Harry C Dietz

Howard Hughes Medical Institute, Ashburn, Virginia, United States

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Publications (215)2272.59 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro reporter alleles demonstrated a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d(+/βGeo) mice. These activities were normalized in response to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d(+/βGeo) mice correlated with reduced neurogenesis and hippocampal memory defects. These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome.
    Science translational medicine 10/2014; 6(256):256ra135. · 10.76 Impact Factor
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    Genetics in medicine: official journal of the American College of Medical Genetics 08/2014; 16(8):642-644. · 3.92 Impact Factor
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    ABSTRACT: OBJECTIVE. Arterial dissection and aneurysm rupture are significant sources of morbidity and mortality in patients with connective tissue diseases. This article provides a detailed analysis of cardiovascular involvement in Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome. CONCLUSION. Although these syndromes share some overlapping features, they have discriminating clinical and imaging features, and knowledge of these features enables the radiologist to aid the referring clinician in making the correct diagnosis.
    American Journal of Roentgenology 05/2014; 202(5):1120-9. · 2.90 Impact Factor
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    ABSTRACT: Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS.European Journal of Human Genetics advance online publication, 16 April 2014; doi:10.1038/ejhg.2014.61.
    European journal of human genetics: EJHG 04/2014; · 3.56 Impact Factor
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    ABSTRACT: Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor beta (TGF-beta) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-beta1 (P=0.009)؍‬ TGF-beta2 (P=0.004)؍‬ and additional inflammatory markers, and increased TGF-beta1 (P=0.0009)؍‬ and TGF-beta2 (P=0.001)؍‬ secretion in dermal fibroblast cell lines from subjects with FMD compared to age-and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-beta signaling and offers TGF-beta as a marker of FMD.
    The FASEB Journal 04/2014; 28. · 5.70 Impact Factor
  • Harry Dietz
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    ABSTRACT: I would like to express my sincere appreciation to the American Society for Clinical Investigation and the Harrington Discovery Institute for the honor of being named the inaugural recipient of the Harrington Prize for Innovation in Medicine. I accept this distinction with a deep sense of gratitude and debt to my mentors, trainees, colleagues, collaborators, patients, and family. Moments of recognition such as this are rare, savored, and sustaining. They also invariably provoke personal reflection about what exactly is being recognized. If something innovative truly stands apart in my work, I have come to the conclusion that it relates less to the methods utilized to address questions and more to the questions I choose to ask, and when I ask them.
    The Journal of clinical investigation 04/2014; 124(4):1425-9. · 15.39 Impact Factor
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    ABSTRACT: Loeys-Dietz syndrome is a connective tissue disorder predisposing individuals to aortic and arterial aneurysms. Presenting with a wide spectrum of multisystem involvement, medical management for some individuals is complex. This review of literature and expert opinion aims to provide medical guidelines for care of individuals with Loeys-Dietz syndrome.Genet Med advance online publication 27 February 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.11.
    Genetics in medicine: official journal of the American College of Medical Genetics 02/2014; · 3.92 Impact Factor
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    ABSTRACT: Patients with Marfan syndrome (MFS), a multisystem disorder caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin 1, are unusually vulnerable to stress-induced cardiac dysfunction. The prevailing view is that MFS-associated cardiac dysfunction is the result of aortic and/or valvular disease. Here, we determined that dilated cardiomyopathy (DCM) in fibrillin 1-deficient mice is a primary manifestation resulting from ECM-induced abnormal mechanosignaling by cardiomyocytes. MFS mice displayed spontaneous emergence of an enlarged and dysfunctional heart, altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including increased angiotensin II type I receptor (AT1R) signaling and abated focal adhesion kinase (FAK) activity. Partial fibrillin 1 gene inactivation in cardiomyocytes was sufficient to precipitate DCM in otherwise phenotypically normal mice. Consistent with abnormal mechanosignaling, normal cardiac size and function were restored in MFS mice treated with an AT1R antagonist and in MFS mice lacking AT1R or β-arrestin 2, but not in MFS mice treated with an angiotensin-converting enzyme inhibitor or lacking angiotensinogen. Conversely, DCM associated with abnormal AT1R and FAK signaling was the sole abnormality in mice that were haploinsufficient for both fibrillin 1 and β1 integrin. Collectively, these findings implicate fibrillin 1 in the physiological adaptation of cardiac muscle to elevated workload.
    Journal of Clinical Investigation 02/2014; · 12.81 Impact Factor
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    ABSTRACT: TGF-β is essential for vascular development; however, excess TGF-β signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-β overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF-β signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-β type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor-independent effects of TGF-β and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-β signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression.
    The Journal of clinical investigation 01/2014; · 15.39 Impact Factor
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    ABSTRACT: Objective To compare 1-year results after aortic valve-sparing (AVS) or valve-replacing (AVR) aortic root replacement from a prospective, international registry of 316 patients with Marfan syndrome (MFS). Methods Patients underwent AVS (n=239, 76%) or AVR (n=77, 24%) aortic root replacement at 19 participating centers between 2005 and 2010. One-year follow-up was completed for 312 patients (99%), with imaging available for 293 patients (94%). Time-to-events were compared between groups using Kaplan-Meier curves and Cox Proportional Hazards models. Results Two patients (0.6%)—1 in each group—died within 30 days. There were no significant differences in early major adverse valve-related events (MAVRE) (P=0.6). Two AVS patients required early reoperation for coronary artery complications. One-year survival rates were similar in the AVR (97%) and AVS groups (98%); procedure type was not significantly associated with any valve-related events. At 1 year and beyond, aortic regurgitation of at least moderate severity (≥2+) was present in 16 patients in the AVS group (7%) but in no patients in the AVR group (P=0.02). One AVS patient required late AVR. Conclusions Valve-sparing aortic root replacement was not associated with higher 30-day mortality or morbidity rates than AVR root replacement. At 1 year, there were no differences in survival, valve-related morbidity, or MAVRE between the AVS and AVR groups. Of concern, 7% of AVS patients developed ≥2+ aortic regurgitation, emphasizing the importance of 5- to 10-year follow-up to learn the long-term durability of AVS versus AVR root replacement in patients with MFS.
    The Journal of thoracic and cardiovascular surgery 01/2014; · 3.41 Impact Factor
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    ABSTRACT: Loeys-Dietz syndrome (LDS) is an autosomal dominant arterial aneurysm disease belonging to the spectrum of transforming growth factor β (TGFβ)-associated vasculopathies. In its most typical form it is characterized by the presence of hypertelorism, bifid uvula/cleft palate and aortic aneurysm and/or arterial tortuosity. LDS is caused by heterozygous loss of function mutations in the genes encoding TGFβ receptor 1 and 2 (TGFBR1 and -2), which lead to a paradoxical increase in TGFβ signaling. To address this apparent paradox and to gain more insight into the pathophysiology of aneurysmal disease, we characterized a new Tgfbr1 mouse model carrying a p.Y378* nonsense mutation. Study of the natural history in this model showed that homozygous mutant mice die during embryonic development due to defective vascularization. Heterozygous mutant mice aged 6 and 12 months were morphologically and (immuno)histochemically indistinguishable from wild-type mice. We show that the mutant allele is degraded by nonsense mediated mRNA decay, expected to result in haploinsufficiency of the mutant allele. Since this haploinsufficiency model does not result in cardiovascular malformations, it does not allow further study of the process of aneurysm formation. In addition to providing a comprehensive method for cardiovascular phenotyping in mice, the results of this study confirm that haploinsuffciency is not the underlying genetic mechanism in human LDS.
    PLoS ONE 01/2014; 9(2):e89749. · 3.53 Impact Factor
  • Lut Van Laer, Harry Dietz, Bart Loeys
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    ABSTRACT: Loeys-Dietz syndrome is an autosomal dominant aortic aneurysm syndrome characterized by multisystemic involvement. The most typical clinical triad includes hypertelorism, bifid uvula or cleft palate and aortic aneurysm with tortuosity. Natural history is significant for aortic dissection at smaller aortic diameter and arterial aneurysms throughout the arterial tree. The genetic cause is heterogeneous and includes mutations in genes encoding for components of the transforming growth factor beta (TGFβ) signalling pathway: TGFBR1, TGFBR2, SMAD3 and TGFB2. Despite the loss of function nature of these mutations, the patient-derived aortic tissues show evidence of increased (rather than decreased) TGFβ signalling. These insights offer new options for therapeutic interventions.
    Advances in experimental medicine and biology 01/2014; 802:95-105. · 1.83 Impact Factor
  • Mark E Lindsay, Harry C Dietz
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    ABSTRACT: Gene identification in human aortic aneurysm conditions is proceeding at a rapid pace and the integration of pathogenesis-based management strategies in clinical practice is an emerging reality. Human genetic alterations causing aneurysm involve diverse gene products including constituents of the extracellular matrix, cell surface receptors, intracellular signaling molecules, and elements of the contractile cytoskeleton. Animal modeling experiments and human genetic discoveries have extensively implicated the transforming growth factor-β (TGF-β) cytokine-signaling cascade in aneurysm progression, but mechanistic links between many gene products remain obscure. This chapter will integrate human genetic alterations associated with aortic aneurysm with current basic research findings in an attempt to form a reconciling if not unifying model for hereditary aortic aneurysm.
    Cold Spring Harbor perspectives in medicine. 01/2014; 4(9).
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    ABSTRACT: Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan syndrome. LDS is caused by heterozygous missense mutations in either TGF-β receptor gene (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-β signaling; however, aortic surgical samples from patients show evidence of paradoxically increased TGF-β signaling. We generated 2 knockin mouse strains with LDS mutations in either Tgfbr1 or Tgfbr2 and a transgenic mouse overexpressing mutant Tgfbr2. Knockin and transgenic mice, but not haploinsufficient animals, recapitulated the LDS phenotype. While heterozygous mutant cells had diminished signaling in response to exogenous TGF-β in vitro, they maintained normal levels of Smad2 phosphorylation under steady-state culture conditions, suggesting a chronic compensation. Analysis of TGF-β signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-β target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-β1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-β1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan. Together, these data suggest that increased TGF-β signaling contributes to postnatal aneurysm progression in LDS.
    The Journal of clinical investigation 12/2013; · 15.39 Impact Factor
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    ABSTRACT: In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-β antagonism. These results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.
    Nature 10/2013; · 38.60 Impact Factor
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    ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent of Marfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-β binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF-β signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-β signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF-β. Our data link the interaction of two important diseases to a fundamental signaling pathway.
    Journal of the American Society of Nephrology 09/2013; · 8.99 Impact Factor
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    ABSTRACT: Transforming growth factor-β (TGFβ) is a multifunctional cytokine that plays diverse roles in physiologic processes as well as human disease, including cancer, heart disease, and fibrotic disorders. In the immune system, TGFβ regulates regulatory T cell (Treg) maturation and immune homeostasis. Although genetic manipulation of the TGFβ pathway modulates immune tolerance in mouse models, the contribution of this pathway to human allergic phenotypes is not well understood. We demonstrate that patients with Loeys-Dietz syndrome (LDS), an autosomal dominant disorder caused by mutations in the genes encoding receptor subunits for TGFβ, TGFBR1 and TGFBR2, are strongly predisposed to develop allergic disease, including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. LDS patients exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (TH2) cytokines in their plasma. They had an increased frequency of CD4(+) T cells that expressed both Foxp3 and interleukin-13, but retained the ability to suppress effector T cell proliferation. TH2 cytokine-producing cells accumulated in cultures of naïve CD4(+) T cells from LDS subjects, but not controls, after stimulation with TGFβ, suggesting that LDS mutations support TH2 skewing in naïve lymphocytes in a cell-autonomous manner. The monogenic nature of LDS demonstrates that altered TGFβ signaling can predispose to allergic phenotypes in humans and underscores a prominent role for TGFβ in directing immune responses to antigens present in the environment and foods. This paradigm may be relevant to nonsyndromic presentations of allergic disease and highlights the potential therapeutic benefit of strategies that inhibit TGFβ signaling.
    Science translational medicine 07/2013; 5(195):195ra94. · 10.76 Impact Factor
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    ABSTRACT: Loeys-Dietz syndrome is a recently recognized connective tissue disorder with widespread systemic involvement. Little is known about its skeletal phenotype. Our goal was to investigate the risk of fracture and incidence of low bone mineral density in patients with Loeys-Dietz syndrome. We performed a cross-sectional, descriptive, survey-based study with subsequent chart review from July 2011 to April 2012. Fifty-seven patients (26 men, 31 women) with Loeys-Dietz syndrome confirmed by genetic testing completed the survey (average age, 25.3 years; range, 0.9-79.6 years). There were a total of 51 fractures (33 patients): 35 fractures in the upper extremities, 14 in the lower extremities, and two in the spine. Fourteen patients (24.6%) reported two or more fractures. There was a 50% risk of fracture by age 14 years. The incidence of any fracture in this cohort was 3.86 per 100 person-years. Seventeen patients had dual-energy X-ray absorptiometry scans available for review, 11 (64.7%) of whom had at least one fracture. Thirteen included lumbar spine absorptiometry reports; eight (61.5%) indicated low or very low bone mineral density. In the left hip, ten of 14 participants (71.4%) had low or very low bone mineral density. In the left femoral neck, nine of 13 participants (69.2%) had low or very low bone mineral density. The lowest Z- and T-scores were not associated with an increased number of fractures. Patients with Loeys-Dietz syndrome have a high risk of fracture and a high incidence of low bone mineral density. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2013; · 2.30 Impact Factor
  • Bart L Loeys, Geert Mortier, Harry C Dietz
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    ABSTRACT: The extracellular matrix (ECM) is a complex entity with structural proteins (such as fibrillins, collagen, elastin), ground substance (proteoglycans), modifying enzymes (ADAMTS, PLOD, lysyloxidases (LOX)) and cytokines that regulate morphogenesis, growth, homeostasis and repair (transforming growth factor-beta [TGF-beta], bone morphogenic protein [BMP]). Over the last decade, the intimate relationship between structural proteins and these growth factors has emerged. The study of the extracellular matrix in human conditions and relevant mouse models is gradually unmasking the key role of these structural molecules in the regulation of the bio-availability of these growth factors. Major progress has been made in the study of the cardiovascular system (1) and the first clues in the skeletal system have emerged. (2) In this review, we will discuss the clinical, molecular, and pathogenic aspects of Marfan syndrome, Loeys-Dietz syndrome and related disorders with emphasis on the role of fibrillins and TGF-beta.
    Pediatric endocrinology reviews: PER 06/2013; 10 Suppl 2:417-23.
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    ABSTRACT: Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 05/2013; · 2.30 Impact Factor

Publication Stats

14k Citations
2,272.59 Total Impact Points


  • 1998–2014
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2013
    • University of Antwerp
      • Centre of Medical Genetics
      Antwerpen, VLG, Belgium
  • 1992–2012
    • Johns Hopkins Medicine
      • • Department of Radiology and Radiological Science
      • • Department of Pediatrics
      • • Department of Orthopaedic Surgery
      • • Division of Cardiac Surgery
      Baltimore, MD, United States
  • 1991–2011
    • Johns Hopkins University
      • • Department of Pediatrics
      • • McKusick-Nathans Institute of Genetic Medicine
      • • Department of Biophysics and Biophysical Chemistry
      • • Department of Gynecology & Obstetrics
      • • Department of Surgery
      Baltimore, MD, United States
    • National Public Health Institute
      Helsinki, Southern Finland Province, Finland
  • 1994–2010
    • Mount Sinai School of Medicine
      • Department of Pharmacology and Systems Therapeutics
      Manhattan, NY, United States
  • 2009
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 2008
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 2007
    • University of South Florida
      Tampa, Florida, United States
    • Robert Wood Johnson University Hospital
      New Brunswick, New Jersey, United States
    • Rutgers New Jersey Medical School
      Newark, New Jersey, United States
  • 2006
    • Kennedy Krieger Institute
      Baltimore, Maryland, United States
  • 2005
    • University of Iowa
      Iowa City, Iowa, United States
    • University of California, San Diego
      • Department of Orthopaedic Surgery
      San Diego, CA, United States
  • 2004
    • Weill Cornell Medical College
      New York City, New York, United States
  • 2003
    • University of Zurich
      Zürich, Zurich, Switzerland
  • 1996
    • Ghent University
      • Center for Medical Genetics
      Gent, VLG, Belgium