Publications by authors named "Timothy C Cox"

93 Publications

Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome.

Hum Genet 2021 Jul 3;140(7):1061-1076. Epub 2021 Apr 3.

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-021-02274-3DOI Listing
July 2021

Survey of spiking in the mouse visual system reveals functional hierarchy.

Nature 2021 04 20;592(7852):86-92. Epub 2021 Jan 20.

Allen Institute for Brain Science, Seattle, WA, USA.

The anatomy of the mammalian visual system, from the retina to the neocortex, is organized hierarchically. However, direct observation of cellular-level functional interactions across this hierarchy is lacking due to the challenge of simultaneously recording activity across numerous regions. Here we describe a large, open dataset-part of the Allen Brain Observatory-that surveys spiking from tens of thousands of units in six cortical and two thalamic regions in the brains of mice responding to a battery of visual stimuli. Using cross-correlation analysis, we reveal that the organization of inter-area functional connectivity during visual stimulation mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas. We find that four classical hierarchical measures-response latency, receptive-field size, phase-locking to drifting gratings and response decay timescale-are all correlated with the hierarchy. Moreover, recordings obtained during a visual task reveal that the correlation between neural activity and behavioural choice also increases along the hierarchy. Our study provides a foundation for understanding coding and signal propagation across hierarchically organized cortical and thalamic visual areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-03171-xDOI Listing
April 2021

A dyadic approach to the delineation of diagnostic entities in clinical genomics.

Am J Hum Genet 2021 01;108(1):8-15

Molecular Medicine & Pathology and Pediatrics, McMaster University, Hamilton, ON L8S 3K9, Canada.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820621PMC
January 2021

A Synonymous Exonic Splice Silencer Variant in IRF6 as a Novel and Cryptic Cause of Non-Syndromic Cleft Lip and Palate.

Genes (Basel) 2020 08 7;11(8). Epub 2020 Aug 7.

Department of Pediatrics, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA.

Missense, nonsense, splice site and regulatory region variants in interferon regulatory factor 6 () have been shown to contribute to both syndromic and non-syndromic forms of cleft lip and/or palate (CL/P). We report the diagnostic evaluation of a complex multigeneration family of Honduran ancestry with a pedigree structure consistent with autosomal-dominant inheritance with both incomplete penetrance and variable expressivity. The proband's grandmother bore children with two partners and CL/P segregates on both sides of each lineage. Through whole-exome sequencing of five members of the family, we identified a single shared synonymous variant, located in the middle of exon 7 of (p.Ser307Ser; g.209963979 G>A; c.921C>T). The variant was shown to segregate in the seven affected individuals and through three unaffected obligate carriers, spanning both sides of this pedigree. This variant is very rare, only being found in three (all of Latino ancestry) of 251,352 alleles in the gnomAD database. While the variant did not create a splice acceptor/donor site, in silico analysis predicted it to impact an exonic splice silencer element and the binding of major splice regulatory factors. In vitro splice assays supported this by revealing multiple abnormal splicing events, estimated to impact >60% of allelic transcripts. Sequencing of the alternate splice products demonstrated the unmasking of a cryptic splice site six nucleotides 5' of the variant, as well as variable utilization of cryptic splice sites in intron 6. The ectopic expression of different splice regulatory proteins altered the proportion of abnormal splicing events seen in the splice assay, although the alteration was dependent on the splice factor. Importantly, each alternatively spliced mRNA is predicted to result in a frame shift and prematurely truncated IRF6 protein. This is the first study to identify a synonymous variant as a likely cause of NS-CL/P and highlights the care that should be taken by laboratories when considering and interpreting variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11080903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465030PMC
August 2020

Effects of Multi-Generational Soft Diet Consumption on Mouse Craniofacial Morphology.

Front Physiol 2020 10;11:783. Epub 2020 Jul 10.

Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.

Variations in craniofacial morphology may arise as a result of adaptation to different environmental factors such as soft diet (SD), which lessens functional masticatory load. Prior studies have shown that changes in the masticatory muscle function associated with a switch to short-term SD led to changes in craniofacial morphology and alveolar bone architecture. However, the long-term effects of SD and the associated adaptive changes in craniofacial shape are unclear. Our novel study set out to profile prospective skull changes in mice fed with SDs over multiple generations using three-dimensional (3D) geometric morphometric analysis (GMA). Our results revealed that short-term SD consumption led to a significant decrease in craniofacial size, along with numerous shape changes. Long-term SD consumption over 15 continuous generations was not associated with changes in craniofacial size; however, shape analysis revealed mice with shortened crania and mandibles in the anteroposterior dimension, as well as relative widening in the transverse dimension compared to the average shape of all mice analyzed in our study. Moreover, changes in shape and size associated with different functional loads appeared to be independent - shape changes persisted after diets were switched for one generation, whereas size decreased after one generation and then returned to baseline size. Our study is the first to study the role of prolonged, multi-generational SD consumption in the determination of craniofacial size and shape.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.00783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367031PMC
July 2020

Microcomputed tomography of craniofacial mineralized tissue: A practical user's guide to study planning and generating quality data.

Authors:
Timothy C Cox

Bone 2020 08 12;137:115408. Epub 2020 May 12.

Departments of Oral & Craniofacial Sciences, School of Dentistry, and Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA. Electronic address:

Whether in a clinical setting or a research environment using model organisms, X-ray-based computed tomography (CT) in its different forms represents the gold standard technology for the non-invasive imaging and quantification of mineralized tissues. While there are many excellent reviews on computed tomography in bone imaging, most focus on the appendicular skeleton. However, the craniofacial skeleton and mineralized dentition, which are frequently imaged for a variety of reasons, can require special considerations to ensure the best quality data are acquired and interpreted correctly. In this review, I will specifically focus on micro-computed tomography (microCT) related to the study of the craniofacial skeleton from the onset of cranioskeletal development through to adulthood using the mouse as the primary reference organism. In so doing, I will cover the important considerations when planning imaging studies, explain critical parameters of both scanning, reconstruction and 3D rendering of data that can impact quantification of different mineralized craniofacial tissues, and options for enabling accurate visualization of tomographic data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2020.115408DOI Listing
August 2020

Rapamycin rejuvenates oral health in aging mice.

Elife 2020 04 28;9. Epub 2020 Apr 28.

Department of Oral Health Sciences, University of Washington, Seattle, United States.

Periodontal disease is an age-associated disorder clinically defined by periodontal bone loss, inflammation of the specialized tissues that surround and support the tooth, and microbiome dysbiosis. Currently, there is no therapy for reversing periodontal disease, and treatment is generally restricted to preventive measures or tooth extraction. The FDA-approved drug rapamycin slows aging and extends lifespan in multiple organisms, including mice. Here, we demonstrate that short-term treatment with rapamycin rejuvenates the aged oral cavity of elderly mice, including regeneration of periodontal bone, attenuation of gingival and periodontal bone inflammation, and revertive shift of the oral microbiome toward a more youthful composition. This provides a geroscience strategy to potentially rejuvenate oral health and reverse periodontal disease in the elderly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.54318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220376PMC
April 2020

Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer.

Genes (Basel) 2020 04 3;11(4). Epub 2020 Apr 3.

New South Wales Health Pathology, Prince of Wales Hospital, Randwick, Sydney 2031, Australia.

Pathogenic variants in , encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least 'likely pathogenic', and correlates their molecular and structural characteristics to phenotype. We demonstrate that variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11040391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231129PMC
April 2020

Sonic Hedgehog upregulation does not enhance the survival and engraftment of stem cell-derived cardiomyocytes in infarcted hearts.

PLoS One 2020 16;15(1):e0227780. Epub 2020 Jan 16.

Department of Pathology, Center for Cardiovascular Biology, and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.

The engraftment of human stem cell-derived cardiomyocytes (hSC-CMs) is a promising treatment for remuscularizing the heart wall post-infarction, but it is plagued by low survival of transplanted cells. We hypothesize that this low survival rate is due to continued ischemia within the infarct, and that increasing the vascularization of the scar will ameliorate the ischemia and improve hSC-CM survival and engraftment. An adenovirus expressing the vascular growth factor Sonic Hedgehog (Shh) was injected into the infarcted myocardium of rats immediately after ischemia/reperfusion, four days prior to hSC-CM injection. By two weeks post-cell injection, Shh treatment had successfully increased capillary density outside the scar, but not within the scar. In addition, there was no change in vessel size or percent vascular volume when compared to cell injection alone. Micro-computed tomography revealed that Shh failed to increase the number and size of larger vessels. It also had no effect on graft size or heart function when compared to cell engraftment alone. Our data suggests that, when combined with the engraftment of hSC-CMs, expression of Shh within the infarct scar and surrounding myocardium is unable to increase vascularization of the infarct scar, and it does not improve survival or function of hSC-CM grafts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227780PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964843PMC
April 2020

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans.

Hum Mutat 2019 10 18;40(10):1813-1825. Epub 2019 Jun 18.

New South Wales Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia.

Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764866PMC
October 2019

Transcranial Doppler and Magnetic Resonance in Tanzanian Children With Sickle Cell Disease.

Stroke 2019 07 14;50(7):1719-1726. Epub 2019 Jun 14.

From the Muhimbili Wellcome Programme, Dar es Salaam, Tanzania (E.N.K., E.M., D.S., J.K., D.A.N., S.E.C., C.R.J.C.N.).

Background and Purpose- We determined prevalences of neurological complications, vascular abnormality, and infarction in Tanzanian children with sickle cell disease. Methods- Children with sickle cell disease were consecutively enrolled for transcranial Doppler; those with slightly elevated (>150 cm/s), low (<50 cm/s) or absent cerebral blood flow velocity (CBFv) were invited for brain magnetic resonance imaging and magnetic resonance angiography. Results- Of 200 children (median age 9; range 6-13 years; 105 [2.5%] boys), 21 (11%) and 15 (8%) had previous seizures and unilateral weakness, respectively. Twenty-eight (14%) had elevated and 39 (20%) had low/absent CBFv, all associated with lower hemoglobin level, but not higher indirect bilirubin level. On multivariable analysis, CBFv>150 cm/s was associated with frequent painful crises and low hemoglobin level. Absent/low CBFv was associated with low hemoglobin level and history of unilateral weakness. In 49 out of 67 children with low/absent/elevated transcranial Doppler undergoing magnetic resonance imaging, 43% had infarction, whereas 24 out of 48 (50%) magnetic resonance angiographies were abnormal. One had hemorrhagic infarction; none had microbleeds. Posterior circulation infarcts occurred in 14%. Of 11 children with previous seizure undergoing magnetic resonance imaging, 10 (91%) had infarction (5 silent) compared with 11 out of 38 (29%) of the remainder ( P=0.003). Of 7 children with clinical stroke, 2 had recurrent stroke and 3 died; 4 out of 5 had absent CBFv. Of 193 without stroke, 1 died and 1 had a stroke; both had absent CBFv. Conclusions- In one-third of Tanzanian children with sickle cell disease, CBFv is outside the normal range, associated with frequent painful crises and low hemoglobin level, but not hemolysis. Half have abnormal magnetic resonance angiography. African children with sickle cell disease should be evaluated with transcranial Doppler; those with low/absent/elevated CBFv should undergo magnetic resonance imaging/magnetic resonance angiography.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.118.018920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594727PMC
July 2019

Altering calcium and phosphorus levels in utero affects adult mouse mandibular morphology.

Orthod Craniofac Res 2019 May;22 Suppl 1:113-119

Program in Craniofacial Biology, UCSF, San Francisco, California.

Objectives: The purpose of our study was to determine morphological changes and bone mineral density (BMD) differences in the adult mandible of offspring exposed to high calcium, low phosphorus diets in utero until weaning age.

Materials And Methods: Time-mated FVB wild-type mice were fed normal or experimental diet during gestation and until weaning of offspring. Experimental diet contained 3-fold increase in calcium and 3-fold decrease in phosphorus compared to normal diet. Adult mandibles of offspring exposed to experimental diet were sacrificed and heads scanned using micro-computed tomography. Three-dimensional 3D geometric morphometric analysis GMA was utilized to detect morphological changes to the mandible including the condyle.

Results: Experimental females showed the greatest morphological differences including shortened mandibular ramus width and height, shortened mandibular body length and height, a wider but shortened condylar neck and a wider condylar head in the lateral-medial direction. Experimental male mandibles trended towards increased mandibular body height and length, opposite the changes observed in experimental female mandibles, whereas condyles were similar to that observed in experimental females. Bone mineral density (BMD) was lowered in experimental females.

Conclusion: Increased calcium and decreased phosphorus levels led to a retrognathic mandible associated with lowered BMD in experimental females, whereas experimental showed partly opposite effects. Further studies are required to understand the mechanism underlying diet- and gender-specific differences in mandibular morphology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ocr.12269DOI Listing
May 2019

Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis.

Nat Commun 2019 02 27;10(1):953. Epub 2019 Feb 27.

Department of Biomedical Engineering- ND20, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.

Although hundreds of cytosolic or transmembrane molecules form the primary cilium, few secreted molecules are known to contribute to ciliogenesis. Here, homologous secreted metalloproteases ADAMTS9 and ADAMTS20 are identified as ciliogenesis regulators that act intracellularly. Secreted and furin-processed ADAMTS9 bound heparan sulfate and was internalized by LRP1, LRP2 and clathrin-mediated endocytosis to be gathered in Rab11 vesicles with a unique periciliary localization defined by super-resolution microscopy. CRISPR-Cas9 inactivation of ADAMTS9 impaired ciliogenesis in RPE-1 cells, which was restored by catalytically active ADAMTS9 or ADAMTS20 acting in trans, but not by their proteolytically inactive mutants. Their mutagenesis in mice impaired neural and yolk sac ciliogenesis, leading to morphogenetic anomalies resulting from impaired hedgehog signaling, which is transduced by primary cilia. In addition to their cognate extracellular proteolytic activity, ADAMTS9 and ADAMTS20 thus have an additional proteolytic role intracellularly, revealing an unexpected regulatory dimension in ciliogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-08520-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393521PMC
February 2019

PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet.

Kidney Int 2018 10 21;94(4):716-727. Epub 2018 Jul 21.

Department of Bioengineering, University of Washington, Seattle, Washington, USA. Electronic address:

PiT-2, a type III sodium-dependent phosphate transporter, is a causative gene for the brain arteriolar calcification in people with familial basal ganglion calcification. Here we examined the effect of PiT-2 haploinsufficiency on vascular calcification in uremic mice using wild-type and global PiT-2 heterozygous knockout mice. PiT-2 haploinsufficiency enhanced the development of vascular calcification in mice with chronic kidney disease fed a high-phosphate diet. No differences were observed in the serum mineral biomarkers and kidney function between the wild-type and PiT-2 heterozygous knockout groups. Micro computed tomography analyses of femurs showed that haploinsufficiency of PiT-2 decreased trabecular bone mineral density in uremia. In vitro, sodium-dependent phosphate uptake was decreased in cultured vascular smooth muscle cells isolated from PiT-2 heterozygous knockout mice compared with those from wild-type mice. PiT-2 haploinsufficiency increased phosphate-induced calcification of cultured vascular smooth muscle cells compared to the wild-type. Furthermore, compared to wild-type vascular smooth muscle cells, PiT-2 deficient vascular smooth muscle cells had lower osteoprotegerin levels and increased matrix calcification, which was attenuated by osteoprotegerin supplementation. Thus, PiT-2 in vascular smooth muscle cells protects against phosphate-induced vascular calcification and may be a therapeutic target in the chronic kidney disease population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2018.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211801PMC
October 2018

Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.

Am J Hum Genet 2018 06 24;102(6):1143-1157. Epub 2018 May 24.

New South Wales Health Pathology, Prince of Wales Hospital, Randwick, NSW 2031, Australia.

Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14% of multi-affected families and 2% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992119PMC
June 2018

Cerebral perfusion characteristics show differences in younger versus older children with sickle cell anaemia: Results from a multiple-inflow-time arterial spin labelling study.

NMR Biomed 2018 06 30;31(6):e3915. Epub 2018 Mar 30.

Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.

Sickle cell anaemia (SCA) is associated with chronic anaemia and oxygen desaturation, which elevate cerebral blood flow (CBF) and increase the risk of neurocognitive complications. Arterial spin labelling (ASL) provides a methodology for measuring CBF non-invasively; however, ASL techniques using only a single inflow time are not sufficient to fully characterize abnormal haemodynamic behaviour in SCA. This study investigated haemodynamic parameters from a multi-inflow-time ASL acquisition in younger (8-12 years) and older (13-18 years) children with SCA with and without silent cerebral infarction (SCI+/-) (n = 20 and 19 respectively, 6 and 4 SCI+ respectively) and healthy controls (n = 9 and 7 respectively). Compared with controls, CBF was elevated globally in both groups of patients. In the younger SCA patients, blood oxygen content was negatively correlated with CBF in the middle and posterior cerebral artery territories and significantly positively correlated with bolus arrival time (BAT) in the anterior and middle cerebral artery territories. In older children, SCA patients had significantly shorter BAT than healthy controls and there was a significant negative correlation between CBF and oxygen content only in the territory of the posterior cerebral artery, with a trend for a correlation in the anterior cerebral artery but no relationship for the middle cerebral artery territory. In the younger group, SCI+ patients had significantly higher CBF in the posterior cerebral artery territory (SCI+ mean = 92.78 ml/100 g/min; SCI- mean = 72.71 ml/100 g/min; F = 4.28, p = 0.04), but this no longer reached significance when two children with abnormal transcranial Doppler and one with haemoglobin SC disease were excluded, and there were no significant differences between patients with and without SCI in the older children. With age, there appears to be increasing disparity between patients and controls in terms of the relationship between CBF and oxygen content in the anterior circulation, potentially predicting the risk of acute and chronic compromise of brain tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nbm.3915DOI Listing
June 2018

Associations between laterality of orofacial clefts and medical and academic outcomes.

Am J Med Genet A 2018 Feb 12;176(2):267-276. Epub 2017 Dec 12.

Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.

Patients with oral clefts have an increased risk of other malformations, syndromes, and lower academic performance in school. Few studies have investigated if laterality of clefts is associated with medical and academic outcomes. Oral clefts have nonrandom laterality, with left-sided clefts occurring approximately twice as often as right-sided clefts. Using a retrospective study design, we examined potential associations of cleft attributes and outcomes in patients with cleft lip with or without cleft palate (CL/P) born in 2003-2010 who were treated at the Seattle Children's Craniofacial Center. The following variables were extracted from medical records: cleft type, medical history, maternal hyperglycemia, other malformations, and the need for academic support at school. We used logistic regression to examine risk of associations with outcomes of interest. Relative to patients with left-sided clefts, patients with bilateral CL/P were more likely to have a syndrome. Patients with nonsyndromic right-sided CL/P had a higher risk (OR and 95%CI: 3.5, 1.3-9.5, and 5.5, 1.9-16.0, respectively) of having other malformations and requiring academic support at school, when compared to patients with left-sided CL/P. Understanding the etiology of oral clefts is complicated, in part because both genetic and environmental factors contribute to the risk of developing a cleft. However, the different outcomes associated with cleft laterality suggest that right-sided clefts may have a distinct etiology. Using laterality to study cleft subgroups may advance our understanding of the etiology of this common birth defect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38567DOI Listing
February 2018

Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment.

Am J Hum Genet 2017 Dec 30;101(6):913-924. Epub 2017 Nov 30.

Chinese Academy of Sciences Key Laboratory of Computational Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China. Electronic address:

The genetic basis of earlobe attachment has been a matter of debate since the early 20 century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2017.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812923PMC
December 2017

Loss of PiT-2 results in abnormal bone development and decreased bone mineral density and length in mice.

Biochem Biophys Res Commun 2018 01 11;495(1):553-559. Epub 2017 Nov 11.

Department of Bioengineering, University of Washington, Seattle, WA 98195, USA. Electronic address:

Normal bone mineralization requires phosphate oversaturation in bone matrix vesicles, as well as normal regulation of phosphate metabolism via the interplay among bone, intestine, and kidney. In turn, derangement of phosphate metabolism greatly affects bone function and structure. The type III sodium-dependent phosphate transporters, PiT-1 and PiT-2, are believed to be important in tissue phosphate metabolism and physiological bone formation, but their requirement and molecular roles in bone remain poorly investigated. In order to decipher the role of PiT-2 in bone, we examined normal bone development, growth, and mineralization in global PiT-2 homozygous knockout mice. PiT-2 deficiency resulted in reduced vertebral column, femur, and tibia length as well as mandibular dimensions. Micro-computed tomography analysis revealed that bone mineral density in the mandible, femur, and tibia were decreased, indicating that maintenance of bone function and structure is impaired in both craniofacial and long bones of PiT-2 deficient mice. Both cortical and trabecular thickness and mineral density were reduced in PiT-2 homozygous knockout mice compared with wild-type mice. These results suggest that PiT-2 is involved in normal bone development and growth and plays roles in cortical and trabecular bone metabolism feasibly by regulating local phosphate transport and mineralization processes in the bone. Further studies that evaluate bone cell-specific loss of PiT-2 are now warranted and may yield insight into complex mechanisms of bone development and growth, leading to identification of new therapeutic options for patients with bone diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2017.11.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739526PMC
January 2018

Nocturnal oxyhemoglobin desaturation and arteriopathy in a pediatric sickle cell disease cohort.

Neurology 2017 Dec 8;89(24):2406-2412. Epub 2017 Nov 8.

From Developmental Neurosciences (N.D., F.J.K.), UCL Great Ormond Street Institute of Child Health, London, UK; Hospital for Sick Children (N.D.), Toronto, Canada; Department of Radiology (D.E.S., M.B., T.C.C.), Great Ormond Street Hospital for Children NHS Trust, London, UK; University of Western Australia (M.B., R.S.B.), Perth; and Department of Haematology (S.T.), University College London Hospital, UK.

Objective: The purpose of this study of sickle cell disease (SCD) was to determine whether arteriopathy, measurable as intracranial vessel signal loss on magnetic resonance angiography (MRA), was associated with low nocturnal hemoglobin oxygen saturation (SpO) or hemolytic rate, measurable as reticulocytosis or unconjugated hyperbilirubinemia.

Methods: Ninety-five East London children with SCD without prior stroke had overnight pulse oximetry, of whom 47 (26 boys, 39 hemoglobin SS; mean age 9.1 ± 3.1 years) also had MRA, transcranial Doppler (TCD), steady-state hemoglobin, and reticulocytes within 34 months. Two radiologists blinded to the other data graded arteriopathy on MRA as 0 (none) or as increasing severity grades 1, 2, or 3.

Results: Grades 2 or 3 arteriopathy (n = 24; 2 with abnormal TCD) predicted stroke/TIA compared with grades 0 and 1 (log-rank χ [1, n = 47] = 8.1, = 0.004). Mean overnight SpO correlated negatively with reticulocyte percentage ( = -0.387; = 0.007). Despite no significant differences across the degrees of arteriopathy in genotype, mean overnight SpO was higher ( < 0.01) in those with grade 0 (97.0% ± 1.6%) than those with grades 2 (93.9 ± 3.7%) or 3 (93.5% ± 3.0%) arteriopathy. Unconjugated bilirubin was not associated but reticulocyte percentage was lower ( < 0.001) in those with grade 0 than those with grades 2 and 3 arteriopathy. In multivariable logistic regression, lower mean overnight SpO (odds ratio 0.50, 95% confidence interval 0.26-0.96; < 0.01) predicted arteriopathy independent of reticulocyte percentage (odds ratio 1.47, 95% confidence interval 1.15-1.87; = 0.003).

Conclusion: Low nocturnal SpO and reticulocytosis are associated with intracranial arteriopathy in children with SCD. Preventative strategies might reduce stroke risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000004728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729796PMC
December 2017

Rapamycin treatment attenuates age-associated periodontitis in mice.

Geroscience 2017 Aug 9;39(4):457-463. Epub 2017 Sep 9.

Department of Oral Health Sciences, University of Washington School of Dentistry, Seattle, WA, 98195, USA.

Interventions that target biological mechanisms of aging have great potential to enhance quality of life by delaying morbidity and mortality. The FDA-approved drug rapamycin is a compelling candidate for such an intervention. In a previous study, it was reported that 3 months of rapamycin treatment is sufficient to increase life expectancy and remodel the gut microbiome in aged mice. Transient treatment with rapamycin or a rapamycin derivative has also been shown to delay immune stem cell senescence and rejuvenate immune function in aged mice and elderly people. Periodontal disease is an important age-related disease involving altered immune function, pathological changes to the oral microbiome, and systemic inflammation. Periodontal disease is defined clinically by loss of alveolar bone and by connective tissue degeneration. Here, we describe significant alveolar bone loss during aging in two different mouse strain backgrounds and report that rapamycin treatment is sufficient to reverse age-associated periodontal disease in mice. Partial restoration of youthful levels of alveolar bone is observed in 22-month-old rapamycin-treated mice as rapidly as 8 weeks after initiation of treatment. To the best of our knowledge, this represents the first intervention shown to substantially prevent or reverse age-associated alveolar bone loss. These findings suggest the possibility that inhibition of mTOR with rapamycin or other pharmacological agents may be useful to treat a clinically relevant condition for which there is currently no effective treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11357-017-9994-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636779PMC
August 2017

Intra- and Intersexual swim bladder dimorphisms in the plainfin midshipman fish (Porichthys notatus): Implications of swim bladder proximity to the inner ear for sound pressure detection.

J Morphol 2017 11 10;278(11):1458-1468. Epub 2017 Jul 10.

Department of Psychology, University of Washington, Seattle, Washington, 98195-1525.

The plainfin midshipman fish, Porichthys notatus, is a nocturnal marine teleost that uses social acoustic signals for communication during the breeding season. Nesting type I males produce multiharmonic advertisement calls by contracting their swim bladder sonic muscles to attract females for courtship and spawning while subsequently attracting cuckholding type II males. Here, we report intra- and intersexual dimorphisms of the swim bladder in a vocal teleost fish and detail the swim bladder dimorphisms in the three sexual phenotypes (females, type I and II males) of plainfin midshipman fish. Micro-computerized tomography revealed that females and type II males have prominent, horn-like rostral swim bladder extensions that project toward the inner ear end organs (saccule, lagena, and utricle). The rostral swim bladder extensions were longer, and the distance between these swim bladder extensions and each inner-ear end organ type was significantly shorter in both females and type II males compared to that in type I males. Our results revealed that the normalized swim bladder length of females and type II males was longer than that in type I males while there was no difference in normalized swim bladder width among the three sexual phenotypes. We predict that these intrasexual and intersexual differences in swim bladder morphology among midshipman sexual phenotypes will afford greater sound pressure sensitivity and higher frequency detection in females and type II males and facilitate the detection and localization of conspecifics in shallow water environments, like those in which midshipman breed and nest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmor.20724DOI Listing
November 2017

Isl1 Controls Patterning and Mineralization of Enamel in the Continuously Renewing Mouse Incisor.

J Bone Miner Res 2017 Nov 31;32(11):2219-2231. Epub 2017 Jul 31.

Program in Craniofacial Biology and Department of Orofacial Sciences, UCSF School of Dentistry, University of California, San Francisco, San Francisco, CA, USA.

Rodents are characterized by continuously renewing incisors whose growth is fueled by epithelial and mesenchymal stem cells housed in the proximal compartments of the tooth. The epithelial stem cells reside in structures known as the labial (toward the lip) and lingual (toward the tongue) cervical loops (laCL and liCL, respectively). An important feature of the rodent incisor is that enamel, the outer, highly mineralized layer, is asymmetrically distributed, because it is normally generated by the laCL but not the liCL. Here, we show that epithelial-specific deletion of the transcription factor Islet1 (Isl1) is sufficient to drive formation of ectopic enamel by the liCL stem cells, and also that it leads to production of altered enamel on the labial surface. Molecular analyses of developing and adult incisors revealed that epithelial deletion of Isl1 affected multiple, major pathways: Bmp (bone morphogenetic protein), Hh (hedgehog), Fgf (fibroblast growth factor), and Notch signaling were upregulated and associated with liCL-generated ectopic enamel; on the labial side, upregulation of Bmp and Fgf signaling, and downregulation of Shh were associated with premature enamel formation. Transcriptome profiling studies identified a suite of differentially regulated genes in developing Isl1 mutant incisors. Our studies demonstrate that ISL1 plays a central role in proper patterning of stem cell-derived enamel in the incisor and indicate that this factor is an important upstream regulator of signaling pathways during tooth development and renewal. © 2017 American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.3202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685895PMC
November 2017

Negative regulation of endothelin signaling by SIX1 is required for proper maxillary development.

Development 2017 06 28;144(11):2021-2031. Epub 2017 Apr 28.

Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA

Jaw morphogenesis is a complex event mediated by inductive signals that establish and maintain the distinct developmental domains required for formation of hinged jaws, the defining feature of gnathostomes. The mandibular portion of pharyngeal arch 1 is patterned dorsally by Jagged-Notch signaling and ventrally by endothelin receptor A (EDNRA) signaling. Loss of EDNRA signaling disrupts normal ventral gene expression, the result of which is homeotic transformation of the mandible into a maxilla-like structure. However, loss of Jagged-Notch signaling does not result in significant changes in maxillary development. Here we show in mouse that the transcription factor SIX1 regulates dorsal arch development not only by inducing dorsal expression but also by inhibiting endothelin 1 () expression in the pharyngeal endoderm of the dorsal arch, thus preventing dorsal EDNRA signaling. In the absence of SIX1, but not JAG1, aberrant EDNRA signaling in the dorsal domain results in partial duplication of the mandible. Together, our results illustrate that SIX1 is the central mediator of dorsal mandibular arch identity, thus ensuring separation of bone development between the upper and lower jaws.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/dev.145144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482985PMC
June 2017

Differences in Oral Structure and Tissue Interactions during Mouse vs. Human Palatogenesis: Implications for the Translation of Findings from Mice.

Front Physiol 2017 15;8:154. Epub 2017 Mar 15.

Department of Pediatrics, Division of Craniofacial Medicine, University of WashingtonSeattle, WA, USA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research InstituteSeattle, WA, USA; Department of Anatomy and Developmental Biology, Monash UniversityClayton, VIC, Australia.

Clefting of the secondary palate is one of the most common human birth defects and results from failure of the palatal shelves to fuse during embryonic development. Palatogenesis is traditionally considered to be a highly conserved developmental process among mammalian species. However, cleft palate phenotypes in humans are considerably more variable than those seen in mice, the most common animal model for studying palatal development and pathogenesis of cleft palate. In this investigation, we utilized macroscopic observations, histology and 3D imaging techniques to directly compare palate morphology and the oral-nasal cavity during palate closure in mouse embryos and human conceptuses. We showed that mouse and human palates display distinct morphologies attributable to the structural differences of the oral-nasal cavity. We further showed that the palatal shelves interact differently with the primary palate and nasal septum in the hard palate region and with pharyngeal walls in the soft palate region during palate closure in mice and humans. Knowledge of these morphological differences is important for improved translation of findings in mouse models of human cleft lip/palate and, as such, should ultimately enhance our understanding of human palatal morphogenesis and the pathogenesis of cleft lip/palate in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2017.00154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350148PMC
March 2017

Multi-species Ontologies of the Craniofacial Musculoskeletal System.

CEUR Workshop Proc 2016 Aug 29;1747. Epub 2016 Nov 29.

Department of Biological Structure, University of Washington; Department of Biomedical Informatics and Medical Education, University of Washington.

We created the Ontology of Craniofacial Development and Malformation (OCDM) [1] to provide a unifying framework for organizing and integrating craniofacial data ranging from genes to clinical phenotypes from multi-species. Within this framework we focused on spatio-structural representation of anatomical entities related to craniofacial development and malformation, such as craniosynostosis and midface hypoplasia. Animal models are used to support human studies and so we built multi-species ontologies that would allow for cross-species correlation of anatomical information. For this purpose we first developed and enhanced the craniofacial component of the human musculoskeletal system in the Foundational Model of Anatomy Ontology (FMA)[2], and then imported this component, which we call the Craniofacial Human Ontology (CHO), into the OCDM. The CHO was then used as a template to create the anatomy for the mouse, the Craniofacial Mouse Ontology (CMO) as well as for the zebrafish, the Craniofacial Zebrafish Ontology (CZO).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311076PMC
August 2016

Retreatability of two endodontic sealers, EndoSequence BC Sealer and AH Plus: a micro-computed tomographic comparison.

Restor Dent Endod 2017 Feb 8;42(1):19-26. Epub 2016 Dec 8.

Department of Endodontics, University of Washington, Seattle, WA, USA.

Objectives: Recently, bioceramic sealers like EndoSequence BC Sealer (BC Sealer) have been introduced and are being used in endodontic practice. However, this sealer has limited research related to its retreatability. Hence, the aim of this study was to evaluate the retreatability of two sealers, BC Sealer as compared with AH Plus using micro-computed tomographic (micro-CT) analysis.

Materials And Methods: Fifty-six extracted human maxillary incisors were instrumented and randomly divided into 4 groups of 14 teeth: 1A, gutta-percha, AH Plus retreated with chloroform; 1B, gutta-percha, AH Plus retreated without chloroform; 2A, gutta-percha, EndoSequence BC Sealer retreated with chloroform; 2B, gutta-percha, EndoSequence BC Sealer retreated without chloroform. Micro-CT scans were taken before and after obturation and retreatment and analyzed for the volume of residual material. The specimens were longitudinally sectioned and digitized images were taken with the dental operating microscope. Data was analyzed using an ANOVA and a Tukey test. Fisher exact tests were performed to analyze the ability to regain patency.

Results: There was significantly less residual root canal filling material in the AH Plus groups retreated with chloroform as compared to the others. The BC Sealer samples retreated with chloroform had better results than those retreated without chloroform. Furthermore, patency could be re-established in only 14% of teeth in the BC Sealer without chloroform group.

Conclusion: The results of this study demonstrate that the BC Sealer group had significantly more residual filling material than the AH Plus group regardless of whether or not both sealers were retreated with chloroform.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5395/rde.2017.42.1.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299751PMC
February 2017

A distal 594 bp ECR specifies Hmx1 expression in pinna and lateral facial morphogenesis and is regulated by the Hox-Pbx-Meis complex.

Development 2016 07 10;143(14):2582-92. Epub 2016 Jun 10.

Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA Department of Oral Health Sciences, University of Washington, Seattle, WA 98195, USA Department of Pediatrics (Craniofacial Medicine), University of Washington, Seattle, WA 98195, USA Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia

Hmx1 encodes a homeodomain transcription factor expressed in the developing lateral craniofacial mesenchyme, retina and sensory ganglia. Mutation or mis-regulation of Hmx1 underlies malformations of the eye and external ear in multiple species. Deletion or insertional duplication of an evolutionarily conserved region (ECR) downstream of Hmx1 has recently been described in rat and cow, respectively. Here, we demonstrate that the impact of Hmx1 loss is greater than previously appreciated, with a variety of lateral cranioskeletal defects, auriculofacial nerve deficits, and duplication of the caudal region of the external ear. Using a transgenic approach, we demonstrate that a 594 bp sequence encompassing the ECR recapitulates specific aspects of the endogenous Hmx1 lateral facial expression pattern. Moreover, we show that Hoxa2, Meis and Pbx proteins act cooperatively on the ECR, via a core 32 bp sequence, to regulate Hmx1 expression. These studies highlight the conserved role for Hmx1 in BA2-derived tissues and provide an entry point for improved understanding of the causes of the frequent lateral facial birth defects in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/dev.133736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958336PMC
July 2016

SLC20A2 Deficiency in Mice Leads to Elevated Phosphate Levels in Cerbrospinal Fluid and Glymphatic Pathway-Associated Arteriolar Calcification, and Recapitulates Human Idiopathic Basal Ganglia Calcification.

Brain Pathol 2017 01 6;27(1):64-76. Epub 2016 May 6.

Department of Bioengineering, University of Washington, Seattle, WA.

Idiopathic basal ganglia calcification is a brain calcification disorder that has been genetically linked to autosomal dominant mutations in the sodium-dependent phosphate co-transporter, SLC20A2. The mechanisms whereby deficiency of Slc20a2 leads to basal ganglion calcification are unknown. In the mouse brain, we found that Slc20a2 was expressed in tissues that produce and/or regulate cerebrospinal fluid, including choroid plexus, ependyma and arteriolar smooth muscle cells. Haploinsufficient Slc20a2 +/- mice developed age-dependent basal ganglia calcification that formed in glymphatic pathway-associated arterioles. Slc20a2 deficiency uncovered phosphate homeostasis dysregulation characterized by abnormally high cerebrospinal fluid phosphate levels and hydrocephalus, in addition to basal ganglia calcification. Slc20a2 siRNA knockdown in smooth muscle cells revealed increased susceptibility to high phosphate-induced calcification. These data suggested that loss of Slc20a2 led to dysregulated phosphate homeostasis and enhanced susceptibility of arteriolar smooth muscle cells to elevated phosphate-induced calcification. Together, dysregulated cerebrospinal fluid phosphate and enhanced smooth muscle cell susceptibility may predispose to glymphatic pathway-associated arteriolar calcification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967033PMC
January 2017
-->