Hereditary Dentin Defects

Kim, J.-W.,Simmer, J. P. Journal of Dental Research, Inc 2007 Journal of dental research Vol.86 No.5

<P>By the Shields classification, articulated over 30 years ago, inherited dentin defects are divided into 5 types: 3 types of dentinogenesis imperfecta (DGI), and 2 types of dentin dysplasia (DD). DGI type I is osteogenesis imperfecta (OI) with DGI. OI with DGI is caused, in most cases, by mutations in the 2 genes encoding type I collagen. Many genes are required to generate the enzymes that catalyze collagen's diverse post-translational modifications and its assembly into fibers, fibrils, bundles, and networks. Rare inherited diseases of bone are caused by defects in these genes, and some are occasionally found to include DGI as a feature. Appreciation of the complicated genetic etiology of DGI associated with bony defects splintered the DGI type I description into a multitude of more precisely defined entities, all with their own designations. In contrast, DD-II, DGI-II, and DGI-III, each with its own pattern of inherited defects limited to the dentition, have been found to be caused by various defects in <I>DSPP</I> (dentin sialophosphoprotein), a gene encoding the major non-collagenous proteins of dentin. Only DD-I, an exceedingly rare condition featuring short, blunt roots with obliterated pulp chambers, remains untouched by the revolution in genetics, and its etiology is still a mystery. A major surprise in the characterization of genes underlying inherited dentin defects is the apparent lack of roles played by the genes encoding the less-abundant non-collagenous proteins in dentin, such as dentin matrix protein 1 (<I>DMP1</I>), integrin-binding sialoprotein (<I>IBSP</I>), matrix extracellular phosphoglycoprotein (<I>MEPE</I>), and secreted phosphoprotein-1, or osteopontin (<I>SPP1, OPN</I>). This review discusses the development of the dentin extracellular matrix in the context of its evolution, and discusses the phenotypes and clinical classifications of isolated hereditary defects of tooth dentin in the context of recent genetic data respecting their genetic etiologies.</P>

Factors influencing endoscopic estimation of colon polyp size in a colon model

Koen Robert Beukema,Jaimy A. Simmering,Marjolein Brusse-Keizer,Sneha John,Rutger Quispel,Peter B. Mensink 대한소화기내시경학회 2022 Clinical Endoscopy Vol.55 No.4

Background/Aims: Colorectal polyps are removed to prevent progression to colorectal cancer. Polyp size is an important factor for risk stratification of malignant transformation. Endoscopic size estimation correlates poorly with pathological reports and several factors have been suggested to influence size estimation. We aimed to gain insight into the factors influencing endoscopic polyp size estimation. Methods: Images of polyps in an artificial model were obtained at 1, 3, and 5 cm from the colonoscope’s tip. Participants were asked to estimate the diameter and volume of each polyp. Results: Fifteen endoscopists from three large-volume centers participated in this study. With an intraclass correlation coefficient of 0.66 (95% confidence interval [CI], 0.62–0.71) for diameter and 0.56 (95% CI, 0.50–0.62) for volume. Polyp size estimated at 3 cm from the colonoscope’s tip yielded the best results. A lower distance between the tip and the polyp was associated with a larger estimated polyp size. Conclusions: Correct endoscopic estimation of polyp size remains challenging. This finding can affect size estimation skills and future training programs for endoscopists.

FAM83H mutations cause ADHCAI and alter intracellular protein localization.

Lee, S-K,Lee, K-E,Jeong, T-S,Hwang, Y-H,Kim, S,Hu, J C-C,Simmer, J P,Kim, J-W Journal of Dental Research, Inc 2011 Journal of dental research Vol.90 No.3

<P>Mutations in a family with sequence similarity 83 member H (FAM83H) cause autosomal-dominant hypocalcification amelogenesis imperfecta (ADH CAI). All FAM83H ADHCAI-causing mutations terminate translation or shift the reading frame within the specific exon 5 segment that encodes from Ser(287) to Glu(694). Mutations near Glu(694) cause a milder, more localized phenotype. We identified disease-causing FAM83H mutations in two families with ADHCAI: family 1 (g.3115C>T, c.1993 C>T, p.Q665X) and family 2 (g.3151C>T, c.2029 C>T, p.Q677X). We also tested the hypothesis that truncation mutations alter the intracellular localization of FAM83H. Wild-type FAM83H and p.E694X mutant FAM83H fused to green fluorescent protein (GFP) localized in the cytoplasm of HEK293T cells, but the mutant FAM83H proteins (p.R325X, p.W460X, and p.Q677X) fused to GFP localized mainly in the nucleus with slight expression in the cytoplasm. We conclude that nuclear targeting of the truncated FAM83H protein contributes to the severe, generalized enamel phenotype.</P>

Fam83h is Associated with Intracellular Vesicles and ADHCAI

Ding, Y.,Estrella, M.R.P.,Hu, Y.Y.,Chan, H.L.,Zhang, H.D.,Kim, J.-W.,Simmer, J.P.,Hu, J.C.-C. SAGE Publications 2009 Journal of dental research Vol.88 No.11

<P>Defects in <I>FAM83H</I> on human chromosome 8q24.3 cause autosomal-dominant hypocalcified amelogenesis imperfecta (ADHCAI). <I>FAM83H</I> does not encode a recognizable signal peptide, so we predicted that the Fam83h protein functions within the cell. We tested this hypothesis by constitutively expressing mouse Fam83h with green fluorescent protein (GFP) fused to its C-terminus in HEK293 and HeLa cell lines. Green fluorescent signal from the Fam83h-GFP fusion protein was associated with perinuclear vesicles, usually in the vicinity of the Golgi apparatus. No signal was observed within the nucleus. In addition, we identified <I> FAM83H</I> nonsense mutations in Hispanic (C1330C>T; p.Q444X) and Caucasian (c.1192C>T; p.Q398X) families with ADHCAI. We conclude that Fam83h localizes in the intracellular environment, is associated with vesicles, and plays an important role in dental enamel formation. <I>FAM83H</I> is the first gene involved in the etiology of amelogenesis imperfecta (AI) that does not encode a secreted protein.</P>

<i>LAMB3</i> Mutations Causing Autosomal-dominant Amelogenesis Imperfecta

Kim, J.W.,Seymen, F.,Lee, K.E.,Ko, J.,Yildirim, M.,Tuna, E.B.,Gencay, K.,Shin, T.J.,Kyun, H.K.,Simmer, J.P.,Hu, J.C.-C. SAGE Publications 2013 Journal of dental research Vol.92 No.10

<P>Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of <I>COL17A1, LAMA3, LAMB3</I>, or <I>LAMC2</I>. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of <I>LAMB3</I> that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related.</P>

<i>ITGB6</i> loss-of-function mutations cause autosomal recessive amelogenesis imperfecta

Wang, Shih-Kai,Choi, Murim,Richardson, Amelia S.,Reid, Bryan M.,Lin, Brent P.,Wang, Susan J.,Kim, Jung-Wook,Simmer, James P.,Hu, Jan C.-C. Oxford University Press 2014 Human Molecular Genetics Vol.23 No.8

<P>Integrins are cell-surface adhesion receptors that bind to extracellular matrices (ECM) and mediate cell–ECM interactions. Some integrins are known to play critical roles in dental enamel formation. We recruited two Hispanic families with generalized hypoplastic amelogenesis imperfecta (AI). Analysis of whole-exome sequences identified three <I>integrin beta 6</I> (<I>ITGB6</I>) mutations responsible for their enamel malformations. The female proband of Family 1 was a compound heterozygote with an <I>ITGB6</I> transition mutation in Exon 4 (g.4545G > A c.427G > A p.Ala143Thr) and an <I>ITGB6</I> transversion mutation in Exon 6 (g.27415T > A c.825T > A p.His275Gln). The male proband of Family 2 was homozygous for an <I>ITGB6</I> transition mutation in Exon 11 (g.73664C > T c.1846C > T p.Arg616*) and hemizygous for a transition mutation in Exon 6 of <I>Nance–Horan Syndrome</I> (<I>NHS</I> Xp22.13; g.355444T > C c.1697T > C p.Met566Thr). These are the first disease-causing <I>ITGB6</I> mutations to be reported. Immunohistochemistry of mouse mandibular incisors localized ITGB6 to the distal membrane of differentiating ameloblasts and pre-ameloblasts, and then ITGB6 appeared to be internalized by secretory stage ameloblasts. ITGB6 expression was strongest in the maturation stage and its localization was associated with ameloblast modulation. Our findings demonstrate that early and late amelogenesis depend upon cell–matrix interactions. Our approach (from knockout mouse phenotype to human disease) demonstrates the power of mouse reverse genetics in mutational analysis of human genetic disorders and attests to the need for a careful dental phenotyping in large-scale knockout mouse projects.</P>

<i>WDR72</i> Mutations Associated with Amelogenesis Imperfecta and Acidosis

Zhang, H.,Koruyucu, M.,Seymen, F.,Kasimoglu, Y.,Kim, J.-W.,Tinawi, S.,Zhang, C.,Jacquemont, M.L.,Vieira, A.R.,Simmer, J.P.,Hu, J.C.C. SAGE Publications 2019 Journal of dental research Vol.98 No.5

Hypoplastic AI with Highly Variable Expressivity Caused by <i>ENAM</i> Mutations

Koruyucu, M.,Kang, J.,Kim, Y.J.,Seymen, F.,Kasimoglu, Y.,Lee, Z.H.,Shin, T.J.,Hyun, H.K.,Kim, Y.J.,Lee, S.H.,Hu, J.C.C.,Simmer, J.P.,Kim, J.W. SAGE Publications 2018 Journal of dental research Vol.97 No.9