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Biomedical subjects

Harry C Dietz

Publications and source records attributed to Harry C Dietz.

At least 19 recordsLinked to original sources
PubMed2007

Symposium on the musculoskeletal aspects of Marfan syndrome: meeting report and state of the science.

The National Marfan Foundation sponsored a symposium in August 2005 to review recent progress in the area of Marfan-related musculoskeletal research. Orthopaedic surgeons, molecular geneticists, medical geneticists, and pain specialists met to review a variety of topics. This report reviews and summarizes the proceedings of the symposium, with emphasis on future directions for study that were identified in the course of the meeting. Areas covered include clinical detection, diagnosis, growth, spine deformity, molecular mechanisms, dural ectasia, protrusio acetabuli, and pain in Marfan syndrome.

Acetabulum↗
PubMed2006

Induction of macrophage chemotaxis by aortic extracts of the mgR Marfan mouse model and a GxxPG-containing fibrillin-1 fragment.

BACKGROUND: The primary cause of early death in untreated Marfan syndrome (MFS) patients is aortic dilatation and dissection. METHODS AND RESULTS: We investigated whether ascending aortic samples from the fibrillin-1-underexpressing mgR mouse model for MFS or a recombinant fibrillin-1 fragment containing an elastin-binding protein (EBP) recognition sequence can act as chemotactic stimuli for macrophages. Both the aortic extracts from the mgR/mgR mice and the fibrillin-1 fragment significantly increased macrophage chemotaxis compared with extracts from wild-type mice or buffer controls. The chemotactic response was significantly diminished by pretreatment of macrophages with lactose or with the elastin-derived peptide VGVAPG and by pretreatment of samples with a monoclonal antibody directed against an EBP recognition sequence. Mutation of the EBP recognition sequence in the fibrillin-1 fragment also abolished the chemotactic response. These results indicate the involvement of EBP in mediating the effects. Additionally, investigation of macrophages in aortic specimens of MFS patients demonstrated macrophage infiltration in the tunica media. CONCLUSIONS: Our findings demonstrate that aortic extracts from mgR/mgR mice can stimulate macrophage chemotaxis by interaction with EBP and show that a fibrillin-1 fragment possesses chemotactic stimulatory activity similar to that of elastin degradation peptides. They provide a plausible molecular mechanism for the inflammatory infiltrates observed in the mgR mouse model and suggest that inflammation may represent a component of the complex pathogenesis of MFS.

Animals↗
PubMed2006

Aneurysm syndromes caused by mutations in the TGF-beta receptor.

BACKGROUND: The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively). METHODS: We undertook the clinical and molecular characterization of 52 affected families. Forty probands presented with typical manifestations of the Loeys-Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers-Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers-Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys-Dietz syndrome. RESULTS: We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys-Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys-Dietz syndrome type I, as compared with those with type II, underwent cardiovascular surgery earlier (mean age, 16.9 years vs. 26.9 years) and died earlier (22.6 years vs. 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from vascular Ehlers-Danlos syndrome. CONCLUSIONS: Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease. The severity of the clinical presentation is predictive of the outcome. Genotyping of patients presenting with symptoms like those of vascular Ehlers-Danlos syndrome may be used to guide therapy, including the use and timing of prophylactic vascular surgery.

Abnormalities, Multiple↗
PubMed2006

Nuclear mRNA degradation pathway(s) are implicated in Xist regulation and X chromosome inactivation.

A critical step in X-chromosome inactivation (XCI), which results in the dosage compensation of X-linked gene expression in mammals, is the coating of the presumptive inactive X chromosome by the large noncoding Xist RNA, which then leads to the recruitment of other factors essential for the heterochromatinisation of the inactive X and its transcriptional silencing. In an approach aimed at identifying genes implicated in the X-inactivation process by comparative transcriptional profiling of female and male mouse gastrula, we identified the Eif1 gene involved in translation initiation and RNA degradation. We show here that female embryonic stem cell lines, silenced by RNA interference for the Eif1 gene, are unable to form Xist RNA domains upon differentiation and fail to undergo X-inactivation. To probe further an effect involving RNA degradation pathways, the inhibition by RNA interference of Rent1, a factor essential for nonsense-mediated decay and Exosc10, a specific nuclear component of the exosome, was analysed and shown to similarly impair Xist upregulation and XCI. In Eif1-, Rent1-, and Exosc10-interfered clones, Xist spliced form(s) are strongly downregulated, while the levels of unspliced form(s) of Xist and the stability of Xist RNA remain comparable to that of the control cell lines. Our data suggests a role for mRNA nuclear degradation pathways in the critical regulation of spliced Xist mRNA levels and the onset of the X-inactivation process.

Alternative Splicing↗
PubMed2006

DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a disorder characterized by fibrofatty replacement of cardiac myocytes that typically manifests in the right ventricle. It is inherited as an autosomal dominant disease with reduced penetrance, although autosomal recessive forms of the disease also occur. We identified four probands with ARVD/C caused by mutations in DSG2, which encodes desmoglein-2, a component of the cardiac desmosome. No association between mutations in this gene and human disease has been reported elsewhere. One of these probands has compound-heterozygous mutations in DSG2, and the remaining three have isolated heterozygous missense mutations, each disrupting known functional components of desmoglein-2. We report that mutations in DSG2 contribute to the development of ARVD/C.

Amino Acid Sequence↗
PubMed2006

Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.

Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor-beta (TGF-beta) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-beta signaling and can be prevented by TGF-beta antagonists such as TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.

Adrenergic beta-Antagonists↗
PubMed2006

Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome.

Arterial tortuosity syndrome (ATS) is an autosomal recessive disorder characterized by tortuosity, elongation, stenosis and aneurysm formation in the major arteries owing to disruption of elastic fibers in the medial layer of the arterial wall. Previously, we used homozygosity mapping to map a candidate locus in a 4.1-Mb region on chromosome 20q13.1 (ref. 2). Here, we narrowed the candidate region to 1.2 Mb containing seven genes. Mutations in one of these genes, SLC2A10, encoding the facilitative glucose transporter GLUT10, were identified in six ATS families. GLUT10 deficiency is associated with upregulation of the TGFbeta pathway in the arterial wall, a finding also observed in Loeys-Dietz syndrome, in which aortic aneurysms associate with arterial tortuosity. The identification of a glucose transporter gene responsible for altered arterial morphogenesis is notable in light of the previously suggested link between GLUT10 and type 2 diabetes. Our data could provide new insight on the mechanisms causing microangiopathic changes associated with diabetes and suggest that therapeutic compounds intervening with TGFbeta signaling represent a new treatment strategy.

Amino Acid Sequence↗
PubMed2006

Valve-sparing aortic root replacement: early experience with the De Paulis Valsalva graft in 51 patients.

BACKGROUND: Valve-sparing aortic root replacement for treatment of aortic sinus disease avoids the problems of prosthetic valves, but some patients suffer late valve incompetence as a result of leaflet distortion or annular dilatation. The reimplantation technique using the De Paulis Valsalva graft might improve late results of valve-sparing aortic root replacement by maintaining annular stability and re-creating sinuses that minimize leaflet stress. METHODS: Retrospective review was conducted of all patients at our institution who underwent valve-sparing aortic root replacement using the Valsalva graft. Clinical data were obtained from hospital and clinic charts and patient contacts; echocardiograms were analyzed for aortic root dimensions and valve function. RESULTS: Between May 2002 and June 2005, 51 patients underwent valve-sparing aortic root replacement using the reimplantation technique with the Valsalva graft. Mean age was 33 +/- 15 years; 22% (11 of 51) were children, and 80% (41 of 51) were male. Primary indication for surgery was root aneurysm in all patients. Preoperative mean root diameter was 5.0 +/- 0.5 cm. Marfan syndrome was present in 67% (34 of 51), and 10% (5 of 51) had the newly described Loeys-Dietz syndrome. There were no operative or late deaths, and no patient required reoperation for bleeding. At mean follow-up of 1.8 years, there were no episodes of endocarditis or thromboembolism. Echocardiograms showed stability of the annulus and root dimensions on follow-up. No patient had more than 0 to 1+ aortic insufficiency or progression of aortic insufficiency. All were in New York Heart Association class I. CONCLUSIONS: Valve-sparing aortic root replacement using the Valsalva graft and reimplantation technique has excellent early results. Preservation of valve competence is encouraging, but long-term results will determine whether the anatomic design of this aortic root prosthesis is superior for preservation of valve integrity.

Adolescent↗
PubMed2006

Structural and functional genetic disorders of the great vessels and outflow tracts.

Development of the aorta and pulmonary artery is a complex process involving multiple molecular genetic pathways that modulate morphogenesis of the outflow tracts and the anastomosis of branch vessels. Recent genetic studies of the cardiovascular system demonstrate that congenital and adult onset progressive disorders of the great vessels such as aneurysms are components of generalized vascular, cardiac, and extracardiovascular syndromes. Current paradigms suggest that aortic disease is founded in patterning anomalies of the conotruncus that occur in utero. These aberrations can be consequences of genetic aberrations in transcriptional regulation of signal transduction both within and outside the developing great vessels.

Blood Vessels↗
PubMed2006

Protrusio acetabuli in Marfan syndrome: age-related prevalence and associated hip function.

BACKGROUND: Protrusio acetabuli is known to occur in patients with Marfan syndrome, but its prevalence, its effects on hip function, and its possible association with the subsequent development of degenerative hip disease have not been studied in a large population. Nevertheless, some clinicians have recommended prophylactic hip surgery for preadolescents with Marfan syndrome and protrusio acetabuli. METHODS: We performed a cross-sectional study of 173 patients (346 hips) with Marfan syndrome who were interviewed and examined for calculation of the Iowa hip score. Anteroposterior radiographs of the pelvis were made, and two radiographic indices of acetabular depth were measured: (1) the center-edge angle of Wiberg and (2) the acetabular-ilioischial distance. The presence of protrusio was defined with use of two extant definitions: (1) a center-edge angle of >50 degrees or (2) an acetabular-ilioischial distance of >/=3 mm in male patients or >/=6 mm in female patients. Linear regression analyses were performed between these radiographic indices of acetabular depth and patient age, Iowa hip scores, the magnitude of the radiographic joint space, and range of motion. RESULTS: The prevalence of protrusio acetabuli was 27% according to the center-edge angle criterion and 16% according to the acetabular-ilioischial distance criterion. The prevalence of protrusio increased until the age of twenty years and remained stable after the age of twenty years. Slight but significant negative correlations were detected between the two radiographic indices of acetabular depth and both the Iowa hip score and the summed range of motion (p < 0.02 for all). No significant relationship was found between the two radiographic indices and pain scores. In patients with Marfan syndrome who were more than forty years old, the Iowa hip scores for hips with protrusio were not significantly lower than those for hips without protrusio. CONCLUSIONS: In patients with Marfan syndrome, the prevalence of protrusio acetabuli increases during the first two decades of life and then plateaus in terms of both population-wide prevalence and radiographic severity. In this population, protrusio generally is not associated with severely problematic hip function but it is associated with slightly decreased range of motion of the hip. We concluded that prophylactic surgical intervention is not indicated for most patients with Marfan syndrome who have a radiographic diagnosis of protrusio.

Acetabulum↗
PubMed2005

Dissection of epistasis in oligogenic Bardet-Biedl syndrome.

Epistatic interactions have an important role in phenotypic variability, yet the genetic dissection of such phenomena remains challenging. Here we report the identification of a novel locus, MGC1203, that contributes epistatic alleles to Bardet-Biedl syndrome (BBS), a pleiotropic, oligogenic disorder. MGC1203 encodes a pericentriolar protein that interacts and colocalizes with the BBS proteins. Sequencing of two independent BBS cohorts revealed a significant enrichment of a heterozygous C430T mutation in patients, and a transmission disequilibrium test (TDT) showed strong over-transmission of this variant. Further analyses showed that the 430T allele enhances the use of a cryptic splice acceptor site, causing the introduction of a premature termination codon (PTC) and the reduction of steady-state MGC1203 messenger RNA levels. Finally, recapitulation of the human genotypes in zebrafish shows that modest suppression of mgc1203 exerts an epistatic effect on the developmental phenotype of BBS morphants. Our data demonstrate how the combined use of biochemical, genetic and in vivo tools can facilitate the dissection of epistatic phenomena, and enhance our appreciation of the genetic basis of phenotypic variability.

Alleles↗
PubMed2005

Marfan's syndrome.

Marfan's syndrome is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin 1. Cardinal manifestations include proximal aortic aneurysm, dislocation of the ocular lens, and long-bone overgrowth. Important advances have been made in the diagnosis and medical and surgical care of affected individuals, yet substantial morbidity and premature mortality remain associated with this disorder. Progress has been made with genetically defined mouse models to elucidate the pathogenetic sequence that is initiated by fibrillin-1 deficiency. The new understanding is that many aspects of the disease are caused by altered regulation of transforming growth factor beta (TGFbeta), a family of cytokines that affect cellular performance, highlighting the potential therapeutic application of TGFbeta antagonists. Insights derived from studying this mendelian disorder are anticipated to have relevance for more common and non-syndromic presentations of selected aspects of the Marfan phenotype.

Adrenergic beta-Antagonists↗
PubMed2005

Recent progress towards a molecular understanding of Marfan syndrome.

Marfan syndrome (MFS) is a systemic disorder of the connective tissue that is inherited as an autosomal dominant trait and which displays variable manifestations in the ocular, skeletal, and cardiovascular systems. These pleiotropic manifestations are accounted for by mutations in fibrillin-1, the building block of extracellular microfibrils. During the past 10 years, we have witnessed significant progress in delineating the pathological events responsible for the manifestations of MFS. Much of this progress has been based on the creation and analysis of fibrillin-1 mutant mouse lines that faithfully recapitulate the spectrum of clinical severity of MFS. These studies have established the critical contribution of fibrillin-1 deficiency to disease progression through altered cell-matrix interactions and dysregulated TGF-beta signaling. As a result, our definition of MFS as the prototypical structural disorder of the connective tissue has changed to that of a developmental abnormality with broad and complex effects on the morphogenesis and function of multiple organ systems. Importantly, new biological targets have emerged that may yield exciting new opportunities for the development of productive treatment strategies in MFS.

Animals↗
PubMed2005

Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors.

During liver development, hepatocytes and biliary cells differentiate from common progenitors called hepatoblasts. The factors that control hepatoblast fate decision are unknown. Here we report that a gradient of activin/TGFbeta signaling controls hepatoblast differentiation. High activin/TGFbeta signaling is required near the portal vein for differentiation of biliary cells. The Onecut transcription factors HNF-6 and OC-2 inhibit activin/TGFbeta signaling in the parenchyma, and this allows normal hepatocyte differentiation. In the absence of Onecut factors, the shape of the activin/TGFbeta gradient is perturbed and the hepatoblasts differentiate into hybrid cells that display characteristics of both hepatocytes and biliary cells. Thus, a gradient of activin/TGFbeta signaling modulated by Onecut factors is required to segregate the hepatocytic and the biliary lineages.

Activins↗
PubMed2005

Identification of candidate regions for familial idiopathic scoliosis.

STUDY DESIGN: A genomic screen and statistical linkage analysis of 202 families with at least two individuals with idiopathic scoliosis was performed. OBJECTIVES: To identify candidate regions or the autosomal loci that may be involved in the expression of familial idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: A large sample of families with individuals having idiopathic scoliosis (202 families; 1,198 individuals) was ascertained; diagnoses were based on physical examination and radiographic criteria. METHODS: Model-independent linkage analysis of qualitative and quantitative traits (degree of lateral curvature) related to scoliosis was used to screen genotyping data from 391 markers in the 202 families. Subsets of families were determined before genotyping based on the most likely mode of inheritance for each family (autosomal dominant vs. X-linked dominant). Fine mapping results corroborated linkage in the primary candidate regions. RESULTS: Candidate regions on chromosomes 6, 9, 16, and 17 were considered to have the strongest evidence for linkage across all subsets considered. CONCLUSION: Linkage analyses have identified several candidate regions, a significant step in defining the genetic etiology of this disorder.

Family↗
PubMed2005

Characterization of the symptoms associated with dural ectasia in the Marfan patient.

Dural ectasia, an expansion of the dural sac surrounding the spinal cord, is one of the most common orthopedic manifestations of Marfan syndrome. The purpose of the present study was to characterize the clinical symptoms associated with dural ectasia in patients with Marfan syndrome and to understand the effects of symptomatic dural ectasia on the overall health of affected patients. Twenty-two volunteers aged 9-55 years with Marfan syndrome, and dural ectasia diagnosed by MRI or CT, filled out a "symptoms" questionnaire and completed an SF-36 health survey. Overall, It appears that the symptoms associated with dural ectasia have a marked impact on the overall health of patients with Marfan syndrome. Based on our findings, a "classic" picture of dural ectasia in the Marfan patient may consist of low back pain, headache, proximal leg pain, weakness and numbness above and below the knee, and genital/rectal pain. Symptoms, when present, are typically moderate to severe, occur several times per week (often daily), are commonly exacerbated by upright posture, and are not always relieved by recumbency.

Adolescent↗
PubMed2005

Toward an understanding of dural ectasia: a light microscopy study in a murine model of Marfan syndrome.

STUDY DESIGN: Light microscopy study of the lumbar spinal meninges of a murine model of Marfan syndrome. OBJECTIVE: Characterize the pathology of the lumbosacral meninges in Marfan syndrome, seeking clues to the pathophysiology behind dural ectasia. SUMMARY OF BACKGROUND DATA: Dural ectasia is common in Marfan syndrome. The etiology of dural ectasia is unknown, but is conjectured to be related to constitutionally weak spinal dura. The morphology of the lumbar dura in Marfan syndrome has not been described, as it has in other tissues affected by Marfan syndrome. METHODS: The lumbosacral dura were removed from three 4-month-old mice, 1 homozygote (mgR/mgR) expressing the murine Marfan phenotype, 1 heterozygote expressing wild-type phenotype, and 1 homozygote wildtype. Hematoxylin and eosin, elastochrome, and immunohistochemical stains against activated transforming growth factor beta, gelatinase A (matrix metalloproteinase-2), and gelatinase-B (matrix metalloproteinase-9) were used for light microscopic evaluation. RESULTS: No difference was noted between the heterozygous and wild-type mice in dural connective tissue morphology. The homozygote (mgR/mgR) had a marked attenuation of the dura overall, in addition to elastic fiber disorganization. The homozygote dura also stained for increased presence of activated transforming growth factor beta and matrix metalloproteinase-2, but not matrix metalloproteinase-9. CONCLUSIONS: These morphologic findings in the Marfan phenotype mouse mimic the findings of disordered elastic-fibers in other Marfan tissues and demonstrate gross attenuation of the tissue architecture, corroborating the theory that dural ectasia in Marfan syndrome results from hydrostatic pressure on weakened dura. These changes may be due in part to transforming growth factor beta overactivation and gelatinase-A-mediated elastolysis and collagen breakdown.

Animals↗