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1.  Hyaluronidase expression and biofilm involvement in Staphylococcus aureus UAMS-1 and its sarA, agr and sarA agr regulatory mutants 
Microbiology  2013;159(Pt 4):782-791.
In a previous study, two proteins identified as hyaluronidases were detected in spent media by MS and found to be in greater quantity in the sarA and sarA agr mutant strains when compared with the parent and agr mutant strains of Staphylococcus aureus UAMS-1. In the present study, spent media and total RNA were isolated from UAMS-1 and its regulatory mutants and analysed for hyaluronidase activity and steady-state hyaluronidase (hysA) RNA message levels. Hyaluronidase activity was observed throughout all time points examined regardless of the regulatory effects of sarA and agr but activity was always substantially higher in the sarA and sarA agr mutant strains than in the UAMS-1 parent and agr mutant strains. Northern analysis did not detect hysA message for either the UAMS-1 parent or the agr mutant strains at any time point examined, while steady-state hysA message levels were detected throughout growth for the sarA mutant strain, but only at exponential and early post-exponential growth for the sarA agr mutant strain. An in vitro biofilm plate assay, pre-coated with human plasma as a source of hyaluronic acid, demonstrated no significant increase in biofilm for a sarA mutant strain of S. aureus UAMS-1 defective in hyaluronidase activity when compared with the sarA mutant strain. These data indicate that, while hysA message levels and hyaluronidase activity are elevated in the sarA mutant strains of S. aureus UAMS-1, the increase in activity did not contribute to the biofilm-negative phenotype observed in the sarA mutant strain of S. aureus UAMS-1.
doi:10.1099/mic.0.065367-0
PMCID: PMC3709827  PMID: 23393148
2.  Lock-Out Valve to Decrease Catheter-Associated Urinary Tract Infections 
Advances in Urology  2014;2014:765756.
Patients with long-term indwelling urinary catheters are at an increased risk for urinary tract infection due to bacteriuria. Catheter-associated urinary tract infections (CAUTIs) are a significant source of morbidity and mortality in long-term care facilities as well as in ambulatory patients requiring long-term catheterization. There is increased interest in the financial impact of CAUTI as Medicare no longer provides reimbursement for nosocomial CAUTIs. Ascending bacteria may in part enter the closed drainage system when the patient switches between leg and night collection bags. In an attempt to reduce this ascent, a double valve lock-out system was devised that maintains a closed system during bag exchange. The concept is introduced and CAUTIs are reviewed.
doi:10.1155/2014/765756
PMCID: PMC3918347  PMID: 24575127
3.  Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations 
Jaureguiberry, Graciana | De la Dure-Molla, Muriel | Parry, David | Quentric, Mickael | Himmerkus, Nina | Koike, Toshiyasu | Poulter, James | Klootwijk, Enriko | Robinette, Steven L. | Howie, Alexander J. | Patel, Vaksha | Figueres, Marie-Lucile | Stanescu, Horia C. | Issler, Naomi | Nicholson, Jeremy K. | Bockenhauer, Detlef | Laing, Christopher | Walsh, Stephen B. | McCredie, David A. | Povey, Sue | Asselin, Audrey | Picard, Arnaud | Coulomb, Aurore | Medlar, Alan J. | Bailleul-Forestier, Isabelle | Verloes, Alain | Le Caignec, Cedric | Roussey, Gwenaelle | Guiol, Julien | Isidor, Bertrand | Logan, Clare | Shore, Roger | Johnson, Colin | Inglehearn, Christopher | Al-Bahlani, Suhaila | Schmittbuhl, Matthieu | Clauss, François | Huckert, Mathilde | Laugel, Virginie | Ginglinger, Emmanuelle | Pajarola, Sandra | Spartà, Giuseppina | Bartholdi, Deborah | Rauch, Anita | Addor, Marie-Claude | Yamaguti, Paulo M. | Safatle, Heloisa P. | Acevedo, Ana Carolina | Martelli-Júnior, Hercílio | dos Santos Netos, Pedro E. | Coletta, Ricardo D. | Gruessel, Sandra | Sandmann, Carolin | Ruehmann, Denise | Langman, Craig B. | Scheinman, Steven J. | Ozdemir-Ozenen, Didem | Hart, Thomas C. | Hart, P. Suzanne | Neugebauer, Ute | Schlatter, Eberhard | Houillier, Pascal | Gahl, William A. | Vikkula, Miikka | Bloch-Zupan, Agnès | Bleich, Markus | Kitagawa, Hiroshi | Unwin, Robert J. | Mighell, Alan | Berdal, Ariane | Kleta, Robert
Nephron. Physiology  2013;122(0):1-6.
Background/Aims
Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.
Methods
We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing.
Results
All patients had biallelic FAM20A mutations segregating with the disease; 20 different mutations were identified.
Conclusions
This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.
doi:10.1159/000349989
PMCID: PMC3782194  PMID: 23434854
Nephrolithiasis; Urolithiasis; Amelogenesis imperfecta; FAM20B; FAM20C
4.  Reversible Control by Vitamin D of Granulocytes and Bacteria in the Lungs of Mice: An Ovalbumin-Induced Model of Allergic Airway Disease 
PLoS ONE  2013;8(6):e67823.
Vitamin D may be essential for restricting the development and severity of allergic diseases and asthma, but a direct causal link between vitamin D deficiency and asthma has yet to be established. We have developed a ‘low dose’ model of allergic airway disease induced by intraperitoneal injection with ovalbumin (1 µg) and aluminium hydroxide (0.2 mg) in which characteristics of atopic asthma are recapitulated, including airway hyperresponsiveness, antigen-specific immunoglobulin type-E and lung inflammation. We assessed the effects of vitamin D deficiency throughout life (from conception until adulthood) on the severity of ovalbumin-induced allergic airway disease in vitamin D-replete and -deficient BALB/c mice using this model. Vitamin D had protective effects such that deficiency significantly enhanced eosinophil and neutrophil numbers in the bronchoalveolar lavage fluid of male but not female mice. Vitamin D also suppressed the proliferation and T helper cell type-2 cytokine-secreting capacity of airway-draining lymph node cells from both male and female mice. Supplementation of initially vitamin D-deficient mice with vitamin D for four weeks returned serum 25-hydroxyvitamin D to levels observed in initially vitamin D-replete mice, and also suppressed eosinophil and neutrophil numbers in the bronchoalveolar lavage fluid of male mice. Using generic 16 S rRNA primers, increased bacterial levels were detected in the lungs of initially vitamin D-deficient male mice, which were also reduced by vitamin D supplementation. These results indicate that vitamin D controls granulocyte levels in the bronchoalveolar lavage fluid in an allergen-sensitive manner, and may contribute towards the severity of asthma in a gender-specific fashion through regulation of respiratory bacteria.
doi:10.1371/journal.pone.0067823
PMCID: PMC3691156  PMID: 23826346
5.  Genetic Structure of Wild Bonobo Populations: Diversity of Mitochondrial DNA and Geographical Distribution 
PLoS ONE  2013;8(3):e59660.
Bonobos (Pan paniscus) inhabit regions south of the Congo River including all areas between its southerly tributaries. To investigate the genetic diversity and evolutionary relationship among bonobo populations, we sequenced mitochondrial DNA from 376 fecal samples collected in seven study populations located within the eastern and western limits of the species’ range. In 136 effective samples from different individuals (range: 7–37 per population), we distinguished 54 haplotypes in six clades (A1, A2, B1, B2, C, D), which included a newly identified clade (D). MtDNA haplotypes were regionally clustered; 83 percent of haplotypes were locality-specific. The distribution of haplotypes across populations and the genetic diversity within populations thus showed highly geographical patterns. Using population distance measures, seven populations were categorized in three clusters: the east, central, and west cohorts. Although further elucidation of historical changes in the geological setting is required, the geographical patterns of genetic diversity seem to be shaped by paleoenvironmental changes during the Pleistocene. The present day riverine barriers appeared to have a weak effect on gene flow among populations, except for the Lomami River, which separates the TL2 population from the others. The central cohort preserves a high genetic diversity, and two unique clades of haplotypes were found in the Wamba/Iyondji populations in the central cohort and in the TL2 population in the eastern cohort respectively. This knowledge may contribute to the planning of bonobo conservation.
doi:10.1371/journal.pone.0059660
PMCID: PMC3609822  PMID: 23544084
6.  Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations 
Jaureguiberry, Graciana | De la Dure-Molla, Muriel | Parry, David | Quentric, Mickael | Himmerkus, Nina | Koike, Toshiyasu | Poulter, James | Klootwijk, Enriko | Robinette, Steven L. | Howie, Alexander J. | Patel, Vaksha | Figueres, Marie-Lucile | Stanescu, Horia C. | Issler, Naomi | Nicholson, Jeremy K. | Bockenhauer, Detlef | Laing, Christopher | Walsh, Stephen B. | McCredie, David A. | Povey, Sue | Asselin, Audrey | Picard, Arnaud | Coulomb, Aurore | Medlar, Alan J. | Bailleul-Forestier, Isabelle | Verloes, Alain | Le Caignec, Cedric | Roussey, Gwenaelle | Guiol, Julien | Isidor, Bertrand | Logan, Clare | Shore, Roger | Johnson, Colin | Inglehearn, Christopher | Al-Bahlani, Suhaila | Schmittbuhl, Matthieu | Clauss, François | Huckert, Mathilde | Laugel, Virginie | Ginglinger, Emmanuelle | Pajarola, Sandra | Spartà, Giuseppina | Bartholdi, Deborah | Rauch, Anita | Addor, Marie-Claude | Yamaguti, Paulo M. | Safatle, Heloisa P. | Acevedo, Ana Carolina | Martelli-Júnior, Hercílio | dos Santos Netos, Pedro E. | Coletta, Ricardo D. | Gruessel, Sandra | Sandmann, Carolin | Ruehmann, Denise | Langman, Craig B. | Scheinman, Steven J. | Ozdemir-Ozenen, Didem | Hart, Thomas C. | Hart, P. Suzanne | Neugebauer, Ute | Schlatter, Eberhard | Houillier, Pascal | Gahl, William A. | Vikkula, Miikka | Bloch-Zupan, Agnès | Bleich, Markus | Kitagawa, Hiroshi | Unwin, Robert J. | Mighell, Alan | Berdal, Ariane | Kleta, Robert
Nephron. Physiology  2013;122(1-2):1-6.
Background/Aims
Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.
Methods
We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing.
Results
All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified.
Conclusions
This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.
doi:10.1159/000349989
PMCID: PMC3782194  PMID: 23434854
Nephrolithiasis; Urolithiasis; Amelogenesis imperfecta; FAM20B; FAM20C

7.  Neutering Dogs: Effects on Joint Disorders and Cancers in Golden Retrievers 
PLoS ONE  2013;8(2):e55937.
In contrast to European countries, the overwhelming majority of dogs in the U.S. are neutered (including spaying), usually done before one year of age. Given the importance of gonadal hormones in growth and development, this cultural contrast invites an analysis of the multiple organ systems that may be adversely affected by neutering. Using a single breed-specific dataset, the objective was to examine the variables of gender and age at the time of neutering versus leaving dogs gonadally intact, on all diseases occurring with sufficient frequency for statistical analyses. Given its popularity and vulnerability to various cancers and joint disorders, the Golden Retriever was chosen for this study. Veterinary hospital records of 759 client-owned, intact and neutered female and male dogs, 1–8 years old, were examined for diagnoses of hip dysplasia (HD), cranial cruciate ligament tear (CCL), lymphosarcoma (LSA), hemangiosarcoma (HSA), and mast cell tumor (MCT). Patients were classified as intact, or neutered early (<12 mo) or late (≥12 mo). Statistical analyses involved survival analyses and incidence rate comparisons. Outcomes at the 5 percent level of significance are reported. Of early-neutered males, 10 percent were diagnosed with HD, double the occurrence in intact males. There were no cases of CCL diagnosed in intact males or females, but in early-neutered males and females the occurrences were 5 percent and 8 percent, respectively. Almost 10 percent of early-neutered males were diagnosed with LSA, 3 times more than intact males. The percentage of HSA cases in late-neutered females (about 8 percent) was 4 times more than intact and early-neutered females. There were no cases of MCT in intact females, but the occurrence was nearly 6 percent in late-neutered females. The results have health implications for Golden Retriever companion and service dogs, and for oncologists using dogs as models of cancers that occur in humans.
doi:10.1371/journal.pone.0055937
PMCID: PMC3572183  PMID: 23418479
8.  Lesula: A New Species of Cercopithecus Monkey Endemic to the Democratic Republic of Congo and Implications for Conservation of Congo’s Central Basin 
PLoS ONE  2012;7(9):e44271.
In June 2007, a previously undescribed monkey known locally as “lesula” was found in the forests of the middle Lomami Basin in central Democratic Republic of Congo (DRC). We describe this new species as Cercopithecus lomamiensis sp. nov., and provide data on its distribution, morphology, genetics, ecology and behavior. C. lomamiensis is restricted to the lowland rain forests of central DRC between the middle Lomami and the upper Tshuapa Rivers. Morphological and molecular data confirm that C. lomamiensis is distinct from its nearest congener, C. hamlyni, from which it is separated geographically by both the Congo (Lualaba) and the Lomami Rivers. C. lomamiensis, like C. hamlyni, is semi-terrestrial with a diet containing terrestrial herbaceous vegetation. The discovery of C. lomamiensis highlights the biogeographic significance and importance for conservation of central Congo’s interfluvial TL2 region, defined from the upper Tshuapa River through the Lomami Basin to the Congo (Lualaba) River. The TL2 region has been found to contain a high diversity of anthropoid primates including three forms, in addition to C. lomamiensis, that are endemic to the area. We recommend the common name, lesula, for this new species, as it is the vernacular name used over most of its known range.
doi:10.1371/journal.pone.0044271
PMCID: PMC3440422  PMID: 22984482
9.  Amelogenesis Imperfecta: Genotype-Phenotype Studies in 71 Families 
Cells, Tissues, Organs  2011;194(2-4):279-283.
Amelogenesis imperfecta (AI) represents hereditary conditions affecting the quality and quantity of enamel. Six genes are known to cause AI (AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72). Our aim was to determine the distribution of different gene mutations in a large AI population and evaluate phenotype-genotype relationships. Affected and unaffected family members were evaluated clinically and radiographically by one examiner. Genotyping was completed using genomic DNA obtained from blood or saliva. A total of 494 individuals were enrolled, with 430 (224 affected, 202 unaffected, and 4 not definitive) belonging to 71 families with conditions consistent with the diagnosis of AI. Diverse clinical phenotypes were observed (i.e. hypoplastic, hypocalcified, and hypomaturation). Genotyping revealed mutations in all 6 candidate genes. A molecular diagnosis was made in 132 affected individuals (59%) and in 26 of the families (37%). Mutations involved 12 families with FAM83H (46%), 6 families with AMELX (23%), 3 families with ENAM (11%), 2 families with KLK4 and MMP20 (8% for each gene), and 1 family with a WDR72 mutation (4%). Phenotypic variants were associated with allelic FAM83H and AMELX mutations. Two seemingly unrelated families had the same KLK4 mutation. Families affected with AI where candidate gene mutations were not identified could have mutations not identifiable by traditional gene sequencing (e.g. exon deletion) or they could have promoter sequence mutations not evaluated in this study. However, the results suggest that there remain new AI causative genes to be identified.
doi:10.1159/000324339
PMCID: PMC3178091  PMID: 21597265
Enamel; Amelogenesis imperfecta; Phenotype; Genotype; Gene; Mutation
10.  C. elegans Notch signaling regulates adult chemosensory response and larval molting quiescence 
Current biology : CB  2011;21(10):825-834.
Summary
Background
The conserved DOS motif proteins OSM-7 and OSM-11 function as co-ligands with canonical DSL ligands to activate C. elegans Notch receptors during development. We report herein that Notch ligands, co-ligands and the receptors LIN-12 and GLP-1 regulate two C. elegans behaviors: chemosensory avoidance of octanol and quiescence during molting lethargus.
Results
C. elegans lacking osm-7 or osm-11 are defective in their response to octanol. We find that OSM-11 is secreted from hypodermal seam cells into the pseudocoelomic body cavity and acts non-cell autonomously as a diffusible factor. OSM-11 acts with the DSL ligand LAG-2 to activate LIN-12 and GLP-1 Notch receptors in the neurons of adult animals,- thereby regulating octanol avoidance response. In adult animals, over-expression of osm-11 and consequent Notch receptor activation induces anachronistic sleep-like quiescence. Perturbation of Notch signaling altered basal activity in adults as well as arousal thresholds and quiescence during molting lethargus. Genetic epistasis studies revealed that Notch signaling regulates quiescence via previously identified circuits and genetic pathways including the egl-4 cGMP-dependent kinase.
Conclusions
Our findings indicate that the conserved Notch pathway modulates behavior in adult C. elegans in response to environmental stress. Additionally, Notch signaling regulates sleep-like quiescence in C. elegans suggesting Notch may regulate sleep in other species.
doi:10.1016/j.cub.2011.04.010
PMCID: PMC3100419  PMID: 21549604
11.  Unintended Perioperative Hypothermia 
The Ochsner Journal  2011;11(3):259-270.
Background
Hypothermia, defined as a core body temperature less than 36°C (96.8°F), is a relatively common occurrence in the unwarmed surgical patient. A mild degree of perioperative hypothermia can be associated with significant morbidity and mortality. A threefold increase in the frequency of surgical site infections is reported in colorectal surgery patients who experience perioperative hypothermia. As part of the Surgical Care Improvement Project, guidelines aim to decrease the incidence of this complication.
Methods
We review the physiology of temperature regulation, mechanisms of hypothermia, effects of anesthetics on thermoregulation, and consequences of hypothermia and summarize recent recommendations for maintaining perioperative normothermia.
Results
Evidence suggests that prewarming for a minimum of 30 minutes may reduce the risk of subsequent hypothermia.
Conclusions
Monitoring of body temperature and avoidance of unintended perioperative hypothermia through active and passive warming measures are the keys to preventing its complications.
PMCID: PMC3179201  PMID: 21960760
Hypothermia; perioperative; prewarming; thermoregulation
12.  Phenotypic Variation in FAM83H-associated Amelogenesis Imperfecta 
Journal of Dental Research  2009;88(4):356-360.
FAM83H gene mutations are associated with autosomal-dominant hypocalcified amelogenesis imperfecta (ADHCAI), which is typically characterized by enamel having normal thickness and a markedly decreased mineral content. This study tested the hypothesis that there are phenotype and genotype associations in families with FAM83H-associated ADHCAI. Seven families segregating ADHCAI (147 individuals) were evaluated. Phenotyping included clinical, radiographic, histological, and biochemical studies, and genotyping was by mutational analysis. Multiple novel FAM83H mutations were identified, including two 2-bp-deletion mutations, the first non-nonsense mutations identified. Craniofacial deviation from normal was more prevalent in the affected individuals. Affected individuals having truncating FAMH3H mutations of 677 or fewer amino acids presented a generalized ADHCAI phenotype, while those having mutations capable of producing a protein of at least 694 amino acids had a unique and previously unreported phenotype affecting primarily the cervical enamel. This investigation shows that unique phenotypes are associated with specific FAM83H mutations.
doi:10.1177/0022034509333822
PMCID: PMC2754853  PMID: 19407157
enamel; FAM83H; amelogenesis imperfecta; hypocalcified; phenotype; craniofacial
13.  Genotypic and Phenotypic Assessment of Hyaluronidase among Type Strains of a Select Group of Staphylococcal Species 
Hyaluronidases degrade hyaluronic acid, a major polysaccharide of the extracellular matrix of tissues, and are considered important for virulence in a number of Gram-positive and -negative bacteria. The purpose of the present study was to determine the prevalence of hyaluronidase among clinical strains of Staphylococcus aureus and among other Staphylococcus species. Spent media and chromosomal DNA were assessed for hyaluronidase activity and the absence or presence of a hyaluronidase gene (hysA) by Southern analysis, respectively. All S. aureus strains examined exhibited at least one hybridizing band (half of the strains exhibited two or more hybridizing bands) when probed for hysA and all but three of these strains produced hyaluronidase. In contrast, none of the type strains of 19 other species exhibited either hyaluronidase activity or hybridizing bands when probed for hysA. These data support the hypothesis that among members of the Staphylococcus genus only strains of S. aureus possess the enzyme hyaluronidase. This would suggest that hyaluronidase represents yet another potential virulence factor employed by S. aureus to cause disease and may represent a diagnostically important characteristic for distinguishing S. aureus from other members of this genus.
doi:10.1155/2009/614371
PMCID: PMC2814232  PMID: 20130817
14.  The PDGF-C regulatory region SNP rs28999109 decreases promoter transcriptional activity and is associated with CL/P 
Human linkage and association studies suggest a gene(s) for nonsyndromic cleft lip with or without cleft palate (CL/P) on chromosome 4q31-q32 at or near the platelet derived growth factor-C (PDGF-C) locus. The mouse pdgfc−/− knockout demonstrates that PDGF-C is essential for palatogenesis. To evaluate the role of PDGF-C in human clefting, we performed sequence analysis and SNP genotyping using 1,048 multiplex CL/P families and 1,000 case-control samples from multiple geographic origins. No coding region mutations were identified, but a novel -986 C>T SNP (rs28999109) was significantly associated with CL/P (p=0.01) in cases from Chinese families yielding evidence of linkage to 4q31-q32. Significant or near significant association was also seen for this and several other PDGF-C SNPs in families from the US, Spain, India, Turkey, China, and Colombia, while no association was seen in families from the Philippines, Guatemala, and case-controls from Brazil. The -986T allele abolished six overlapping potential transcription regulatory motifs. Transfection assays of PDGF-C promoter reporter constructs demonstrate the -986T allele is associated with a significant decrease (up to 80%) of PDGF-C gene promoter activity. This functional polymorphism acting on a susceptible genetic background may represent a component of human CL/P etiology.
doi:10.1038/ejhg.2008.245
PMCID: PMC2788748  PMID: 19092777
PDGF-C; SNP; CL/P; promoter activity
15.  Phenotypic Variation in FAM83H Associated Amelogenesis Imperfecta 
Journal of dental research  2009;88(4):356-360.
FAM83H gene mutations are associated with autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) which is typically characterized by enamel having normal thickness and a markedly decreased mineral content. This study tests the hypothesis that there are phenotype and genotype associations in families with FAM83H associated ADHCAI. Seven families segregating ADHCAI (147 individuals) were evaluated. Phenotyping included clinical, radiographic, histological and biochemical studies and genotyping was by mutational analysis. Multiple novel FAM83H mutations were identified including two 2 bp deletion mutations, the first non-nonsense mutations identified. Craniofacial deviation from normal was more prevalent in the affected individuals. Affected individuals having truncating FAMH3H mutations of 677 amino acids or less presented generalized ADHCAI phenotype while those having mutations capable of producing a protein of at least 694 amino acids had a unique and previously unreported phenotype affecting primarily the cervical enamel. This investigation shows unique phenotypes are associated with specific FAM83H mutations.
doi:10.1177/0022034509333822
PMCID: PMC2754853  PMID: 19407157
enamel; FAM83H; amelogenesis imperfecta; hypocalcified; phenotype; craniofacial
16.  Human and Mouse Enamel Phenotypes Resulting from Mutation or Altered Expression of AMEL, ENAM, MMP20 and KLK4 
Cells, tissues, organs  2008;189(1-4):224-229.
The amelogenesis imperfectas (AI) are caused by AMEL, ENAM, MMP20 and KLK4 gene mutations. Mice lacking expression of the AmelX, Enam and Mmp20 genes have been generated. These mouse models provide tools for understanding enamel formation and AI pathogenesis. This study describes the AI phenotypes and relates them to their mouse model counterparts. Human AI phenotypes were determined in a clinical population of AI families and published cases. Human and murine teeth were evaluated using light and electron microscopy. 463 individuals from 54 families were evaluated and mutations in the AMEL, ENAM, and KLK4 genes were identified. The majority of human mutations for genes coding enamel non-proteinase proteins (AMEL and ENAM) resulted in variable hypoplasia ranging from local pitting to a marked, generalized enamel thinning. Specific AMEL mutations were associated with abnormal mineralization and maturation defects. Amel and Enam null murine models displayed marked enamel hypoplasia and a complete loss of prism structure. Human mutations in genes coding for the enamel proteinases (MMP20 and KLK4) cause variable degrees of hypomineralization. The murine Mmp20 null mouse exhibits both hypoplastic and hypomineralized defects. The currently available Amel and Enam mouse models for AI exhibit enamel phenotypes (hypoplastic) that are generally similar to those seen in humans. Mmp20 null mice have a greater degree of hypoplasia compared with humans having MMP20 mutations. Mice lacking expression of the currently known genes associated with the human AI conditions provide powerful models for understanding the pathogenesis of these conditions.
doi:10.1159/000151378
PMCID: PMC2754863  PMID: 18714142
enamel; amelogenesis imperfecta; mouse; human; gene; mutation
17.  Phenotype of ENAM Mutations is Dosage-dependent 
Journal of dental research  2005;84(11):1036-1041.
Five mutations in the ENAM gene have been found to cause hypoplastic amelogenesis imperfecta (AI), with phenotypes ranging from localized enamel pitting in carriers to severe hypoplastic AI. To determine the generality of ENAM mutations in hypoplastic AI, we sequenced the ENAM gene in ten Turkish families segregating autosomal hypoplastic AI. In two families, ENAM mutations were found. A novel nonsense mutation (g.12663C>A; p.S246X) was identified in one family segregating local hypoplastic AI as a dominant trait. Affected individuals in a second family segregating autosomal-recessive AI were compound heterozygotes for a novel insertion mutation (g.12946_12947insAGTCAGTACCAGTACTGT GTC) and a previously described insertion (g.13185_13186insAG) mutation. Heterozygous carriers of either insertion had a localized enamel-pitting phenotype. These findings substantiate that enamel phenotypes of ENAM mutations may be dose-dependent, with generalized hypoplastic AI segregating as a recessive trait and localized enamel pitting segregating as a dominant trait.
PMCID: PMC2708095  PMID: 16246937
amelogenesis imperfecta; enamel; enamel pitting; gene dosage; enamelin
18.  The PDGF-C regulatory region SNP rs28999109 decreases promoter transcriptional activity and is associated with CL/P 
Human linkage and association studies suggest a gene(s) for nonsyndromic cleft lip with or without cleft palate (CL/P) on chromosome 4q31–q32 at or near the platelet-derived growth factor-C (PDGF-C) locus. The mouse Pdgfc−/− knockout shows that PDGF-C is essential for palatogenesis. To evaluate the role of PDGF-C in human clefting, we performed sequence analysis and SNP genotyping using 1048 multiplex CL/P families and 1000 case–control samples from multiple geographic origins. No coding region mutations were identified, but a novel −986 C>T SNP (rs28999109) was significantly associated with CL/P (P=0.01) in cases from Chinese families yielding evidence of linkage to 4q31–q32. Significant or near-significant association was also seen for this and several other PDGF-C SNPs in families from the United States, Spain, India, Turkey, China, and Colombia, whereas no association was seen in families from the Philippines, and Guatemala, and case–controls from Brazil. The −986T allele abolished six overlapping potential transcription regulatory motifs. Transfection assays of PDGF-C promoter reporter constructs show that the −986T allele is associated with a significant decrease (up to 80%) of PDGF-C gene promoter activity. This functional polymorphism acting on a susceptible genetic background may represent a component of human CL/P etiology.
doi:10.1038/ejhg.2008.245
PMCID: PMC2788748  PMID: 19092777
PDGF-C; SNP; CL/P; promoter activity
19.  A 4 bp deletion mutation in DLX3 enhances osteoblastic differentiation and bone formation in vitro 
Bone  2007;42(1):162-171.
A 4 base-pair deletion mutation in the Distal-Less 3 (DLX3) gene is etiologic for Tricho-Dento-Osseous syndrome (TDO). A cardinal feature of TDO is an increased thickness and density of bone. We tested the effects of the DLX3 gene mutation responsible for TDO on the osteoblastic differentiation of preosteoblastic MC3T3E1 cells and multipontent mesenchymal C2C12 cells. Differential expression analysis of C2C12 cells transfected with wild type DLX3 or mutant DLX3 was performed and desmin gene expression, an early myoblastic differentiation marker in mesenchymal cells, was evaluated by RT-PCR, western blot analysis, and desmin promoter transcriptional activity. Transfection of wild type DLX3 into MC3T3E1 and C2C12 cells increased alkaline phosphatase-2 activity, mineral deposition, and promoter activities of the osteocalcin and type1 collagen genes compared to empty vector transfected cells. Transfection of mutant DLX3 into these cells further enhanced alkaline phosphatase activity, mineral deposition, and osteocalcin promoter activities, but did not further enhance type 1 collagen promoter activity. Transfection of mutant DLX3 into C2C12 cells markedly down regulated desmin gene expression, and protein expression of desmin and MyoD, while increasing protein expression of osterix and Runx2. These results demonstrate that the DLX3 deletion mutation associated with TDO enhances mesenchymal cell differentiation to an osteoblastic lineage rather than a myoblastic lineage by changing the fate of mesenchymal cells. This DLX3 mutation also accelerates the differentiation of osteoprogenitor cells to osteoblasts at later stages of osteogenesis.
doi:10.1016/j.bone.2007.08.047
PMCID: PMC2253671  PMID: 17950683
Distal-Less 3; Tricho-Dento-Osseous syndrome; Osteoblast differentiation; Osteocalcin; Collagen
20.  Overlapping DSPP Mutations Cause DD and DGI 
Journal of dental research  2008;87(12):1108-1111.
Dentinogenesis imperfecta (DGI) and dentin dysplasia (DD) are allelic disorders due to mutations in DSPP. Typically, the phenotype breeds true within a family. Recently, two reports showed that three different net -1 bp frameshift mutations early in DSPP's repeat domain caused DD whereas six, more 3′ frameshift mutations, were associated with DGI. Here we identify a DD kindred with a novel -1 bp frameshift (c.3141delC) that falls within the portion of the DSPP repeat domain previously associated solely with the DGI phenotype. This new frameshift mutation shows that overlapping DSPP mutations can give rise to either DGI or DD phenotypes. Furthermore, the consistent kindred presentation of the DD or DGI phenotype appears to be dependent on an as yet undescribed genetic modifier closely linked to DSPP.
PMCID: PMC2596760  PMID: 19029076
DSPP; dentinogenesis imperfecta; dentin dysplasia; DPP
21.  Human and Mouse Enamel Phenotypes Resulting from Mutation or Altered Expression of AMEL, ENAM, MMP20 and KLK4 
Cells, Tissues, Organs  2008;189(1-4):224-229.
Amelogenesis imperfecta (AI) is caused by AMEL, ENAM, MMP20 and KLK4 gene mutations. Mice lacking expression of the AmelX, Enam and Mmp20 genes have been generated. These mouse models provide tools for understanding enamel formation and AI pathogenesis. This study describes the AI phenotypes and relates them to their mouse model counterparts. Human AI phenotypes were determined in a clinical population of AI families and published cases. Human and murine teeth were evaluated using light and electron microscopy. A total of 463 individuals from 54 families were evaluated and mutations in the AMEL, ENAM and KLK4 genes were identified. The majority of human mutations for genes coding enamel nonproteinase proteins (AMEL and ENAM) resulted in variable hypoplasia ranging from local pitting to a marked, generalized enamel thinning. Specific AMEL mutations were associated with abnormal mineralization and maturation defects. Amel and Enam null murine models displayed marked enamel hypoplasia and a complete loss of prism structure. Human mutations in genes coding for the enamel proteinases (MMP20 and KLK4) cause variable degrees of hypomineralization. The murine Mmp20 null mouse exhibits both hypoplastic and hypomineralized defects. The currently available Amel and Enam mouse models for AI exhibit enamel phenotypes (hypoplastic) that are generally similar to those seen in humans. Mmp20 null mice have a greater degree of hypoplasia than humans with MMP20 mutations. Mice lacking expression of the currently known genes associated with the human AI conditions provide useful models for understanding the pathogenesis of these conditions.
doi:10.1159/000151378
PMCID: PMC2754863  PMID: 18714142
Enamel; Amelogenesis imperfecta; Mouse; Human; Gene; Mutation
22.  MMP-20 mutation in autosomal recessive pigmented hypomaturation amelogenesis imperfecta 
Journal of Medical Genetics  2005;42(3):271-275.
doi:10.1136/jmg.2004.024505
PMCID: PMC1736010  PMID: 15744043
23.  Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta 
Journal of Medical Genetics  2004;41(7):545-549.
doi:10.1136/jmg.2003.017657
PMCID: PMC1735847  PMID: 15235027
24.  MMP20 Active-site Mutation in Hypomaturation Amelogenesis Imperfecta 
The Amelogenesis Imperfecta (AI) are a group of clinically and genetically heterogeneous disorders that affect enamel formation. To date, mutations in 4 genes have been reported in various types of AI. Mutations in the genes encoding the 2 enamel proteases, matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4), have each been reported in a single family segregating autosomal-recessive hypomaturation AI. To determine the frequency of mutations in these genes, we analyzed 15 Turkish probands with autosomal-recessive hypo-maturation AI for MMP20 and KLK4 gene mutations. No KLK4 mutations were found. A novel MMP20 mutation (g.16250T>A) was found in one family. This missense mutation changed the conserved active-site His226 residue of the zinc catalytic domain to Gln (p.H226Q). Zymogram analysis demonstrated that this missense mutation abolished MMP20 proteolytic activity. No MMP20 mutations were found in the remaining 14 probands, underscoring the genetic heterogeneity of hypomaturation AI.
PMCID: PMC1850238  PMID: 15053
amelogenesis imperfecta; MMP20; proteolytic activity; hypomaturation; enamelysin
25.  Exclusion of known gene for enamel development in two Brazilian families with amelogenesis imperfecta 
Amelogenesis imperfecta (AI) is a genetically heterogeneous group of diseases that result in defective development of tooth enamel. Mutations in several enamel proteins and proteinases have been associated with AI. The object of this study was to evaluate evidence of etiology for the six major candidate gene loci in two Brazilian families with AI. Genomic DNA was obtained from family members and all exons and exon-intron boundaries of the ENAM, AMBN, AMELX, MMP20, KLK4 and Amelotin gene were amplified and sequenced. Each family was also evaluated for linkage to chromosome regions known to contain genes important in enamel development. The present study indicates that the AI in these two families is not caused by any of the known loci for AI or any of the major candidate genes proposed in the literature. These findings indicate extensive genetic heterogeneity for non-syndromic AI.
doi:10.1186/1746-160X-3-8
PMCID: PMC1800839  PMID: 17266769

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