made trans-palatal arch. Comprehensive orthodontic treatment was performed using edgewise appliances. After 3 years and 2 months, group function occlusion was achieved. The canines underwent composite resin restorations. At one year post-retention, the dentition remained stable. Family-based genetic analysis did not reveal any mutations in the aforementioned genes pointing to further genetic heterogeneity of this disorder. As dental medicine becomes more sophisticated and personalized, the association between mutation type/function and orthodontic treatment response may provide useful therapeutic insights. The positive treatment response of the presented case could be attributed to a more “benign” mutation awaiting to be identified.

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Novel FAM83H mutations in patients with amelogenesis imperfecta

Cited by 17 publications

References 32 publications

The Enamel Phenotype in Homozygous Fam83h Truncation Mice

The Enamel Phenotype in Homozygous Fam83h Truncation Mice

Generation of Fam83h knockout mice by CRISPR/Cas9‐mediated gene engineering

Orthodontic Treatment of a Patient with Dentin Dysplasia Type I and Bilateral Maxillary Canine Impaction: Case Presentation and a Family-Based Genetic Analysis

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