Publications by authors named "Beth Kozel"

42 Publications

Developmental vascular malformations in EPAS1-gain-of-function syndrome.

JCI Insight 2021 Jan 26. Epub 2021 Jan 26.

Section on Medical Neuroendrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Develop, Bethesda, United States of America.

EPAS1, encoding HIF-2α, mutations were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to our institution for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1-gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital two photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and Micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retina from corresponding developmental timepoints (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all of our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental timepoints. These findings add vascular malformation as a new clinical feature of EPAS1-gain-of-function syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.144368DOI Listing
January 2021

X-ray microtomosynthesis of unstained pathology tissue samples.

J Microsc 2021 Jan 22. Epub 2021 Jan 22.

National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.

In pathology protocols, a tissue block, such as one containing a mouse brain or a biopsy sample from a patient, can produce several hundred thin sections. Substantial time may be required to analyse all sections. In cases of uncertainty regarding which sections to focus on, noninvasive scout imaging of intact blocks can help in guiding the pathology procedure. The scouting step is ideally done in a time window of minutes without special sample preparation that may interfere with the pathology procedures. The challenge is to obtain some visibility of unstained tissue structures at sub-10 µm resolution. We explored a novel x-ray tomosynthesis method as a way to maximise contrast-to-noise ratio, a determinant of tissue visibility. It provided a z-stack of thousands of images at 7.3 μm resolution (10% contrast, half-period of 68.5 line pairs/mm), in scans of 5-15 minutes. When compared with micro-CT scans, the straight-line tomosynthesis scan did not need to rotate the sample, which allowed flat samples, such as paraffin blocks, to be kept as close as possible to the x-ray source. Thus, given the same hardware, scan time and resolution, this mode maximised the photon flux density through the sample, which helped in maximising the contrast-to-noise ratio. The tradeoff of tomosynthesis is incomplete 3D information. The microtomosynthesis scanner has scanned 110 unstained human and animal tissue samples as part of their respective pathology protocols. In all cases, the z-stack of images showed tissue structures that guided sectioning or provided correlative structural information. We describe six examples that presented different levels of visibility of soft tissue structures. Additionally, in a set of coronary artery samples from an HIV patient donor, microtomosynthesis made a new discovery of isolated focal calcification in the internal elastic lamina of coronary wall, which was the onset of medial calcific sclerosis in the arteries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jmi.13003DOI Listing
January 2021

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

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

Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.

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

Identifying environmental risk factors and gene-environment interactions in holoprosencephaly.

Birth Defects Res 2021 Jan 28;113(1):63-76. Epub 2020 Oct 28.

Medical Genetics Branch, National Human Genome Research Institute, The National Institutes of Health, Bethesda, Maryland, USA.

Background: Holoprosencephaly is the most common malformation of the forebrain (1 in 250 embryos) with severe consequences for fetal and child development. This study evaluates nongenetic factors associated with holoprosencephaly risk, severity, and gene-environment interactions.

Methods: For this retrospective case control study, we developed an online questionnaire focusing on exposures to common and rare toxins/toxicants before and during pregnancy, nutritional factors, maternal health history, and demographic factors. Patients with holoprosencephaly were primarily ascertained from our ongoing genetic and clinical studies of holoprosencephaly. Controls included children with Williams-Beuren syndrome (WBS) ascertained through online advertisements in a WBD support group and fliers.

Results: Difference in odds of exposures between cases and controls as well as within cases with varying holoprosencephaly severity were studied. Cases included children born with holoprosencephaly (n = 92) and the control group consisted of children with WBS (n = 56). Pregnancy associated risk associated with holoprosencephaly included maternal pregestational diabetes (9.2% of cases and 0 controls, p = .02), higher alcohol consumption (adjusted odds ratio [aOR], 1.73; 95% CI, 0.88-15.71), and exposure to consumer products such as aerosols or sprays including hair sprays (aOR, 2.46; 95% CI, 0.89-7.19). Significant gene-environment interactions were identified including for consumption of cheese (p < .05) and espresso drinks (p = .03).

Conclusion: The study identifies modifiable risk factors and gene-environment interactions that should be considered in future prevention of holoprosencephaly. Studies with larger HPE cohorts will be needed to confirm these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdr2.1834DOI Listing
January 2021

Vascular Casting of Adult and Early Postnatal Mouse Lungs for Micro-CT Imaging.

J Vis Exp 2020 06 20(160). Epub 2020 Jun 20.

Translational Vascular Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health;

Blood vessels form intricate networks in 3-dimensional space. Consequently, it is difficult to visually appreciate how vascular networks interact and behave by observing the surface of a tissue. This method provides a means to visualize the complex 3-dimensional vascular architecture of the lung. To accomplish this, a catheter is inserted into the pulmonary artery and the vasculature is simultaneously flushed of blood and chemically dilated to limit resistance. Lungs are then inflated through the trachea at a standard pressure and the polymer compound is infused into the vascular bed at a standard flow rate. Once the entire arterial network is filled and allowed to cure, the lung vasculature may be visualized directly or imaged on a micro-CT (µCT) scanner. When performed successfully, one can appreciate the pulmonary arterial network in mice ranging from early postnatal ages to adults. Additionally, while demonstrated in the pulmonary arterial bed, this method can be applied to any vascular bed with optimized catheter placement and endpoints.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3791/61242DOI Listing
June 2020

Prenatal exposure to pesticides and risk for holoprosencephaly: a case-control study.

Environ Health 2020 06 8;19(1):65. Epub 2020 Jun 8.

Medical Genetics Branch, National Human Genome Research Institute, The National Institutes of Health, Bethesda, MD, USA.

Background: Pesticide exposure during susceptible windows and at certain doses are linked to numerous birth defects. Early experimental evidence suggests an association between active ingredients in pesticides and holoprosencephaly (HPE), the most common malformation of the forebrain in humans (1 in 250 embryos). No human studies to date have examined the association. This study investigated pesticides during multiple windows of exposure and fetal risk for HPE. It is hypothesized that pre-conception and early pregnancy, the time of brain development in utero, are the most critical windows of exposure.

Methods: A questionnaire was developed for this retrospective case-control study to estimate household, occupational, and environmental pesticide exposures. Four windows of exposure were considered: preconception, early, mid and late pregnancy. Cases were identified through the National Human Genome Research Institute's ongoing clinical studies of HPE. Similarly, controls were identified as children with Williams-Beuren syndrome, a genetic syndrome also characterized by congenital malformations, but etiologically unrelated to HPE. We assessed for differences in odds of exposures to pesticides between cases and controls.

Results: Findings from 91 cases and 56 controls showed an increased risk for HPE with reports of maternal exposure during pregnancy to select pesticides including personal insect repellants (adjusted odds ratio (aOR) 2.89, confidence interval (CI): 0.96-9.50) and insecticides and acaricides for pets (aOR 3.84, CI:1.04-16.32). Exposure to household pest control products during the preconception period or during pregnancy was associated with increased risk for HPE (aOR 2.60, OR: 0.84-8.68). No associations were found for occupational exposures to pesticides during pregnancy (aOR: 1.15, CI: 0.11-11.42), although exposure rates were low. Higher likelihood for HPE was also observed with residency next to an agricultural field (aOR 3.24, CI: 0.94-12.31).

Conclusions: Observational findings are consistent with experimental evidence and suggest that exposure to personal, household, and agricultural pesticides during pregnancy may increase risk for HPE. Further investigations of gene by environment interactions are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12940-020-00611-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278164PMC
June 2020

Whole exome sequencing in patients with Williams-Beuren syndrome followed by disease modeling in mice points to four novel pathways that may modify stenosis risk.

Hum Mol Genet 2020 Jul;29(12):2035-2050

Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Supravalvular aortic stenosis (SVAS) is a narrowing of the aorta caused by elastin (ELN) haploinsufficiency. SVAS severity varies among patients with Williams-Beuren syndrome (WBS), a rare disorder that removes one copy of ELN and 25-27 other genes. Twenty percent of children with WBS require one or more invasive and often risky procedures to correct the defect while 30% have no appreciable stenosis, despite sharing the same basic genetic lesion. There is no known medical therapy. Consequently, identifying genes that modify SVAS offers the potential for novel modifier-based therapeutics. To improve statistical power in our rare-disease cohort (N = 104 exomes), we utilized extreme-phenotype cohorting, functional variant filtration and pathway-based analysis. Gene set enrichment analysis of exome-wide association data identified increased adaptive immune system variant burden among genes associated with SVAS severity. Additional enrichment, using only potentially pathogenic variants known to differ in frequency between the extreme phenotype subsets, identified significant association of SVAS severity with not only immune pathway genes, but also genes involved with the extracellular matrix, G protein-coupled receptor signaling and lipid metabolism using both SKAT-O and RQTest. Complementary studies in Eln+/-; Rag1-/- mice, which lack a functional adaptive immune system, showed improvement in cardiovascular features of ELN insufficiency. Similarly, studies in mixed background Eln+/- mice confirmed that variations in genes that increase elastic fiber deposition also had positive impact on aortic caliber. By using tools to improve statistical power in combination with orthogonal analyses in mice, we detected four main pathways that contribute to SVAS risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddaa093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390938PMC
July 2020

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome.

J Clin Invest 2020 08;130(8):4167-4181

Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular Medicine Branch.

There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job's syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α-stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI135490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410079PMC
August 2020

Neuraxial dysraphism in associated syndrome due to improper mesenchymal transition.

Neurol Genet 2020 Jun 1;6(3):e414. Epub 2020 Apr 1.

National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD.

Objective: To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 () encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia.

Methods: Patients referred to our institution for evaluation of new, recurrent, and/or metastatic paragangliomas/pheochromocytoma were confirmed for gain-of-function syndrome by identification of the gain-of-function mutation in resected tumors and/or circulating leukocytes. The posterior fossa, its contents, and the spine were evaluated retrospectively on available MRI and CT images of the head and neck performed for tumor staging and restaging. The transgenic mouse model underwent Microfil vascular perfusion and subsequent intact ex vivo 14T MRI and micro-CT as well as gross dissection, histology, and immunohistochemistry to assess the role of in identified malformations.

Results: All 8 patients with gain-of-function syndrome demonstrated incidental posterior fossa malformations-one Dandy-Walker variant and 7 Chiari malformations without syringomyelia. These findings were not associated with a small posterior fossa; rather, the posterior fossa volume exceeded that of its neural contents. Seven of 8 patients demonstrated spinal dysraphism; 4 of 8 demonstrated abnormal vertebral segmentation. The mouse model similarly demonstrated features of neuraxial dysraphism, including cervical myelomeningocele and spinal dysraphism, and cerebellar tonsil displacement through the foramen magnum. Histology and immunohistochemistry demonstrated incomplete mesenchymal transition in the mutant but not the control mouse.

Conclusions: This study characterized posterior fossa and spinal malformations seen in gain-of-function syndrome and suggests that gain-of-function mutation in HIF-2α results in improper mesenchymal transition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164966PMC
June 2020

Vascular elastic fiber heterogeneity in health and disease.

Curr Opin Hematol 2020 05;27(3):190-196

Translational Vascular Medicine Branch, Laboratory of Vascular and Matrix Genetics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

Purpose Of Review: Elastin has historically been described as an amorphous protein that functions to provide recoil to tissues that stretch. However, evidence is growing that elastin's role may not be limited to biomechanics. In this minireview, we will summarize current knowledge regarding vascular elastic fibers, focusing on structural differences along the arterial tree and how those differences may influence the behavior of affiliated cells.

Recent Findings: Regional heterogeneity, including differences in elastic lamellar number, density and cell developmental origin, plays an important role in vessel health and function. These differences impact cell-cell communication, proliferation and movement. Perturbations of normal cell-matrix interactions are correlated with human diseases including aneurysm, atherosclerosis and hypertension.

Summary: Although classically described as a structural protein, recent data suggest that differences in elastin deposition along the arterial tree have important effects on heterotypic cell interactions and human disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MOH.0000000000000578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325869PMC
May 2020

Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams-Beuren syndrome.

Am J Med Genet A 2020 05 20;182(5):1008-1020. Epub 2020 Feb 20.

Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

Williams-Beuren syndrome (WBS) is a multisystem disorder caused by a hemizygous deletion on 7q11.23 encompassing 26-28 genes. An estimated 2-5% of patients have "atypical" deletions, which extend in the centromeric and/or telomeric direction from the WBS critical region. To elucidate clinical differentiators among these deletion types, we evaluated 10 individuals with atypical deletions in our cohort and 17 individuals with similarly classified deletions previously described in the literature. Larger deletions in either direction often led to more severe developmental delays, while deletions containing MAGI2 were associated with infantile spasms and seizures in patients. In addition, head size was notably smaller in those with centromeric deletions including AUTS2. Because children with atypical deletions were noted to be less socially engaged, we additionally sought to determine how atypical deletions relate to social phenotypes. Using the Social Responsiveness Scale-2, raters scored individuals with atypical deletions as having different social characteristics to those with typical WBS deletions (p = .001), with higher (more impaired) scores for social motivation (p = .005) in the atypical deletion group. In recognizing these distinctions, physicians can better identify patients, including those who may already carry a clinical or FISH WBS diagnosis, who may benefit from additional molecular evaluation, screening, and therapy. In addition to the clinical findings, we note mild endocrine findings distinct from those typically seen in WBS in several patients with telomeric deletions that included POR. Further study in additional telomeric deletion cases will be needed to confirm this observation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61522DOI Listing
May 2020

Elastic fiber ultrastructure and assembly.

Matrix Biol 2019 11 24;84:31-40. Epub 2019 Oct 24.

Department of Cell Biology and Physiology, Washington University School of Medicine, Campus Box 8228, 660 South Euclid Ave, St. Louis, MO, 63110, USA. Electronic address:

Studies over the years have described a filamentous structure to mature elastin that suggests a complicated packing arrangement of tropoelastin subunits. The currently accepted mechanism for tropoelastin assembly requires microfibrils to serve as a physical extracellular scaffold for alignment of tropoelastin monomers during and before crosslinking. However, recent evidence suggests that the initial stages of tropoelastin assembly occur within the cell or at unique assembly sites on the plasma membrane where tropoelastin self assembles to form elastin aggregates. Outside the cell, elastin aggregates transfer to growing elastic fibers in the extracellular matrix where tensional forces on microfibrils generated through cell movement help shape the growing fiber. Overall, these observations challenge the widely held idea that interaction between monomeric tropoelastin and microfibrils is a requirement for elastin assembly, and point to self-assembly of tropoelastin as a driving force in elastin maturation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.matbio.2019.10.002DOI Listing
November 2019

Mild macrocytosis in Williams-Beuren syndrome.

Eur J Med Genet 2020 Mar 14;63(3):103740. Epub 2019 Aug 14.

Frank H. Netter School of Medicine, Quinnipiac University, USA; Massachusetts General Hospital, USA; Harvard Medical School, USA. Electronic address:

Objective: To evaluate the occurrence and estimate the frequency of macrocytosis in Williams-Beuren syndrome (WBS).

Study Design: Complete blood count (CBC) data from 179 subjects with WBS aged 1-69 were collected, with common parameters assessed for trends. Z-transformed mean corpuscular volume (MCV) was compared with each laboratory's reference range as well as with control data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 data archives.

Results: Just over a third (35%) subjects had at least one recorded incidence of macrocytosis. In comparisons of CBC parameters with an expected population mean, MCV and MCH were greater than, while Hct and RDW were lower than, expected values. The distribution of erythrocyte MCV is shifted to the right in WBS compared to controls, as was the mean value. Despite this, anemia was absent, except in a single medically complex WBS subject. Though there was a paucity of data available of variables that could potentially cause an elevated MCV, no obvious etiology could be elucidated.

Conclusions: Mild macrocytosis without anemia affects a moderate subset of WBS patients, leading to a rightward shift in the MCV distribution curve. Providers encountering isolated mild macrocytosis in WBS can consider observation over further workup.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2019.103740DOI Listing
March 2020

Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes.

Bone 2019 03 15;120:354-363. Epub 2018 Nov 15.

Department of Pediatrics, Division of Medical Genetics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

LBR (Lamin B Receptor) encodes a bifunctional protein important for cholesterol biosynthesis and heterochromatin organization on the inner nuclear membrane. Pathogenic variants in LBR are associated with marked phenotypic variability, ranging from the benign Pelger-Huët anomaly to lethal Greenberg Dysplasia. We performed trio exome sequencing (ES) on two patients with atypical variants of skeletal dysplasia and their unaffected parents. Patient 1 exhibited frontal bossing, mid-face hypoplasia, short stature with rhizomelic limb shortening, and relative macrocephaly at birth. Although remained short, Patient 1 later showed spontaneous improvement in her skeletal findings. Exome sequencing revealed two novel variants in LBR, c.1504C > G (p.Arg502Gly) in exon 12 and c.1748G > T (p.Arg583Leu) in exon 14, which were inherited from her unaffected father and mother, respectively. Sterol analysis revealed an increased level of cholesta‑8,14‑dien‑3β‑ol to 2.9% of total sterols, consistent with a functional deficiency of 3β‑hydroxysterol Δ14‑reductase. Patient 2 presented at birth with short stature and marked rhizomelic limb shortening but later exhibited decreasing severity of shortening of the long bones and improvement in the radiographic skeletal abnormalities although he continued to be significantly short at age 10 years. Exome sequencing revealed that Patient 2 is homozygous for a pathogenic variant c.1534C > T (p.Arg512Trp) in exon 12 of LBR, which was inherited from his unaffected consanguineous parents. This report provides further evidence for a phenotypic spectrum of LBR-associated disorders and expands the genotypic spectrum by describing 3 novel disease-causing variants that have not been previously associated with a disease. Moreover, our data on Patient 1 demonstrate that variants throughout the gene appear to influence both the sterol reductase and nuclear functions of LBR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2018.11.006DOI Listing
March 2019

Special Therapy and Psychosocial Needs Identified in a Multidisciplinary Cancer Predisposition Syndrome Clinic.

J Pediatr Hematol Oncol 2019 03;41(2):133-136

Departments of Pediatrics, Division of Pediatric Hematology and Oncology.

Identification of patients with cancer predisposition syndromes (CPSs) can provide vital information to guide care of an existing cancer, survey for future malignancy, and counsel families. The same underlying mutation responsible for a CPS may also result in other phenotypic abnormalities amenable to therapeutic intervention. The purpose of this study was to examine patients followed in our multidisciplinary CPS clinic to determine the prevalence and scope of medical and psychosocial needs. Data from a baseline evaluation of a single-center patient registry was reviewed. Eligible patients included those with a known or suspected CPS. Over 3 years, 73 patients consented and had successful follow-up. Utilization rate of special therapies, defined as speech therapy, occupational therapy, and/or physical therapy, in the CPS population was 50.7%, significantly higher than a representative sample of children with special needs. Prevalence of 504/IEP (Individualized Education Program) utilization was 20.5%. Patients with CPSs have a high prevalence of medical and psychosocial needs beyond their risk for cancer, for which early screening for necessary interventions should be offered to maximize the patient's developmental potential. Future research is needed to further define the developmental and cognitive phenotypes of these syndromes, and to evaluate the effectiveness of subsequent interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000001251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348029PMC
March 2019

Exome sequencing of 85 Williams-Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior.

Mol Genet Genomic Med 2018 09 15;6(5):749-765. Epub 2018 Jul 15.

National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.

Background: Large, multigenic deletions at chromosome 7q11.23 result in a highly penetrant constellation of physical and behavioral symptoms known as Williams-Beuren syndrome (WS). Of particular interest is the unusual social-cognitive profile evidenced by deficits in social cognition and communication reminiscent of autism spectrum disorders (ASD) that are juxtaposed with normal or even relatively enhanced social motivation. Interestingly, duplications in the same region also result in ASD-like phenotypes as well as social phobias. Thus, the region clearly regulates human social motivation and behavior, yet the relevant gene(s) have not been definitively identified.

Method: Here, we deeply phenotyped 85 individuals with WS and used exome sequencing to analyze common and rare variation for association with the remaining variance in social behavior as assessed by the Social Responsiveness Scale.

Results: We replicated the previously reported unusual juxtaposition of behavioral symptoms in this new patient collection, but we did not find any new alleles of large effect in the targeted analysis of the remaining copy of genes in the Williams syndrome critical region. However, we report on two nominally significant SNPs in two genes that have been implicated in the cognitive and social phenotypes of Williams syndrome, BAZ1B and GTF2IRD1. Secondary discovery driven explorations focusing on known ASD genes and an exome wide scan do not highlight any variants of a large effect.

Conclusions: Whole exome sequencing of 85 individuals with WS did not support the hypothesis that there are variants of large effect within the remaining Williams syndrome critical region that contribute to the social phenotype. This deeply phenotyped and genotyped patient cohort with a defined mutation provides the opportunity for similar analyses focusing on noncoding variation and/or other phenotypic domains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160704PMC
September 2018

Williams-Beuren syndrome in diverse populations.

Am J Med Genet A 2018 05;176(5):1128-1136

Medical Genetics Branch, National Human Genome Research Institute, The National Institutes of Health, Bethesda, Maryland.

Williams-Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P-value < 0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007881PMC
May 2018

Elastin-driven genetic diseases.

Matrix Biol 2018 10 28;71-72:144-160. Epub 2018 Feb 28.

National Institutes of Health, National Heart Lung and Blood Institute, Bethesda, MD, USA. Electronic address:

Elastic fibers provide recoil to tissues that undergo repeated deformation, such as blood vessels, lungs and skin. Composed of elastin and its accessory proteins, the fibers are produced within a restricted developmental window and are stable for decades. Their eventual breakdown is associated with a loss of tissue resiliency and aging. Rare alteration of the elastin (ELN) gene produces disease by impacting protein dosage (supravalvar aortic stenosis, Williams Beuren syndrome and Williams Beuren region duplication syndrome) and protein function (autosomal dominant cutis laxa). This review highlights aspects of the elastin molecule and its assembly process that contribute to human disease and also discusses potential therapies aimed at treating diseases of elastin insufficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.matbio.2018.02.021DOI Listing
October 2018

Minoxidil improves vascular compliance, restores cerebral blood flow, and alters extracellular matrix gene expression in a model of chronic vascular stiffness.

Am J Physiol Heart Circ Physiol 2018 07 2;315(1):H18-H32. Epub 2018 Mar 2.

National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.

Increased vascular stiffness correlates with a higher risk of cardiovascular complications in aging adults. Elastin (ELN) insufficiency, as observed in patients with Williams-Beuren syndrome or with familial supravalvular aortic stenosis, also increases vascular stiffness and leads to arterial narrowing. We used Eln mice to test the hypothesis that pathologically increased vascular stiffness with concomitant arterial narrowing leads to decreased blood flow to end organs such as the brain. We also hypothesized that drugs that remodel arteries and increase lumen diameter would improve flow. To test these hypotheses, we compared carotid blood flow using ultrasound and cerebral blood flow using MRI-based arterial spin labeling in wild-type (WT) and Eln mice. We then studied how minoxidil, an ATP-sensitive K channel opener and vasodilator, affects vessel mechanics, blood flow, and gene expression. Both carotid and cerebral blood flows were lower in Eln mice than in WT mice. Treatment of Eln mice with minoxidil lowered blood pressure and reduced functional arterial stiffness to WT levels. Minoxidil also improved arterial diameter and restored carotid and cerebral blood flows in Eln mice. The beneficial effects persisted for weeks after drug removal. RNA-Seq analysis revealed differential expression of 127 extracellular matrix-related genes among the treatment groups. These results indicate that ELN insufficiency impairs end-organ perfusion, which may contribute to the increased cardiovascular risk. Minoxidil, despite lowering blood pressure, improves end-organ perfusion. Changes in matrix gene expression and persistence of treatment effects after drug withdrawal suggest arterial remodeling. Such remodeling may benefit patients with genetic or age-dependent ELN insufficiency. NEW & NOTEWORTHY Our work with a model of chronic vascular stiffness, the elastin ( Eln) mouse, shows reduced brain perfusion as measured by carotid ultrasound and MRI arterial spin labeling. Vessel caliber, functional stiffness, and blood flow improved with minoxidil. The ATP-sensitive K channel opener increased Eln gene expression and altered 126 other matrix-associated genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00683.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087770PMC
July 2018

The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results.

Genet Med 2017 09 2;19(9):1040-1048. Epub 2017 Mar 2.

Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.

Purpose: Evaluation of the clinician's role in the optimal interpretation of clinical exome sequencing (ES) results.

Methods: Retrospective chart review of the first 155 patients who underwent clinical ES in our Exome Clinic and direct interaction with the ordering geneticist to evaluate the process of interpretation of results.

Results: The most common primary indication was neurodevelopmental problems (~66%), followed by multiple congenital anomalies (~10%). Based on sequencing data, the overall diagnostic yield was 36%. After assessment by the medical geneticist, incorporation of detailed phenotypic and molecular data, and utilization of additional diagnostic modalities, the final diagnostic yield increased to 43%. Seven patients in our cohort were included in initial case series that described novel genetic syndromes, and 23% of patients were involved in subsequent research studies directly related to their results or involved in efforts to move beyond clinical ES for diagnosis. Clinical management was directly altered due to the ES findings in 12% of definitively diagnosed cases.

Conclusions: Our results emphasize the usefulness of ES, demonstrate the significant role of the medical geneticist in the diagnostic process of patients undergoing ES, and illustrate the benefits of postanalytical diagnostic work-up in solving the "diagnostic odyssey." Genet Med advance online publication 02 March 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2016.224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581723PMC
September 2017

Hypercalcemia in Patients with Williams-Beuren Syndrome.

J Pediatr 2016 Nov 26;178:254-260.e4. Epub 2016 Aug 26.

Department of Pediatrics, Washington University School of Medicine, St. Louis, MO; National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD. Electronic address:

Objective: To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome (WBS) through a multicenter retrospective study.

Study Design: Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities.

Results: On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported.

Conclusions: Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpeds.2016.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085847PMC
November 2016

Effects of Obesity and Hypertension on Pulse Wave Velocity in Children.

J Clin Hypertens (Greenwich) 2017 Mar 11;19(3):221-226. Epub 2016 Aug 11.

Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.

Pulse wave velocity (PWV) is a biomarker of arterial stiffness. Findings from prior studies are conflicting regarding the impact of obesity on PWV in children. The authors measured carotid-femoral PWV in 159 children aged 4 to 18 years, of whom 95 were healthy, 25 were obese, 15 had hypertension (HTN), and 24 were both obese and hypertensive. Mean PWV increased with age but did not differ by race or sex. In adjusted analyses in children 10 years and older (n=102), PWV was significantly higher in children with hypertension (PWV±standard deviation, 4.9±0.7 m/s), obesity (5.0±0.9 m/s), and combined obesity-hypertension (5.2±0.6 m/s) vs healthy children (4.3±0.7 m/s) (each group, P<.001 vs control). In our study, obesity and HTN both significantly and independently increased PWV, while African American children did not have a higher PWV than Caucasian children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jch.12892DOI Listing
March 2017

K(ATP) channel gain-of-function leads to increased myocardial L-type Ca(2+) current and contractility in Cantu syndrome.

Proc Natl Acad Sci U S A 2016 06 31;113(24):6773-8. Epub 2016 May 31.

Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110;

Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) KATP channel subunits. We show that patients with CS, as well as mice with constitutive (cGOF) or tamoxifen-induced (icGOF) cardiac-specific Kir6.1 GOF subunit expression, have enlarged hearts, with increased ejection fraction and increased contractility. Whole-cell voltage-clamp recordings from cGOF or icGOF ventricular myocytes (VM) show increased basal L-type Ca(2+) current (LTCC), comparable to that seen in WT VM treated with isoproterenol. Mice with vascular-specific expression (vGOF) show left ventricular dilation as well as less-markedly increased LTCC. Increased LTCC in KATP GOF models is paralleled by changes in phosphorylation of the pore-forming α1 subunit of the cardiac voltage-gated calcium channel Cav1.2 at Ser1928, suggesting enhanced protein kinase activity as a potential link between increased KATP current and CS cardiac pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1606465113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914204PMC
June 2016

Chronic antihypertensive treatment improves pulse pressure but not large artery mechanics in a mouse model of congenital vascular stiffness.

Am J Physiol Heart Circ Physiol 2015 Sep 31;309(5):H1008-16. Epub 2015 Jul 31.

Departments of Pediatrics Washington University School of Medicine, St. Louis, Missouri; and

Increased arterial stiffness is a common characteristic of humans with Williams-Beuren syndrome and mouse models of elastin insufficiency. Arterial stiffness is associated with multiple negative cardiovascular outcomes, including myocardial infarction, stroke, and sudden death. Therefore, identifying therapeutic interventions that improve arterial stiffness in response to changes in elastin levels is of vital importance. The goal of this study was to determine the effect of chronic pharmacologic therapy with different classes of antihypertensive medications on arterial stiffness in elastin insufficiency. Elastin-insufficient mice 4-6 wk of age and wild-type littermates were subcutaneously implanted with osmotic micropumps delivering a continuous dose of one of the following: vehicle, losartan, nicardipine, or propranolol for 8 wk. At the end of treatment period, arterial blood pressure and large artery compliance and remodeling were assessed. Our results show that losartan and nicardipine treatment lowered blood pressure and pulse pressure in elastin-insufficient mice. Elastin and collagen content of abdominal aortas as well as ascending aorta and carotid artery biomechanics were not affected by any of the drug treatments in either genotype. By reducing pulse pressure and shifting the working pressure range of an artery to a more compliant region of the pressure-diameter curve, antihypertensive medications may mitigate the consequences of arterial stiffness, an effect that is drug class independent. These data emphasize the importance of early recognition and long-term management of hypertension in Williams-Beuren syndrome and elastin insufficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00288.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591401PMC
September 2015

Elastin Insufficiency Predisposes Mice to Impaired Glucose Metabolism.

J Mol Genet Med 2014 Oct;8(3)

Department of Cell Biology & Physiology, Washington University in St. Louis, MO, USA.

Williams-Beuren syndrome is the consequence of a large contiguous-gene deletion on the seventh human chromosome that includes the elastin gene. Elastin is an extracellular matrix protein responsible for the cardiovascular abnormalities associated with Williams's syndrome, including hypertension and aortic stenosis. A high percentage of individuals with Williams's syndrome also have impaired glucose tolerance, independent of traditional risk factors for diabetes. Here, we show that murine adipose tissue does assemble elastic fibers; however, isolated elastin insufficiency () in mice does not independently influence glucose metabolism or tissue lipid accumulation. Similarly, isolated ApoE deficiency (), a model of hyperlipidemia and atherosclerosis, does not impair insulin sensitivity. However, ; double mutant mice exhibit notable hyperglycemia, adipocyte hypertrophy, inflammation of adipose tissue, and ectopic lipid accumulation in liver tissue. Further, ; mutants have significant impairment of insulin sensitivity by insulin tolerance testing, independent of body weight or diet, suggesting that elastin insufficiency predisposes to metabolic disease in susceptible individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4172/1747-0862.1000129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497575PMC
October 2014

Skin findings in Williams syndrome.

Am J Med Genet A 2014 Sep 11;164A(9):2217-25. Epub 2014 Jun 11.

Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri.

Previous examination in a small number of individuals with Williams syndrome (also referred to as Williams-Beuren syndrome) has shown subtly softer skin and reduced deposition of elastin, an elastic matrix protein important in tissue recoil. No quantitative information about skin elasticity in individuals with Williams syndrome is available; nor has there been a complete report of dermatologic findings in this population. To fill this knowledge gap, 94 patients with Williams syndrome aged 7-50 years were recruited as part of the skin and vascular elasticity (WS-SAVE) study. They underwent either a clinical dermatologic assessment by trained dermatologists (2010 WSA family meeting) or measurement of biomechanical properties of the skin with the DermaLab™ suction cup (2012 WSA family meeting). Clinical assessment confirmed that soft skin is common in this population (83%), as is premature graying of the hair (80% of those 20 years or older), while wrinkles (92%), and abnormal scarring (33%) were detected in larger than expected proportions. Biomechanical studies detected statistically significant differences in dP (the pressure required to lift the skin), dT (the time required to raise the skin through a prescribed gradient), VE (viscoelasticity), and E (Young's modulus) relative to matched controls. The RT (retraction time) also trended longer but was not significant. The biomechanical differences noted in these patients did not correlate with the presence of vascular defects also attributable to elastin insufficiency (vascular stiffness, hypertension, and arterial stenosis) suggesting the presence of tissue specific modifiers that modulate the impact of elastin insufficiency in each tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134746PMC
September 2014

Biomechanical properties of the skin in cutis laxa.

J Invest Dermatol 2014 Nov 20;134(11):2836-2838. Epub 2014 May 20.

Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/jid.2014.224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199921PMC
November 2014

Copy number analysis of NIPBL in a cohort of 510 patients reveals rare copy number variants and a mosaic deletion.

Mol Genet Genomic Med 2014 Mar 14;2(2):115-23. Epub 2013 Nov 14.

Department of Human Genetics, University of Chicago Chicago, Illinois.

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by growth retardation, intellectual disability, upper limb abnormalities, hirsutism, and characteristic facial features. In this study we explored the occurrence of intragenic NIPBL copy number variations (CNVs) in a cohort of 510 NIPBL sequence-negative patients with suspected CdLS. Copy number analysis was performed by custom exon-targeted oligonucleotide array-comparative genomic hybridization and/or MLPA. Whole-genome SNP array was used to further characterize rearrangements extending beyond the NIPBL gene. We identified NIPBL CNVs in 13 patients (2.5%) including one intragenic duplication and a deletion in mosaic state. Breakpoint sequences in two patients provided further evidence of a microhomology-mediated replicative mechanism as a potential predominant contributor to CNVs in NIPBL. Patients for whom clinical information was available share classical CdLS features including craniofacial and limb defects. Our experience in studying the frequency of NIBPL CNVs in the largest series of patients to date widens the mutational spectrum of NIPBL and emphasizes the clinical utility of performing NIPBL deletion/duplication analysis in patients with CdLS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960053PMC
March 2014

Clinical utility gene card for: Williams-Beuren Syndrome [7q11.23].

Eur J Hum Genet 2014 Sep 26;22(9). Epub 2014 Feb 26.

Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2014.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135419PMC
September 2014

Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency.

Am J Physiol Heart Circ Physiol 2014 Mar 10;306(5):H654-66. Epub 2014 Jan 10.

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri;

Elastin (Eln) insufficiency in mice and humans is associated with hypertension and altered structure and mechanical properties of large arteries. However, it is not known to what extent functional or structural changes in resistance arteries contribute to the elevated blood pressure that is characteristic of Eln insufficiency. Here, we investigated how Eln insufficiency affects the structure and function of the resistance vasculature. A functional profile of resistance vasculature in Eln(+/-) mice was generated by assessing small mesenteric artery (MA) contractile and vasodilatory responses to vasoactive agents. We found that Eln haploinsufficiency had a modest effect on phenylephrine-induced vasoconstriction, whereas ANG II-evoked vasoconstriction was markedly increased. Blockade of ANG II type 2 receptors with PD-123319 or modulation of Rho kinase activity with the inhibitor Y-27632 attenuated the augmented vasoconstriction, whereas acute Y-27632 administration normalized blood pressure in Eln(+/-) mice. Sodium nitroprusside- and isoproterenol-induced vasodilatation were normal, whereas ACh-induced vasodilatation was severely impaired in Eln(+/-) MAs. Histologically, the number of smooth muscle layers did not change in Eln(+/-) MAs; however, an additional discontinuous layer of Eln appeared between the smooth muscle layers that was absent in wild-type arteries. We conclude that high blood pressure arising from Eln insufficiency is due partly to permanent changes in vascular tone as a result of increased sensitivity of the resistance vasculature to circulating ANG II and to impaired vasodilatory mechanisms arising from endothelial dysfunction characterized by impaired endothelium-dependent vasodilatation. Eln insufficiency causes augmented ANG II-induced vasoconstriction in part through a novel mechanism that facilitates contraction evoked by ANG II type 2 receptors and altered G protein signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00601.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949062PMC
March 2014