scholarly journals A Mutation in the Enamelin Gene in a Mouse Model

2007 ◽  
Vol 86 (8) ◽  
pp. 764-768 ◽  
Author(s):  
H. Seedorf ◽  
M. Klaften ◽  
F. Eke ◽  
H. Fuchs ◽  
U. Seedorf ◽  
...  
Keyword(s):  
Mouse Model ◽  
Candidate Genes ◽  
Mouse Chromosome ◽  
Mouse Strain ◽  
Autosomal Dominant ◽  
Tooth Enamel ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Amelogenesis Imperfecta ◽  
Chromosome 5

Amelogenesis imperfecta is an inherited disorder affecting tooth enamel formation. We previously isolated a mouse strain with an amelogenesis imperfecta phenotype (ATE1 mice) from a dominant ethylnitrosourea screen and mapped the disease-causing defect to a 9-cM region of mouse chromosome 5. In the current study, we tested the hypothesis that there is a mutation in enamelin (ENAM) or ameloblastin (AMBN), both of which are located wihin the linkage region, by sequencing these two candidate genes. Analysis of our data shows that the amelogenesis imperfecta phenotype is linked to a C > T transition in exon 8 of the enamelin gene. The mutation predicts a C826T transition, which is present in the enamelin transcript and changes the glutamine (Gln) codon at position 176 into a premature stop codon (Gln176X). Conversely, no mutation could be detected in the ameloblastin gene. These results define the ATE1 mice as a model for local hypoplastic autosomal-dominant amelogenesis imperfecta (AIH2), which is caused by enamelin truncation mutations in humans.

Amelogenesis Imperfecta in a New Animal Model—a Mutation in Chromosome 5 (human 4q21)

2004 ◽  
Vol 83 (8) ◽  
pp. 608-612 ◽  
Author(s):  
H. Seedorf ◽  
I.N. Springer ◽  
E. Grundner-Culemann ◽  
H.-K. Albers ◽  
A. Reis ◽  
...  
Keyword(s):  
Human Chromosome ◽  
Mouse Chromosome ◽  
Tooth Enamel ◽  
Amelogenesis Imperfecta ◽  
Chromosome 5 ◽  
Dentinal Tubules ◽  
C3h Mice ◽  
Cross Links ◽  
Structure And Ultrastructure ◽  
Chromosome 4Q21

Candidate genes for amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are located on 4q21 in humans. We tested our hypothesis that mutations in the portion of mouse chromosome 5 corresponding to human chromosome 4q21 would cause enamel and dentin abnormalities. Male C3H mice were injected with ethylnitrosourea (ENU). Within a dominant ENU mutagenesis screen, a mouse mutant was isolated with an abnormal tooth enamel (ATE) phenotype. The structure and ultrastructure of teeth were studied. The mutation was located on mouse chromosome 5 in an interval of 9 cM between markers D5Mit18 and D5Mit10. Homozygotic mutants showed total enamel aplasia with exposed dentinal tubules, while heterozygotic mutants showed a significant reduction in enamel width. Dentin of mutant mice showed a reduced content of mature collagen cross-links. We were able to demonstrate that a mutation on chromosome 5 corresponding to human chromosome 4q21 can cause amelogenesis imperfecta and changes in dentin composition.

scholarly journals Premature Stop Codon in MMP20 Causing Amelogenesis Imperfecta

2008 ◽  
Vol 87 (1) ◽  
pp. 56-59 ◽  
Author(s):  
P. Papagerakis ◽  
H.-K. Lin ◽  
K.Y. Lee ◽  
Y. Hu ◽  
J.P. Simmer ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Proteolytic Enzymes ◽  
Stop Codon ◽  
Translation Termination ◽  
Premature Stop Codon ◽  
Dental Enamel ◽  
Amino Acid Position ◽  
Amelogenesis Imperfecta ◽  
Exon 1 ◽  
Kallikrein 4

Proteolytic enzymes are necessary for the mineralization of dental enamel during development, and mutations in the kallikrein 4 ( KLK4) and enamelysin ( MMP20) genes cause autosomal-recessive amelogenesis imperfecta (ARAI). So far, only one KLK4 and two MMP20 mutations have been reported. We have identified an ARAI-causing point mutation (c.102G>A, g.102G>A, and p.W34X) in exon 1 of MMP20 in a proband with autosomal-recessive hypoplastic-hypomaturation amelogenesis imperfecta. The G to A transition changes the tryptophan (W) codon (TGG) at amino acid position 34 into a translation termination (X) codon (TGA). No disease-causing sequence variations were detected in KLK4. The affected enamel is thin, with mild spacing in the anterior dentition. The enamel layer is hypomineralized, does not contrast with dentin on radiographs, and tends to chip away from the underlying dentin. An intrinsic yellowish pigmentation is evident, even during eruption. The phenotype supports current ideas concerning the function of enamelysin.

scholarly journals Autosomal Recessive Oculodentodigital Dysplasia: A Case Report and Review of the Literature

2018 ◽  
Vol 154 (4) ◽  
pp. 181-186 ◽  
Author(s):  
Elifcan Taşdelen ◽  
Ceren D. Durmaz ◽  
Halil G. Karabulut
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Rare Condition ◽  
Clinical Findings ◽  
Homozygous Mutation ◽  
Nasal Bridge ◽  
Oculodentodigital Dysplasia ◽  
Autosomal Recessive Manner

Oculodentodigital dysplasia (ODDD) is a rare condition characterized by a typical facial appearance and variable findings of the eyes, teeth, and fingers. ODDD is caused by mutations in the GJA1 gene in chromosome 6q22 and inherited in an autosomal dominant manner in the majority of the patients. However, in recent clinical reports, autosomal recessive ODDD cases due to by GJA1 mutations were also described. Here, we report on a 14-year-old boy with microphthalmia, microcornea, narrow nasal bridge, hypoplastic alae nasi, prominent columnella, hypodontia, dental caries, and partial syndactyly of the 2nd and 3rd toes. These clinical findings were concordant with the diagnosis of ODDD, and a novel homozygous mutation (c.442C>T, p.Arg148Ter) was determined in the GJA1 gene leading to a premature stop codon. His phenotypically normal parents were found to be carriers of the same mutation. This is the third family in the literature in which ODDD segregates in an autosomal recessive manner.

scholarly journals A Novel de Novo sp6 Mutation Causes Severe Hypoplastic Ame-Logenesis Imperfecta

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 346
Author(s):  
Youn Jung Kim ◽  
Yejin Lee ◽  
Hong Zhang ◽  
Ji-Soo Song ◽  
Jan C-C. Hu ◽  
...  
Keyword(s):  
Western Blot ◽  
Missense Mutation ◽  
Autosomal Dominant ◽  
De Novo ◽  
Clinical Phenotype ◽  
Tooth Enamel ◽  
Genetic Disorders ◽  
Mrna Level ◽  
Amelogenesis Imperfecta ◽  
Wild Type

Amelogenesis imperfecta (AI) is a heterogeneous group of rare genetic disorders affecting tooth enamel formation. Here we report an identification of a novel de novo missense mutation [c.817_818delinsAT, p.(Ala273Met)] in the SP6 gene, causing non-syndromic autosomal dominant AI. This is the second paper on amelogenesis imperfecta caused by SP6 mutation. Interestingly the identified mutation in this study is a 2-bp variant at the same nucleotide positions as the first report, but with AT instead of AA insertion. Clinical phenotype was much more severe compared to the previous report, and western blot showed an extremely decreased level of mutant protein compared to the wild-type, even though the mRNA level was similar.

scholarly journals In vivoRNA targeting of point mutations via suppressor tRNAs and adenosine deaminases

2017 ◽  
Author(s):  
Dhruva Katrekar ◽  
Prashant Mali
Keyword(s):  
Mouse Model ◽  
Rna Editing ◽  
Unnatural Amino Acids ◽  
Stop Codon ◽  
Genetic Diseases ◽  
Point Mutations ◽  
Premature Stop Codon ◽  
Dystrophin Gene ◽  
Multiple Challenges

ABSTRACTPoint mutations underlie many genetic diseases. In this regard, while programmable DNA nucleases have been used to repair mutations, their use for gene therapy poses multiple challenges: one, efficiency of homologous recombination is typically low in cells; two, an active nuclease presents a risk of introducing permanent off-target mutations; and three, prevalent programmable nucleases typically comprise elements of non-human origin raising the potential ofin vivoimmunogenicity. In light of these, approaches to instead directly target RNA, and use of molecular machinery native to the host would be highly desirable. Towards this, we engineered and optimized two complementary approaches, referred together hereon astRiAD, based on the use oftRNAsin codon suppression andadenosinedeaminases in RNA editing. Specifically, by delivering modified endogenous tRNAs and/or the RNA editing enzyme ADAR2 and an associated guiding RNA (adRNA) via adeno-associated viruses, we enabled premature stop codon read-through and correction in themdxmouse model of muscular dystrophy that harbors a nonsense mutation in the dystrophin gene. We further demonstrated inducible restoration of dystrophin expression by pyrolysyl-tRNA mediated incorporation of unnatural amino acids (UAAs) at the stop codon. Additionally, we also engineered ADAR2 mediated correction of a point mutation in liver RNA of thespfashmouse model of ornithine transcarbamylase (OTC) deficiency. Taken together, our results establish the use of suppressor tRNAs and ADAR2 forin vivoRNA targeting, and this integrated tRiAD approach is robust, genomically scarless, and potentially non-immunogenic as it utilizes effector RNAs and human proteins.

Detection of a novel premature stop codon in the OPA1 gene in autosomal dominant optic atrophy

2012 ◽  
Vol 90 ◽  
pp. 0-0 ◽  
Author(s):  
M OLDAK ◽  
A FEDEROWICZ ◽  
K SZULBORSKI ◽  
J WIERZBOWSKA ◽  
J KOSINSKA ◽  
...  
Keyword(s):  
Optic Atrophy ◽  
Autosomal Dominant ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Autosomal Dominant Optic Atrophy ◽  
Dominant Optic Atrophy ◽  
Opa1 Gene

Abstract 1252: A Mouse Model of a Familial Dilated Cardiomyopathy Mutation in Titin Recapitulates the Human Phenotype

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Michael Gramlich ◽  
Beate Michely ◽  
Brenda Gerull ◽  
Christian Krohne ◽  
Ingo Morano ◽  
...  
Keyword(s):  
Mouse Model ◽  
Western Blot ◽  
Dilated Cardiomyopathy ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Autosomal Dominant ◽  
Premature Stop Codon ◽  
Left Ventricular ◽  
Insertion Mutation ◽  
Human Phenotype

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial diseases and the third most common cause of heart failure. Familial occurrence, mostly as an autosomal dominant trait, is responsible for 20 –30% of all DCM cases. We have previously shown that mutations in the giant muscle filament titin ( TTN ) cause dilated cardiomyopathy. In a large DCM kindred (A1) with autosomal dominant inherited DCM, we could identify a 2 bp insertion mutation in exon 326 of TTN . This heterozygous nonsense mutation leads to a framshift generating a premature stop codon after the addition of 4 novel amino acid residues. We have recently evaluated a cardiac biopsy sample from an affected family member of kindred A1 showing that no truncated protein is observed in a western blot analysis. To further investigate the functional consequences of the identified human TTN mutation, we now generated a mouse model that includes the 2bp insertion at the corresponding site in the mouse genome. Heterozygous mice are viable and fertile. As in the human situation, the truncated titin is not detectable in western blot analysis of cardiac tissue indicating haploinsufficiency. The ventricles of the heterozygous animals show a decrease in ventricular stiffness as seen in isolated working heart pressure measurements and transmitral Doppler echocardiography (E:A 1.34 vs. 1.075, p<0.01; IVRT 13.57ms vs. 17.01ms, p<0.05). When exposed to angiotensin II (1.4 mg/kg/d for 14d) as a cardiac stressor, heterozygous animals develop dilatation of the left ventricles (4.45mm vs. 3.77 mm, p<0.05) with impaired fractional shortening (25.12% vs. 32.86%, p<0.01) and a diffuse myocardial fibrosis. Homozygous mice die in utero before E8.0. Whether a defect in the formation of sarcomeres or, alternatively, a defect in yet unknown non-muscle functions of titin account for this early embryonic lethality remains to be determined. Conclusion: Our mouse model shows that a mutation in TTN leads to impaired biomechanical properties of the heart, resulting in left ventricular dilatation and decreased systolic function, thereby recapitulating the human phenotype.

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