Cheryl Maslen - Academia.edu (original) (raw)
Papers by Cheryl Maslen
Advances in experimental medicine and biology, 2024
Genomics, Oct 1, 1991
Fibrillin (FBN), a large extracellular matrix glycoprotein, is an important component of structur... more Fibrillin (FBN), a large extracellular matrix glycoprotein, is an important component of structures called microfibrils. Because fibrillin microfibrils appear to be abnormal in patients with the Marfan syndrome, fibrillin is a candidate for the gene defect in the Marfan syndrome. Derived clones from fibrillin cDNA were used as probes in isotopic and nonisotopic in situ hybridization studies to map the chromosomal location of the fibrillin gene. Fluorescent signals were found on chromosome 15 band q21.1; an excess of silver grains was noted over a similar region of chromosome 15 following in situ hybridization with a tritium-labeled probe. These results are consistent with linkage studies that localize the Marfan gene to chromosome 15.
Nature, Jul 1, 1991
Fibrillin is a large (relative molecular mass 350,000) glycoprotein which can be isolated from fi... more Fibrillin is a large (relative molecular mass 350,000) glycoprotein which can be isolated from fibroblast cell cultures and is a component of the microfibrils that are ubiquitous in the connective tissue space. The microfibrils of the suspensory ligament of the lens as well as the elastic fibre microfibrils of the blood vessel wall are composed of fibrillin. The ocular and cardiovascular manifestations of the Marfan syndrome are consistent with a defect in the gene coding for a structural constituent of these connective tissues. Immunohistological experiments have recently implicated fibrillin microfibrils in the pathogenesis of the Marfan syndrome. Genetic linkage data localizing the Marfan gene to chromosome 15 and the in situ hybridization of fibrillin complementary DNA to 15q21.1 together support fibrillin as a candidate Marfan gene. As a first step towards investigating the function of fibrillin in the architecture and development of connective tissues and its relationship to the Marfan syndrome, we report the cloning and partial sequencing of fibrillin cDNA.
American Journal of Human Genetics, Sep 1, 1994
Journal of the American College of Cardiology, May 1, 2022
American Journal of Medical Genetics, Jun 27, 2012
Genetics in Medicine, 2014
The published version of this article did not include complete acknowledgement information for th... more The published version of this article did not include complete acknowledgement information for the dbGAP datasets that were analyzed. The Data Use Agreements for these datasets stipulate that these acknowledgments must include the NIH GWAS Data Repository, contributing investigator(s) and primary funding organization(s). The following statements should therefore appear in the
Journal of the American College of Cardiology, Apr 1, 2011
Background: Bicuspid aortic valve (BAV) is the most common adult congenital abnormality and is se... more Background: Bicuspid aortic valve (BAV) is the most common adult congenital abnormality and is seen in 1-2% of the population. These patients (pts) often have an associated aortopathy which increases their risk of aortic complications such as dissection (AoD). Identification of factors associated with risk of AoD is important in BAV pt management. We sought to address the hypothesis that pts with BAV and AoD have identifiable characteristics that predispose them to AoD. Methods: The GENTAC registry was queried for all patients with BAV. Those with AoD and BAV (+AoD) were compared to BAV pts without AoD (-AoD). Demographic, clinical, imaging and genetic data were assessed for differences between the 2 groups. No BAV pts were excluded. Results: Overall, 579 pts with BAV were assessed; mean age of 44.8+19.6 years (yrs) and 75.5% male. The 25 (4.3%) +AoD pts were older than-AoD pts (52.7+11.6 yrs vs. 44.4+19.9 yrs, p=0.003). Gender distribution was similar between groups (72.0% male in +AoD vs. 75.7% male in-AoD). All +AoD pts were identified after AoD had occurred. Surgery was performed in 14 of 25 +AoD pts (52%) for complications related to AoD. When identified, the site of the primary tear was in the root or ascending aorta. Identified family history of BAV or AoD was not different between groups (3/25 pts (12%) with +AoD vs. 51/524 (11.8%) of-AoD pts, p=1.0). Aortic insufficiency severity was most often mild and not different between groups. Sinus of Valsalva measurements were not different between groups (3.6+0.9cm in +AoD vs. 4.3+2.0cm in-AoD, p=0.20). Conclusions: In pts with BAV, + AoD had a tendency to be older than-AoD pts. Otherwise these groups were similar in regard to clinical, imaging or genetic variables. Individual risk assessment for AoD in pts with BAV requires further study.
Journal of the American College of Cardiology, Mar 1, 2010
![Research paper thumbnail of Phage 8–9 defines a cluster of site polymorphisms on chromosome 16q22-q24 [HGM9 no. D16S20]](https://attachments.academia-assets.com/115053175/thumbnails/1.jpg)
](Nucleic Acids Research, 1988
SOURCE AND DESCRIPTION OF CLONE: Phage 8-9 was isolated from a genomic library of a mouse x human... more SOURCE AND DESCRIPTION OF CLONE: Phage 8-9 was isolated from a genomic library of a mouse x human somatic cell hybrid (CF-52) containing an 1 1 q-1 6q translocation as the only human chromosome. A 17 kb partial Sau 3A fragment was cloned in the BamHI site of EMBL3. POLYMORPHISMS: Sac I identifies constant bands at 4.1, 2.3 and 1.3 kb and two 2-allele RFLPs with A1=10, A2=7.4 +2.6 kb and B1=2.9, B2=1 .9+1.0 kb. Bgl 11 identifies a constant band of 8 kb and a 3-allele RFLP with C1>20, C2=14 and C3=8.5 +5.2 kb. Pvu 11 identifies 8 constant bands <3.5 kb and a 2-allele RFLP with Dl = 6.5, D2=5.8+0.7 kb. FREQUENCIES: Studied at least 34 European Caucasians. A1=.43, A2=.57; Bi =.26, B2=.74; Cl =.03, C2=.71, C3=.29; Dl =.32, D2=.68. CHROMOSOMAL LOCALIZATION: 16q22-q24, by in situ hybridization. Localized approx. 7 cM distal to CTRB on CEPH linkage map of chromosome 16. MENDELIAN INHERITANCE: Codominant inheritance has been shown at each of the four loci in at least 2 informative families with a total of at least 13 children. PROBE AVAILABILITY: Will be available from ATCC. OTHER COMMENTS: The probe must be prehybridized with excess human DNA to compete out hybridization of repeated sequences. Of 36 unrelated individuals typed at loci A, B and D, 31 (86%) were heterozygous at one or more of the 3 loci. Dl 6S20 is also polymorphic with Pst 1, Bgl 1,
British Journal of Surgery, Aug 9, 2021
Background: Population-wide ultrasound screening programmes for abdominal aortic aneurysm (AAA) f... more Background: Population-wide ultrasound screening programmes for abdominal aortic aneurysm (AAA) for men have already been established in some countries. Women account for one third of aneurysm-related mortality and are four times more likely to experience an AAA rupture than men. Whole-population screening for AAA in women is unlikely to be clinically or economically effective. The aim of this study was to determine the outcomes of a targeted AAA screening programme for women at high risk of AAA. Method: Women aged 65-74 years deemed at high risk of having an AAA (current smokers, ex-smokers, or with a history of coronary artery disease) were invited to attend ultrasound screening (July 2016 to March 2019) for AAA in the Female Aneurysm screening STudy (FAST). Primary outcomes were attendance for screening and prevalence of AAA. Biometric data, medical history, quality of life (QoL) and aortic diameter on ultrasound imaging were recorded prospectively. Results: Some 6037 women were invited and 5200 attended screening (86.7 per cent). Fifteen AAAs larger than 29 mm were detected (prevalence 0.29 (95 per cent c.i. 0.18 to 0.48) per cent). Current smokers had the highest prevalence (0.83 (95 per cent c.i. 0.34 to 1.89) per cent) but lowest attendance (75.2 per cent). Three AAAs greater than 5.5 cm were identified and referred for consideration of surgical repair; one woman underwent repair. There was a significant reduction in patient-reported QoL scores following screening. Conclusion: A low prevalence of AAA was detected in high-risk women, with lowest screening uptake in those at highest risk. Screening for AAA in high-risk women may not be beneficial.
Ultrasound in Obstetrics & Gynecology, Oct 1, 2002
Congenital contractural arachnodactyly (CCA) or Beals–Hecht syndrome is an autosomal dominant dis... more Congenital contractural arachnodactyly (CCA) or Beals–Hecht syndrome is an autosomal dominant disorder caused by mutations in the fibrillin‐2 (FBN2) gene. The principal features of CCA are a marfanoid habitus, multiple congenital contractures, camptodactyly, arachnodactyly, kyphoscoliosis, muscular hypoplasia, and external ear malformations.Our case is the first that shows typical sonographic signs in a fetus at 25 weeks' gestation with molecular genetically verified CCA in a large family with many members affected over four generations. This demonstrates that CCA can be detected prenatally by non‐invasive ultrasonography. The importance of confirmation of CCA by means of DNA sequence analysis of the FBN2 gene is stressed. Copyright © 2002 International Society of Ultrasound in Obstetrics and Gynecology
PLOS Genetics, Oct 3, 2018
Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in~... more Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10 −7), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91-178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57-99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.
Circulation, May 12, 1998
Background-Controversy exists as to whether the deletion/deletion genotype (DD) of the ACE gene p... more Background-Controversy exists as to whether the deletion/deletion genotype (DD) of the ACE gene polymorphism increases the risk of myocardial infarction (MI). Studies have suggested that the ACE DD genotype is associated with increased plaque instability. We hypothesized that the ACE DD genotype may increase the risk of myocardial infarction and coronary heart disease (CHD) in patients with heterozygous familial hypercholesterolemia (FH) or familial defective apolipoprotein B-100 (FDB) who, as a group, are at high risk of having lipid-rich plaques in their coronary arteries. Methods and Results-We determined the ACE genotypes and incidence of MI or surgical intervention for CHD in 213 adult patients with heterozygous FH or FDB. The incidence of MI in 35 male patients who carried the ACE DD genotype was 2.5 times that observed in male patients with the II or DI genotypes, and the incidence of CHD in male patients with the DD genotype was 2.2 times higher than in those who had ACE DIϩII. The potential effects of ACE genotype on CHD could not be directly compared in female patients because of a disparity in the smoking history of the genotypic groups. From logistic regression analysis, the estimated odds ratio associated with the ACE DD genotype was 2.57 for MI and 2.21 for CHD adjusted for age, sex, and smoking history. Conclusions-The ACE DD genotype is associated with an increased risk of MI and CHD in patients with heterozygous FH or FDB. Determination of the ACE genotype in asymptomatic FH and FDB patients provides an additional means to identify those patients at greatest risk for the premature development of CHD.
American Journal of Medical Genetics, 2006
Acta Biomaterialia, 2012
The development of vascular grafts has focused on finding a biomaterial that is non-thrombogenic,... more The development of vascular grafts has focused on finding a biomaterial that is non-thrombogenic, minimizes intimal hyperplasia, matches the mechanical properties of native vessels and allows for regeneration of arterial tissue. In this study, the structural and mechanical properties and the vascular cell compatibility of electrospun recombinant human tropoelastin (rTE) were evaluated as a potential vascular graft support matrix. Disuccinimidyl suberate (DSS) was used to cross-link electrospun rTE fibers to produce a polymeric recombinant tropoelastin (prTE) matrix that is stable in aqueous environments. Tubular 1 cm diameter prTE samples were constructed for uniaxial tensile testing and 4 mm small-diameter prTE tubular scaffolds were produced for burst pressure and cell compatibility evaluations from 15 wt% rTE solutions. Uniaxial tensile tests demonstrated an average ultimate tensile strength (UTS) of 0.36±0.05 MPa and elastic moduli of 0.15±0.04 MPa and 0.91±0.16 MPa, which were comparable to extracted native elastin. Burst pressures of 485 ± 25 mmHg were obtained from 4 mm ID scaffolds with 453 ± 74 μm average wall thickness. prTE supported endothelial cell growth with typical endothelial cell cobblestone morphology after 48 hours in culture. Cross-linked electrospun recombinant human tropoelastin has promising properties for utilization as a vascular graft biomaterial with customizable dimensions, a compliant matrix, and vascular cell compatibility.
![Research paper thumbnail of Phage 8–10 identifies an RFLP on 11q23-qter [HGM9 no. D11S286]](https://attachments.academia-assets.com/115053168/thumbnails/1.jpg)
](Nucleic Acids Research, 1988
SOURCE AND DESCRIPTION OF CLONE. *8-10 was isolated from a genomic library of a mouse/human somat... more SOURCE AND DESCRIPTION OF CLONE. *8-10 was isolated from a genomic library of a mouse/human somatic cell hybrid containing an 1 Iq-I6q translocation as the only human chromosome. The 15 kb partial Sau3A human insert was cloned into the BamHI site of EMBL-3. POLYMORPHISMS: BamHI ldentifles a constant fragment of 7.3 kb and a 2-allele RFLP with Al=8.8A A2=8.0 kb. FREQUENCIES: Studied 29 European Caucasians. Al =.33, A2=.67 NOT POLYMORPHIC WITH: MspI, Sacl, Pvull, BglII, Rsal CHROMOSOMAL LOCALIZATION: Probe localized to I Iq23-qter by use of somatic cell hybrid panel. MENDELIAN INHERITANCE: Codominant inheritance has been shown In four Utah reference families wlth a total of 32 children. AVAILABILITY: Will be available from ATCC. OTHER COMMENTS: The probe contains repetitive sequences and must be prehybridized with total human DNA. REFERENCE: C. Maslen et al (1988) Genomics, In press.
Endocrinologist, Jul 1, 1993
Molecular Genetics and Metabolism, Sep 1, 2004
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol metabolism ch... more Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol metabolism characterized by multiple congenital anomalies and mental retardation. SLOS results from mutations in 7-dehydrocholesterol D 7 reductase (DHCR7), the gene encoding the final enzyme involved in cholesterol biosynthesis. The resulting cholesterol deficiency and excessive 7-and 8-dehydrocholesterol (7-DHC, 8-DHC) in plasma and tissues are almost always diagnostic for SLOS. We measured DHCR7 activity in fibroblasts, amniocytes, and chorionic villi from controls, heterozygotes, and SLOS subjects. The enzyme activity (expressed as percent conversion of substrate) was significantly lower in untransformed fibroblasts from SLOS subjects (4.47% ± 0.72) compared to untransformed fibroblasts from heterozygotes (26.6% ± 4.6, p < 0.01) or controls (50.6% ± 5.3, p < 0.001). We also measured plasma cholesterol and 7-DHC, determined the severity score and identified DHCR7 mutations for most of the subjects. There was no significant correlation of enzyme activity with severity score, plasma cholesterol level, plasma 7-DHC level, or the 7-DHC:cholesterol ratio. We conclude that even though enzyme activity as measured by the ergosterol assay may not correlate with severity, this assay has the potential to distinguish SLOS cells from carrier or unaffected cells in a variety of cell types, and should prove useful in confirming a diagnosis in atypical cases where sterol levels are equivocal. Additionally, it may be important to measure residual enzyme activity in SLOS subjects being considered for a trial of statins, as this treatment could theoretically be detrimental in subjects with little or no DHCR7 activity. Finally, the data suggest a threshold enzyme activity of 8% conversion, below which disease occurs.
DNA and Cell Biology, Sep 1, 1993
The Marfan syndrome is an inherited, autosomal dominant disorder that affects the skeletal, ocula... more The Marfan syndrome is an inherited, autosomal dominant disorder that affects the skeletal, ocular, and cardiovascular systems. Recent biochemical and genetic studies have demonstrated that this deadly genetic disorder arises from defects in the connective tissue protein fibrillin. Fibrillin is a component of microfibrils, structures found in the extracellular matrices of most tissues, including those affected in Marfan patients. The appearance of microfibrils in the matrix produced by Marfan patient fibroblasts is different from that of normal cells. Genetic linkage between the fibrillin gene and the Marfan phenotype has been established and the gene mapped to the same chromosomal position as the disease locus. In several instances, the disease has been associated with mutations in the fibrillin gene, confirming that defects in fibrillin cause the Marfan syndrome.
Advances in experimental medicine and biology, 2024
Genomics, Oct 1, 1991
Fibrillin (FBN), a large extracellular matrix glycoprotein, is an important component of structur... more Fibrillin (FBN), a large extracellular matrix glycoprotein, is an important component of structures called microfibrils. Because fibrillin microfibrils appear to be abnormal in patients with the Marfan syndrome, fibrillin is a candidate for the gene defect in the Marfan syndrome. Derived clones from fibrillin cDNA were used as probes in isotopic and nonisotopic in situ hybridization studies to map the chromosomal location of the fibrillin gene. Fluorescent signals were found on chromosome 15 band q21.1; an excess of silver grains was noted over a similar region of chromosome 15 following in situ hybridization with a tritium-labeled probe. These results are consistent with linkage studies that localize the Marfan gene to chromosome 15.
Nature, Jul 1, 1991
Fibrillin is a large (relative molecular mass 350,000) glycoprotein which can be isolated from fi... more Fibrillin is a large (relative molecular mass 350,000) glycoprotein which can be isolated from fibroblast cell cultures and is a component of the microfibrils that are ubiquitous in the connective tissue space. The microfibrils of the suspensory ligament of the lens as well as the elastic fibre microfibrils of the blood vessel wall are composed of fibrillin. The ocular and cardiovascular manifestations of the Marfan syndrome are consistent with a defect in the gene coding for a structural constituent of these connective tissues. Immunohistological experiments have recently implicated fibrillin microfibrils in the pathogenesis of the Marfan syndrome. Genetic linkage data localizing the Marfan gene to chromosome 15 and the in situ hybridization of fibrillin complementary DNA to 15q21.1 together support fibrillin as a candidate Marfan gene. As a first step towards investigating the function of fibrillin in the architecture and development of connective tissues and its relationship to the Marfan syndrome, we report the cloning and partial sequencing of fibrillin cDNA.
American Journal of Human Genetics, Sep 1, 1994
Journal of the American College of Cardiology, May 1, 2022
American Journal of Medical Genetics, Jun 27, 2012
Genetics in Medicine, 2014
The published version of this article did not include complete acknowledgement information for th... more The published version of this article did not include complete acknowledgement information for the dbGAP datasets that were analyzed. The Data Use Agreements for these datasets stipulate that these acknowledgments must include the NIH GWAS Data Repository, contributing investigator(s) and primary funding organization(s). The following statements should therefore appear in the
Journal of the American College of Cardiology, Apr 1, 2011
Background: Bicuspid aortic valve (BAV) is the most common adult congenital abnormality and is se... more Background: Bicuspid aortic valve (BAV) is the most common adult congenital abnormality and is seen in 1-2% of the population. These patients (pts) often have an associated aortopathy which increases their risk of aortic complications such as dissection (AoD). Identification of factors associated with risk of AoD is important in BAV pt management. We sought to address the hypothesis that pts with BAV and AoD have identifiable characteristics that predispose them to AoD. Methods: The GENTAC registry was queried for all patients with BAV. Those with AoD and BAV (+AoD) were compared to BAV pts without AoD (-AoD). Demographic, clinical, imaging and genetic data were assessed for differences between the 2 groups. No BAV pts were excluded. Results: Overall, 579 pts with BAV were assessed; mean age of 44.8+19.6 years (yrs) and 75.5% male. The 25 (4.3%) +AoD pts were older than-AoD pts (52.7+11.6 yrs vs. 44.4+19.9 yrs, p=0.003). Gender distribution was similar between groups (72.0% male in +AoD vs. 75.7% male in-AoD). All +AoD pts were identified after AoD had occurred. Surgery was performed in 14 of 25 +AoD pts (52%) for complications related to AoD. When identified, the site of the primary tear was in the root or ascending aorta. Identified family history of BAV or AoD was not different between groups (3/25 pts (12%) with +AoD vs. 51/524 (11.8%) of-AoD pts, p=1.0). Aortic insufficiency severity was most often mild and not different between groups. Sinus of Valsalva measurements were not different between groups (3.6+0.9cm in +AoD vs. 4.3+2.0cm in-AoD, p=0.20). Conclusions: In pts with BAV, + AoD had a tendency to be older than-AoD pts. Otherwise these groups were similar in regard to clinical, imaging or genetic variables. Individual risk assessment for AoD in pts with BAV requires further study.
Journal of the American College of Cardiology, Mar 1, 2010
Nucleic Acids Research, 1988
SOURCE AND DESCRIPTION OF CLONE: Phage 8-9 was isolated from a genomic library of a mouse x human... more SOURCE AND DESCRIPTION OF CLONE: Phage 8-9 was isolated from a genomic library of a mouse x human somatic cell hybrid (CF-52) containing an 1 1 q-1 6q translocation as the only human chromosome. A 17 kb partial Sau 3A fragment was cloned in the BamHI site of EMBL3. POLYMORPHISMS: Sac I identifies constant bands at 4.1, 2.3 and 1.3 kb and two 2-allele RFLPs with A1=10, A2=7.4 +2.6 kb and B1=2.9, B2=1 .9+1.0 kb. Bgl 11 identifies a constant band of 8 kb and a 3-allele RFLP with C1>20, C2=14 and C3=8.5 +5.2 kb. Pvu 11 identifies 8 constant bands <3.5 kb and a 2-allele RFLP with Dl = 6.5, D2=5.8+0.7 kb. FREQUENCIES: Studied at least 34 European Caucasians. A1=.43, A2=.57; Bi =.26, B2=.74; Cl =.03, C2=.71, C3=.29; Dl =.32, D2=.68. CHROMOSOMAL LOCALIZATION: 16q22-q24, by in situ hybridization. Localized approx. 7 cM distal to CTRB on CEPH linkage map of chromosome 16. MENDELIAN INHERITANCE: Codominant inheritance has been shown at each of the four loci in at least 2 informative families with a total of at least 13 children. PROBE AVAILABILITY: Will be available from ATCC. OTHER COMMENTS: The probe must be prehybridized with excess human DNA to compete out hybridization of repeated sequences. Of 36 unrelated individuals typed at loci A, B and D, 31 (86%) were heterozygous at one or more of the 3 loci. Dl 6S20 is also polymorphic with Pst 1, Bgl 1,
British Journal of Surgery, Aug 9, 2021
Background: Population-wide ultrasound screening programmes for abdominal aortic aneurysm (AAA) f... more Background: Population-wide ultrasound screening programmes for abdominal aortic aneurysm (AAA) for men have already been established in some countries. Women account for one third of aneurysm-related mortality and are four times more likely to experience an AAA rupture than men. Whole-population screening for AAA in women is unlikely to be clinically or economically effective. The aim of this study was to determine the outcomes of a targeted AAA screening programme for women at high risk of AAA. Method: Women aged 65-74 years deemed at high risk of having an AAA (current smokers, ex-smokers, or with a history of coronary artery disease) were invited to attend ultrasound screening (July 2016 to March 2019) for AAA in the Female Aneurysm screening STudy (FAST). Primary outcomes were attendance for screening and prevalence of AAA. Biometric data, medical history, quality of life (QoL) and aortic diameter on ultrasound imaging were recorded prospectively. Results: Some 6037 women were invited and 5200 attended screening (86.7 per cent). Fifteen AAAs larger than 29 mm were detected (prevalence 0.29 (95 per cent c.i. 0.18 to 0.48) per cent). Current smokers had the highest prevalence (0.83 (95 per cent c.i. 0.34 to 1.89) per cent) but lowest attendance (75.2 per cent). Three AAAs greater than 5.5 cm were identified and referred for consideration of surgical repair; one woman underwent repair. There was a significant reduction in patient-reported QoL scores following screening. Conclusion: A low prevalence of AAA was detected in high-risk women, with lowest screening uptake in those at highest risk. Screening for AAA in high-risk women may not be beneficial.
Ultrasound in Obstetrics & Gynecology, Oct 1, 2002
Congenital contractural arachnodactyly (CCA) or Beals–Hecht syndrome is an autosomal dominant dis... more Congenital contractural arachnodactyly (CCA) or Beals–Hecht syndrome is an autosomal dominant disorder caused by mutations in the fibrillin‐2 (FBN2) gene. The principal features of CCA are a marfanoid habitus, multiple congenital contractures, camptodactyly, arachnodactyly, kyphoscoliosis, muscular hypoplasia, and external ear malformations.Our case is the first that shows typical sonographic signs in a fetus at 25 weeks' gestation with molecular genetically verified CCA in a large family with many members affected over four generations. This demonstrates that CCA can be detected prenatally by non‐invasive ultrasonography. The importance of confirmation of CCA by means of DNA sequence analysis of the FBN2 gene is stressed. Copyright © 2002 International Society of Ultrasound in Obstetrics and Gynecology
PLOS Genetics, Oct 3, 2018
Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in~... more Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10 −7), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91-178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57-99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.
Circulation, May 12, 1998
Background-Controversy exists as to whether the deletion/deletion genotype (DD) of the ACE gene p... more Background-Controversy exists as to whether the deletion/deletion genotype (DD) of the ACE gene polymorphism increases the risk of myocardial infarction (MI). Studies have suggested that the ACE DD genotype is associated with increased plaque instability. We hypothesized that the ACE DD genotype may increase the risk of myocardial infarction and coronary heart disease (CHD) in patients with heterozygous familial hypercholesterolemia (FH) or familial defective apolipoprotein B-100 (FDB) who, as a group, are at high risk of having lipid-rich plaques in their coronary arteries. Methods and Results-We determined the ACE genotypes and incidence of MI or surgical intervention for CHD in 213 adult patients with heterozygous FH or FDB. The incidence of MI in 35 male patients who carried the ACE DD genotype was 2.5 times that observed in male patients with the II or DI genotypes, and the incidence of CHD in male patients with the DD genotype was 2.2 times higher than in those who had ACE DIϩII. The potential effects of ACE genotype on CHD could not be directly compared in female patients because of a disparity in the smoking history of the genotypic groups. From logistic regression analysis, the estimated odds ratio associated with the ACE DD genotype was 2.57 for MI and 2.21 for CHD adjusted for age, sex, and smoking history. Conclusions-The ACE DD genotype is associated with an increased risk of MI and CHD in patients with heterozygous FH or FDB. Determination of the ACE genotype in asymptomatic FH and FDB patients provides an additional means to identify those patients at greatest risk for the premature development of CHD.
American Journal of Medical Genetics, 2006
Acta Biomaterialia, 2012
The development of vascular grafts has focused on finding a biomaterial that is non-thrombogenic,... more The development of vascular grafts has focused on finding a biomaterial that is non-thrombogenic, minimizes intimal hyperplasia, matches the mechanical properties of native vessels and allows for regeneration of arterial tissue. In this study, the structural and mechanical properties and the vascular cell compatibility of electrospun recombinant human tropoelastin (rTE) were evaluated as a potential vascular graft support matrix. Disuccinimidyl suberate (DSS) was used to cross-link electrospun rTE fibers to produce a polymeric recombinant tropoelastin (prTE) matrix that is stable in aqueous environments. Tubular 1 cm diameter prTE samples were constructed for uniaxial tensile testing and 4 mm small-diameter prTE tubular scaffolds were produced for burst pressure and cell compatibility evaluations from 15 wt% rTE solutions. Uniaxial tensile tests demonstrated an average ultimate tensile strength (UTS) of 0.36±0.05 MPa and elastic moduli of 0.15±0.04 MPa and 0.91±0.16 MPa, which were comparable to extracted native elastin. Burst pressures of 485 ± 25 mmHg were obtained from 4 mm ID scaffolds with 453 ± 74 μm average wall thickness. prTE supported endothelial cell growth with typical endothelial cell cobblestone morphology after 48 hours in culture. Cross-linked electrospun recombinant human tropoelastin has promising properties for utilization as a vascular graft biomaterial with customizable dimensions, a compliant matrix, and vascular cell compatibility.
Nucleic Acids Research, 1988
SOURCE AND DESCRIPTION OF CLONE. *8-10 was isolated from a genomic library of a mouse/human somat... more SOURCE AND DESCRIPTION OF CLONE. *8-10 was isolated from a genomic library of a mouse/human somatic cell hybrid containing an 1 Iq-I6q translocation as the only human chromosome. The 15 kb partial Sau3A human insert was cloned into the BamHI site of EMBL-3. POLYMORPHISMS: BamHI ldentifles a constant fragment of 7.3 kb and a 2-allele RFLP with Al=8.8A A2=8.0 kb. FREQUENCIES: Studied 29 European Caucasians. Al =.33, A2=.67 NOT POLYMORPHIC WITH: MspI, Sacl, Pvull, BglII, Rsal CHROMOSOMAL LOCALIZATION: Probe localized to I Iq23-qter by use of somatic cell hybrid panel. MENDELIAN INHERITANCE: Codominant inheritance has been shown In four Utah reference families wlth a total of 32 children. AVAILABILITY: Will be available from ATCC. OTHER COMMENTS: The probe contains repetitive sequences and must be prehybridized with total human DNA. REFERENCE: C. Maslen et al (1988) Genomics, In press.
Endocrinologist, Jul 1, 1993
Molecular Genetics and Metabolism, Sep 1, 2004
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol metabolism ch... more Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol metabolism characterized by multiple congenital anomalies and mental retardation. SLOS results from mutations in 7-dehydrocholesterol D 7 reductase (DHCR7), the gene encoding the final enzyme involved in cholesterol biosynthesis. The resulting cholesterol deficiency and excessive 7-and 8-dehydrocholesterol (7-DHC, 8-DHC) in plasma and tissues are almost always diagnostic for SLOS. We measured DHCR7 activity in fibroblasts, amniocytes, and chorionic villi from controls, heterozygotes, and SLOS subjects. The enzyme activity (expressed as percent conversion of substrate) was significantly lower in untransformed fibroblasts from SLOS subjects (4.47% ± 0.72) compared to untransformed fibroblasts from heterozygotes (26.6% ± 4.6, p < 0.01) or controls (50.6% ± 5.3, p < 0.001). We also measured plasma cholesterol and 7-DHC, determined the severity score and identified DHCR7 mutations for most of the subjects. There was no significant correlation of enzyme activity with severity score, plasma cholesterol level, plasma 7-DHC level, or the 7-DHC:cholesterol ratio. We conclude that even though enzyme activity as measured by the ergosterol assay may not correlate with severity, this assay has the potential to distinguish SLOS cells from carrier or unaffected cells in a variety of cell types, and should prove useful in confirming a diagnosis in atypical cases where sterol levels are equivocal. Additionally, it may be important to measure residual enzyme activity in SLOS subjects being considered for a trial of statins, as this treatment could theoretically be detrimental in subjects with little or no DHCR7 activity. Finally, the data suggest a threshold enzyme activity of 8% conversion, below which disease occurs.
DNA and Cell Biology, Sep 1, 1993
The Marfan syndrome is an inherited, autosomal dominant disorder that affects the skeletal, ocula... more The Marfan syndrome is an inherited, autosomal dominant disorder that affects the skeletal, ocular, and cardiovascular systems. Recent biochemical and genetic studies have demonstrated that this deadly genetic disorder arises from defects in the connective tissue protein fibrillin. Fibrillin is a component of microfibrils, structures found in the extracellular matrices of most tissues, including those affected in Marfan patients. The appearance of microfibrils in the matrix produced by Marfan patient fibroblasts is different from that of normal cells. Genetic linkage between the fibrillin gene and the Marfan phenotype has been established and the gene mapped to the same chromosomal position as the disease locus. In several instances, the disease has been associated with mutations in the fibrillin gene, confirming that defects in fibrillin cause the Marfan syndrome.