A Novel Mutation in the <i>DSPP</i> Gene Associated with                Dentinogenesis Imperfecta Type II

Lee, Seong-Kook; Lee, K.-E.; Jeon, D.; Lee, G.; Lee, H.; Shin, Chanseok; Jung, Young‐Jung; Lee, S.-H.; Hahn, S.-H.; Kim, J.-W.

doi:10.1177/0022034508328168

Cited by 54 publications

(42 citation statements)

References 20 publications

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“…10)2122232425262728293031323334. Seven genes including VWA1 , PTH1R , KDM1A and CSF1 have been related to abnormal cartilage and bone formations, with the CSF1 gene also linked to tenosynovial giant cell tumour3536373839. Interestingly, clinical situations have shown that patients with neurologic disorders exhibit localized bone changes and altered fracture healing with excessive callus formation40.…”

Section: Resultsmentioning

confidence: 99%

Tetrahelical structural family adopted by AGCGA-rich regulatory DNA regions

Kocman

Plavec

2017

Nat Commun

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Here we describe AGCGA-quadruplexes, an unexpected addition to the well-known tetrahelical families, G-quadruplexes and i-motifs, that have been a focus of intense research due to their potential biological impact in G- and C-rich DNA regions, respectively. High-resolution structures determined by solution-state nuclear magnetic resonance (NMR) spectroscopy demonstrate that AGCGA-quadruplexes comprise four 5′-AGCGA-3′ tracts and are stabilized by G-A and G-C base pairs forming GAGA- and GCGC-quartets, respectively. Residues in the core of the structure are connected with edge-type loops. Sequences of alternating 5′-AGCGA-3′ and 5′-GGG-3′ repeats could be expected to form G-quadruplexes, but are shown herein to form AGCGA-quadruplexes instead. Unique structural features of AGCGA-quadruplexes together with lower sensitivity to cation and pH variation imply their potential biological relevance in regulatory regions of genes responsible for basic cellular processes that are related to neurological disorders, cancer and abnormalities in bone and cartilage development.

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Section: Resultsmentioning

confidence: 99%

Tetrahelical structural family adopted by AGCGA-rich regulatory DNA regions

Kocman

Plavec

2017

Nat Commun

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“…[Kim et al, 2005a] Defects in this gene are the cause of many diseases such as dentinogenesis imperfecta type 1 (DGI1) and dentin dysplasia type 2 (DTDP2), both of which are autosomal dominant disorders. [Bhandari and Pannu, 2008; Lee et al, 2009] Researchers also found that mutations in the the DSPP gene lead to the production of abnormal DSPP-derived proteins or reduce the amount of these proteins in developing teeth. As a result, teeth have abnormally soft dentin.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Environmental Factors Associated with Dental Caries in Children: The Iowa Fluoride Study

Wang¹,

Willing

Marazita³

et al. 2012

Caries Res

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Dental caries remains the most common chronic childhood disease. Despite strong evidence of genetic components, there have been few studies of candidate genes and caries. In this analysis we tried to assess genetic and environmental factors contributing to childhood caries in the Iowa Fluoride Study. Environmental factors (age, sex, race, tooth-brushing frequencies and water fluoride level) and three dental caries scores (d₂fs-total, d₂fs-pit/fissure, and d₂fs-smooth surface) were assessed in 575 unrelated children (mean age 5.2 years). Regression analyses were applied to assess environmental correlates. The Family-Based Association Test was used to test genetic associations for 23 single nucleotide polymorphism (SNP) markers in 7 caries candidate genes on 333 Caucasian parent-child trios. We evaluated the associations between caries status and the level of both single and multiple SNPs (haplotype) respectively. Permutation procedure was performed for correction of inflated type I errors due to multiple testing. Age, tooth-brushing frequency and water fluoride level were significantly correlated to at least one carious score. Caries on pit and fissure surfaces was substantially higher than on smooth surfaces (61 vs. 39%). SNPs in three genes (DSPP, KLK4 and AQP5) showed consistent associations with protection against caries. Of note, KLK4 and AQP5 were also highlighted by subsequent haplotype analysis. Our results support the concept that genes can modify the susceptibility of caries in children. Replication analysis in independent cohorts is highly needed in order to verify the validity of our findings.

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“…DSPP: The first 31 amino acids of normal human DSPP (IPV) as well as the same fragment encoding the ISV (5), ITV (21), ILV (hypothetical), IPD (31), IPD3 (exon 3-skipping), IPF (21), and A15V (32) mutations in-frame with a 3' AgeI site were synthesized as oligonuclotides, double stranded by PCR and cloned into Gateway pENTR/D TOPO vector (Invitrogen, Carlsbad, CA). An identical approach was used to make normal and mutant (V-to-D) constructs using the first 31 amino acids of human OPN and DMP1.…”

Section: Methodsmentioning

confidence: 99%

Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP

Marschall

Mok

Phillips

et al. 2012

Journal of Bone and Mineral Research

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Families with nonsyndromic dentinogenesis imperfecta (DGI) and the milder, dentin dysplasia (DD), have mutations in one allele of the dentin sialophosphoprotein (DSPP) gene. Because loss of a single Dspp allele in mice (and likely, humans) causes no dental phenotype, the mechanism(s) underling the dominant-negative effects were investigated. DSPP mutations occur in three classes. (The first class, the mid-leader missense mutation, Y6D, was not investigated in this report.) All other 5' mutations of DSPP result in changes/loss in the first three amino acids (IPV) of mature DSPP or, for A15V, some retention of the hydrophobic leader sequence. All of this second class of mutations caused mutant DSPP to be retained in the rER of transfected HEK293 cells. Trafficking out of the rER by co-expressed normal DSPP was reduced in a dose-responsive manner, probably due to formation of Ca2+-dependent complexes with the retained mutant DSPP. IPV-like sequences begin many secreted Ca2+-binding proteins, and changing the third amino acid to the charged aspartate (D) in three other acidic proteins also caused increased rER accumulation. Both the leader-retaining A15V and the long string of hydrophobic amino acids resulting from all known frameshift mutations within the 3'-encoded Ca2+-binding repeat domain (third class of mutations) caused retention by association of the mutant proteins with rER membranes. More 5' frameshift mutations result in longer mutant hydrophobic domains but the milder phenotype, DD, probably due to lower effectiveness of the remaining, shorter Ca2+-binding domain in capturing normal DSPP protein within the rER. This study presents evidence of a shared underlying mechanism of capturing of normal DSPP by two different classes of DSPP mutations and offers an explanation for the mild (DD-II) versus severe (DGI-II & III) nonsyndromic dentin phenotypes. Evidence is also presented that many acidic, Ca2+-binding proteins may use the same IPV-like receptor/pathway for exiting the rER.

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A Novel Mutation in the DSPP Gene Associated with Dentinogenesis Imperfecta Type II

Cited by 54 publications

References 20 publications

Tetrahelical structural family adopted by AGCGA-rich regulatory DNA regions

Tetrahelical structural family adopted by AGCGA-rich regulatory DNA regions

Genetic and Environmental Factors Associated with Dental Caries in Children: The Iowa Fluoride Study

Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP

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