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 Alteration of Exon Definition Causes Amelogenesis Imperfecta

2020 ◽  
Vol 99 (4) ◽  
pp. 410-418
Author(s):  
Y.J. Kim ◽  
J. Kang ◽  
F. Seymen ◽  
M. Koruyucu ◽  
H. Zhang ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Tooth Enamel ◽  
Genetic Disorders ◽  
Molecular Genetic ◽  
Amelogenesis Imperfecta ◽  
Compound Heterozygous ◽  
Exon Definition ◽  
Whole Exome ◽  
Exon 1 ◽  
Definition Of

Amelogenesis imperfecta (AI) is a collection of genetic disorders affecting the quality and/or quantity of tooth enamel. More than 20 genes are, so far, known to be responsible for this condition. In this study, we recruited 3 Turkish families with hypomaturation AI. Whole-exome sequence analyses identified disease-causing mutations in each proband, and these mutations cosegregated with the AI phenotype in all recruited members of each family. The AI-causing mutations in family 1 were a novel AMELX mutation [NM_182680.1:c.143T>C, p.(Leu48Ser)] in the proband and a novel homozygous MMP20 mutation [NM_004771.3:c.616G>A, p.(Asp206Asn)] in the mother of the proband. Previously reported compound heterozygous MMP20 mutations [NM_004771.3:c.103A>C, p.(Arg35=) and c.389C>T, p.(Thr130Ile)] caused the AI in family 2 and family 3. Minigene splicing analyses revealed that the AMELX missense mutation increased exonic definition of exon 4 and the MMP20 synonymous mutation decreased exonic definition of exon 1. These mutations would trigger an alteration of exon usage during RNA splicing, causing the enamel malformations. These results broaden our understanding of molecular genetic pathology of tooth enamel formation.

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.

scholarly journals P.028 A milder congenital myopathy in the french canadians caused by a novel TNNT1 homozygous missense mutation

2019 ◽  
Vol 46 (s1) ◽  
pp. S21
Author(s):  
D Pellerin ◽  
A Aykanat ◽  
B Ellezam ◽  
J Karamchandani ◽  
J Mathieu ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Clinical Phenotype ◽  
Fatty Infiltration ◽  
Nemaline Myopathy ◽  
Wild Type ◽  
French Canadians ◽  
Restrictive Lung Disease ◽  
Leg Muscles ◽  
Slow Skeletal Muscle ◽  
Nemaline Rods

Background: Mutations of the slow skeletal muscle troponin-T1 (TNNT1) gene are a rare cause of nemaline myopathy. The phenotype is characterized by severe amyotrophy and contractures. Death from respiratory insufficiency occurs in infancy. We report on four French Canadians with a novel congenital TNNT1-related myopathy. Methods: Patients underwent MRI of leg muscles, quadriceps biopsy and genetic testing. Wild type or mutated human TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess their relative abilities to rescue the morphant phenotype. Results: Three adults and one child shared a novel missense homozygous pathogenic variant in the TNNT1 gene. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of infection-triggered rhabdomyolysis, which were relieved by dantrolene in one patient. Older patients remained ambulatory into their sixties. MRI of leg muscles showed symmetrical atrophy and fatty infiltration in a proximal-to-distal gradient. Biopsies showed multi-minicores, while nemaline rods were seen in half the patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to rescue the morphants. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel missense mutation.

scholarly journals Haploinsufficiency of MSX1: a Mechanism for Selective Tooth Agenesis

1998 ◽  
Vol 18 (10) ◽  
pp. 6044-6051 ◽  
Author(s):  
Gezhi Hu ◽  
Heleni Vastardis ◽  
Andrew J. Bendall ◽  
Zhaoqing Wang ◽  
Malcolm Logan ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Transcriptional Repression ◽  
Autosomal Dominant ◽  
Ectopic Expression ◽  
Dominant Negative ◽  
Tooth Agenesis ◽  
Wild Type ◽  
Proline Substitution ◽  
Functional Analyses

ABSTRACT Previously, we found that the cause of autosomal dominant selective tooth agenesis in one family is a missense mutation resulting in an arginine-to-proline substitution in the homeodomain of MSX1. To determine whether the tooth agenesis phenotype may result from haploinsufficiency or a dominant-negative mechanism, we have performed biochemical and functional analyses of the mutant protein Msx1(R31P). We show that Msx1(R31P) has perturbed structure and reduced thermostability compared with wild-type Msx1. As a consequence, the biochemical activities of Msx1(R31P) are severely impaired, since it exhibits little or no ability to interact with DNA or other protein factors or to function in transcriptional repression. We also show that Msx1(R31P) is inactive in vivo, since it does not display the activities of wild-type Msx1 in assays of ectopic expression in the limb. Furthermore, Msx1(R31P) does not antagonize the activity of wild-type Msx1 in any of these assays. Because Msx1(R31P) appears to be inactive and does not affect the action of wild-type Msx1, we propose that the phenotype of affected individuals with selective tooth agenesis is due to haploinsufficiency.

Recessive Mutations in ACP4 Cause Amelogenesis Imperfecta

2021 ◽  
pp. 002203452110151
Author(s):  
Y.J. Kim ◽  
Y. Lee ◽  
Y. Kasimoglu ◽  
F. Seymen ◽  
J.P. Simmer ◽  
...  
Keyword(s):  
Acid Phosphatase ◽  
Phosphatase Activity ◽  
Acid Phosphatase Activity ◽  
De Novo ◽  
Tooth Enamel ◽  
Activity Level ◽  
Amelogenesis Imperfecta ◽  
Catalytic Core ◽  
Enamel Thickness ◽  
Mutant Forms

Amelogenesis imperfecta (AI) is an innate disorder that affects the formation and mineralization of the tooth enamel. When diagnosed with AI, one’s teeth can be hypoplastic (thin enamel), hypomature (normal enamel thickness but discolored and softer than normal enamel), hypocalcified (normal enamel thickness but extremely weak), or mixed conditions of the above. Numerous studies have revealed the genes that are involved in causing AI. Recently, ACP4 (acid phosphatase 4) was newly found as a gene causing hypoplastic AI, and it was suggested that mutant forms of ACP4 might affect access to the catalytic core or the ability to form a homodimer. In this study, a Korean and a Turkish family with hypoplastic AI were recruited, and their exome sequences were analyzed. Biallelic mutations were revealed in ACP4: paternal (NM_033068: c.419C>T, p.(Pro140Leu)) and maternal (c.262C>A, p.(Arg88Ser)) mutations in family 1 and a paternal (c.713C>T, p.(Ser238Leu)) mutation and de novo (c.350A>G, p.(Gln117Arg)) mutation in the maternal allele in family 2. Mutations were analyzed by cloning, mutagenesis, immunofluorescence, immunoprecipitation, and acid phosphatase activity test. Comparison between the wild-type and mutant ACP4s showed a decreased amount of protein expression from the mutant forms, a decreased ability to form a homodimer, and a decreased acid phosphatase activity level. We believe that these findings will not only expand the mutational spectrum of ACP4 but also increase our understanding of the mechanism of ACP4 function during normal and pathologic amelogenesis.

scholarly journals A Chinese patient with developmental and epileptic encephalopathies (DEE) carrying a TRPM3 gene mutation: a paediatric case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qingyun Kang ◽  
Liming Yang ◽  
Hongmei Liao ◽  
Sai Yang ◽  
Xiaojun Kuang ◽  
...  
Keyword(s):  
Case Report ◽  
Missense Mutation ◽  
De Novo ◽  
Clinical Phenotype ◽  
Chinese Patient ◽  
Case Presentation ◽  
Epileptic Encephalopathies ◽  
Surface Receptors ◽  
Paediatric Case ◽  
Coding Variants

Abstract Background Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of chronic encephalopathies characterized by epilepsy with comorbid intellectual disability that are frequently associated with de novo nonsynonymous coding variants in ion channels, cell-surface receptors, and other neuronally expressed genes. Mutations in TRPM3 were identified as the cause of DEE. We report a novel patient with DEE carrying a de novo missense mutation in TRPM3, p.(S1202T); this missense mutation has never been reported. Case presentation A 7-year and 2-month-old Chinese patient who had recurrent polymorphic seizures was clinically diagnosed with DEE. A de novo missense mutation in TRPM3, which has not yet been reported, was identified in this case. The patient had a clinical phenotype consistent with previous reports. Conclusions These findings could expand the spectrum of TRPM3 mutations and might also support that de novo substitutions of TRPM3 are a cause of DEE.

scholarly journals De novo VHL germline mutation detected in a patient with mild clinical phenotype of von Hippel-Lindau disease

2014 ◽  
Vol 121 (2) ◽  
pp. 384-386 ◽  
Author(s):  
Xinghua Ding ◽  
Chao Zhang ◽  
Jason M. Frerich ◽  
Anand Germanwala ◽  
Chunzhang Yang ◽  
...  
Keyword(s):  
Germline Mutation ◽  
Autosomal Dominant ◽  
De Novo ◽  
Clinical Phenotype ◽  
Pancreatic Neuroendocrine Tumors ◽  
Renal Cell Carcinomas ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease ◽  
Mild Clinical Phenotype

Von Hippel-Lindau (VHL) disease is an autosomal dominant multiorgan tumor syndrome caused by a germline mutation in the VHL gene. Characteristic tumors include CNS hemangioblastomas (HBs), endolymphatic sac tumors, renal cell carcinomas, pheochromocytomas, and pancreatic neuroendocrine tumors. Sporadic VHL disease with a de novo germline mutation is rare. The authors describe a case of multiple CNS HBs in a patient with a heterozygous de novo germline mutation at c.239G>T [p.S80I] of VHL. This is the first known case of a sporadic de novo germline mutation of VHL at c.239G>T. Clinicians should continue to consider VHL disease in patients presenting with sporadic CNS HBs, including those without a family history, to confirm or exclude additional VHL-associated visceral lesions.

scholarly journals Reduced Amelogenin-MMP20 Interactions in Amelogenesis Imperfecta

2008 ◽  
Vol 87 (5) ◽  
pp. 451-455 ◽  
Author(s):  
K. Tanimoto ◽  
T. Le ◽  
L. Zhu ◽  
H.E. Witkowska ◽  
S. Robinson ◽  
...  
Keyword(s):  
Surface Plasmon Resonance ◽  
Matrix Metalloproteinase ◽  
Surface Plasmon ◽  
Plasmon Resonance ◽  
Tooth Enamel ◽  
Amelogenesis Imperfecta ◽  
Wild Type ◽  
Competition Assay ◽  
Enamel Defect ◽  
Substrate Competition

Amelogenin with a proline 41 to threonine mutation (P41T) is hydrolyzed at a lower rate by matrix metalloproteinase 20 (MMP20), resulting in an inherited tooth enamel defect, amelogenesis imperfecta (AI). The aim of this study was to elucidate the effect of P41T on the interactions between amelogenin and MMP20, which may contribute to the formation of this type of AI. The interactions of a recombinant wild-type human amelogenin and its P41T mutant with recombinant human MMP20 were compared by substrate competition assay, pull-down assay, and surface plasmon resonance (SPR). The results showed that the binding of the P41T mutant amelogenin for MMP20 was significantly lower than that of wild-type amelogenin. Our study supports a model in which the P41T mutation reduces the interactions between amelogenin and MMP20, leading to decreased degradation of amelogenin by MMP20, and resulting in AI.

Arabidopsis 4-COUMAROYL-COA LIGASE 8 contributes to the biosynthesis of the benzenoid ring of coenzyme Q in peroxisomes

2019 ◽  
Vol 476 (22) ◽  
pp. 3521-3532
Author(s):  
Eric Soubeyrand ◽  
Megan Kelly ◽  
Shea A. Keene ◽  
Ann C. Bernert ◽  
Scott Latimer ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Time Course ◽  
Reverse Genetics ◽  
De Novo ◽  
Coenzyme Q ◽  
Control Level ◽  
Wild Type ◽  
Fluorescent Reporters ◽  
Coa Ligase ◽  
Peroxisomal Targeting

Plants have evolved the ability to derive the benzenoid moiety of the respiratory cofactor and antioxidant, ubiquinone (coenzyme Q), either from the β-oxidative metabolism of p-coumarate or from the peroxidative cleavage of kaempferol. Here, isotopic feeding assays, gene co-expression analysis and reverse genetics identified Arabidopsis 4-COUMARATE-COA LIGASE 8 (4-CL8; At5g38120) as a contributor to the β-oxidation of p-coumarate for ubiquinone biosynthesis. The enzyme is part of the same clade (V) of acyl-activating enzymes than At4g19010, a p-coumarate CoA ligase known to play a central role in the conversion of p-coumarate into 4-hydroxybenzoate. A 4-cl8 T-DNA knockout displayed a 20% decrease in ubiquinone content compared with wild-type plants, while 4-CL8 overexpression boosted ubiquinone content up to 150% of the control level. Similarly, the isotopic enrichment of ubiquinone's ring was decreased by 28% in the 4-cl8 knockout as compared with wild-type controls when Phe-[Ring-13C6] was fed to the plants. This metabolic blockage could be bypassed via the exogenous supply of 4-hydroxybenzoate, the product of p-coumarate β-oxidation. Arabidopsis 4-CL8 displays a canonical peroxisomal targeting sequence type 1, and confocal microscopy experiments using fused fluorescent reporters demonstrated that this enzyme is imported into peroxisomes. Time course feeding assays using Phe-[Ring-13C6] in a series of Arabidopsis single and double knockouts blocked in the β-oxidative metabolism of p-coumarate (4-cl8; at4g19010; at4g19010 × 4-cl8), flavonol biosynthesis (flavanone-3-hydroxylase), or both (at4g19010 × flavanone-3-hydroxylase) indicated that continuous high light treatments (500 µE m−2 s−1; 24 h) markedly stimulated the de novo biosynthesis of ubiquinone independently of kaempferol catabolism.

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