DC in the News

Statement on Unproven Stem Cell Interventions for Lung Diseases (Posted in the August 2016 Annals of the American Thoracic Society by the Respiratory Cell Molecular Biology Stem Cell Working Group) 

A central component of the mission of medical societies is to translate new scientific information into patient education. The undersigned lung, respiratory, and thoracic societies, and patient advocacy groups strongly believe that patients and their families along with the general public should have at their disposal unbiased and scientifically sound information on new potential therapeutic options including stem cell-based treatments.

Continuing advances in stem cell biology have created justified excitement at the prospect of personalized stem cell-based therapies through the use of clinically relevant cell populations. We recognize the enormous potential of stem cells for disease management including acute and chronic ailments of the respiratory system. As we learn more about the therapeutic potential of stem cells and other cell therapies in clinical trials of non-lung diseases and in initial trials in lung diseases, we hope to move towards further consideration and potential implementation of these approaches.

However, as with all medical interventions, patient safety must be the top priority of any prospective stem cell-based therapy or treatment. As yet, there is very little known about the short- and long-term effects in terms of safety and efficacy of administering any type of stem cell-based therapy to patients with lung diseases. Until we know more, we must be strongly concerned that the treatment could cause adverse effects and could worsen the patient's condition rather than improve it.

At present, there are only a small number of peer reviewed and appropriately regulated approved clinical trials in the United States, Canada, the European Union, Brazil, Asia and Australia investigating cell therapy approaches for lung diseases. These can be found on the website of the National Institutes of Health at www.clinicaltrials.gov, of the European Medicines Agency at https://www.clinicaltrialsregister.eu/ctr-search/search, and of UMIN-ICDR in Japan at http://www.umin.ac.jp/icdr/index.html. We are watching these carefully to determine whether they will demonstrate that stem cell-based treatments could be effective and safe for treating lung diseases.

Thus, we are particularly wary of the ever-increasing examples of direct-to-consumer advertising of untested, unapproved, and potentially dangerous “stem-cell” treatments that take place in several countries. One may come across information on the internet or other sources about stem cells being administered to patients with lung diseases such as emphysema, pulmonary hypertension, cystic fibrosis, or pulmonary fibrosis in several locations worldwide including the United States. We fully acknowledge that patients with severe irreversible lung diseases are under extreme physical and emotional distress that provide the motivation to resort to expensive unproven treatments. Nevertheless, we strongly caution all patients that the claims of benefit being made by many of these programs have not been substantiated nor have they been reviewed by experts in the field or any regulatory agency. These programs are usually characterized by:

  • Exorbitant fees
  • Misrepresentation of risks and benefits
  • Overreliance on, and advertisement of, patient testimony
  • Poor patient follow-up
  • Absence of regulatory oversight and objective clinical evidence for claimed benefits

Therefore, they differ substantially from therapies approved by legitimate regulatory agencies, from well-designed, controlled, and appropriately regulated clinical trials, and from regulated compassionate use of innovative cell therapies. Because of the potential for harm and the lack of any proven benefit, we strongly caution patients not to participate in these or any other comparable unauthorized or unapproved stem cell interventions, unless independent credible, reliable, and objective sources of information are available to substantiate the information and claims being made.

To better educate the lung scientific community about the complex issues of stem cell medical tourism, we propose the inclusion of relevant sessions, whenever possible, in future national and international conferences related to lung biology and disease. Representatives of regulatory agencies, patient advocacy groups, and bioethics and health policy scholars should be included as speakers and discussants. We also urge patient advocacy groups and foundations to work together with their national lung, respiratory, and thoracic societies, their local chapters, and with regulatory agencies on the issues of stem cell medical tourism and unproven stem cell interventions. Open channels of communication between these organizations and dissemination of reliable, evidence-based information through patient networks including social media, will ensure that lung disease patients make informed and safe decisions regarding cell-based treatments.

One such reliable source of information is the International Society for Stem Cell Research (ISSCR), which has developed an excellent web-based resource that includes the ISSCR patient handbook (http://www.isscr.org/home/publications/ClinTransGuide, http://www.closerlookatstemcells.org/stem-cells-and-medicine). The handbook provides information on mechanisms for monitoring or substantiating the claims being made by various organizations that purport to offer “stem cell therapies.”

Additional resources are provided by the International Society for Cellular Therapy (http://www.celltherapysociety.org/?page=PTF2015, http://bit.ly/1lAjOIV), the California Institute for Regenerative Medicine (www.cirm.ca.gov), the Canadian Stem Cell Network (http://www.stemcellnetwork.ca/) and the Canadian Stem Cell Foundation (stemcellfoundation.ca).

This Assembly on Respiratory Cell & Molecular Biology Stem Cell Working Group statement is supported by the following lung, respiratory, and thoracic societies and patient advocacy groups:

Alpha-1-Foundation (U.S.A.)

American Lung Association (U.S.A.)

Asian Pacific Society of Respirology

Brazilian Thoracic Society

COPD Foundation (U.S.A.)

Cystic Fibrosis Foundation (U.S.A.)

Dyskeratosis Congenita Outreach (U.S.A.)

European Lung Foundation

European Respiratory Society

The Japanese Respiratory Society

Macedonian Respiratory Society

Malaysian Thoracic Society

Pulmonary Fibrosis Foundation (U.S.A.)

Pulmonary Hypertension Association (U.S.A.)

South African Thoracic Society

Swiss Society of Respiratory Medicine

The Thoracic Society of Australia and New Zealand

The Transplantation Society of Australia and New Zealand

Turkish Thoracic Society

 

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Dyskeratosis Congenita Outreach, Inc. part of announcement at Precision Medicine Summit with President Obama

PCORnet Patient Powered Research Networks Pledge Announced

 

Washington, DC (February 25, 2016) – Dyskeratosis Congenita Outreach, Inc., a member of the Community Engaged Network for All (CENA), is participating in the Precision Medicine Initiative Summit with President Obama today. Amidst several other ‘health data flow’ announcements, Sharon Terry, President and CEO of Genetic Alliance, announced that the Patient Powered Research Networks (PPRN) of the National Patient-Centered Clinical Research Network (PCORnet) will prioritize patient access to electronic health record (EHR) data in order to let it flow into research studies. CENA is a PPRN, and as such is changing the culture of medical research by involving participants, their families, and communities in all phases of research. Dyskeratosis Congenita Outreach, Inc., represented today by Sharon Terry, CEO and principal investigator of CENA, is thrilled to be involved in this commitment to help people more readily obtain their health information for advancing research.

 

The Community Engaged Network for All (CENA is quite novel in that it is a collaborative effort of 10 disease advocacy organizations, the University of California, San Francisco, the University of California, Davis and Private Access. CENA utilizes the Platform for Engaging Everyone Responsibly (PEER) built by Private Access and Genetic Alliance to enable individuals to share their health information according to their personal data access and privacy preferences.

 

“CENA has implemented the capability to receive EHR data transmitted using the Direct secure-email protocol within PEER, and their participants are giving CENA’s Direct address to their providers with the request that their EHR data be sent to CENA. We know the Argonaut Project’s progress and are eager to implement apps that will enable our participants to request the PCORnet clinical data elements through a FHIR-based API,” said Dixie Baker of Martin Blanck & Associates, who is assisting the PPRN in designing and implementing systems to extract EHR data.

 

To create a more robust network, all the PPRNs pledge to help participants access their EHR data and to make it available for research. This will greatly enhance the quality, sensitivity, and power of the available research data. The PPRNs will enable participants to retrieve their own EHR data through existing patient portals, giving them an immediate option to make these data available for research, while building toward data retrieval using apps to query OAuth 2.0 based APIs, and ultimately retrieval of FHIR resources. The first PPRN deployments are already in use.

 

“I am delighted to see these data flow! The goal for CENA is to empower people to ask for their health data from healthcare providers and receive it in the easiest and most useful way,” said Sharon Terry, CENA PPRN PI, and CEO of PXE International and Genetic Alliance. Terry is also a member of the Precision Medicine Initiative Cohort Program Advisory Panel.

 

“This EHR data, combined with information from self-reported data and other sources, will be critical in understanding health outcomes for millions of Americans,” Terry added.

 

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About Dyskeratosis Congenita Outreach, Inc.

Dyskeratosis Congenita Outreach, Inc. was founded in 2008 to support individuals and families affected by Dyskeratosis Congenita and Telomere Biology Disorders. Principal to our mission is connecting families living with this rare disease to each other and to medical care providers and research specialists. We strive to educate families and clinicians, and bring awareness to the world. DC Outreach, Inc. works diligently to nurture hope and compassion for individuals and families around the world living with DC & TBD.  Visit: https://www.dcoutreach.org

 

About CENA

CENA is part of PCORnet, the National Patient-Centered Clinical Research Network, an innovative initiative of the Patient-Centered Outcomes Research Institute (PCORI). Genetic Alliance leads this project, which is a collaborative of ten disease advocacy organizations, the University of California San Francisco, the University of California Davis, and Private Access. For more information about CENA please visit: http://www.geneticalliance.org/programs/biotrust/cena

 

About Platform for Engaging Everyone Responsibly

Platform for Engaging Everyone Responsibly (PEER) is the world's first participant-controlled, cross-condition health registry. From the ground up, PEER is based on the principle that genuinely engaging individuals in medical research demands giving each individual (or their legally authorized representative) the power to decide for themself how, and with whom, they wish to share their health information. For more information: http://peerplatform.org/

 

 


 

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DC Outreach, Inc. and PXE International Launch Patient Registry networks on November 19th, 2014

What is CENA?

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DC Outreach is excited to announce that we have been chosen as one of just 9 advocacy groups to participate in a National Patient Centered Clinical Research Network being run by Genetic Alliance.  Over the next several months we will be asking you to help us by filling out anonymous surveys about your overall medical health--you can get the entire family to do it as they will need controls in addition to affected patients.  This is a wonderful opportunity for us in terms of the information it will generate for researchers and doctors, and it is extremely exciting that DC Outreach is involved in this project from the ground floor.  That means that more information about DC can be generated sooner.
 
 Below is the press release from Genetic Alliance.​​
4301 Connecticut Avenue NW - Suite 404
Washington DC 20008-2304
Telephone: 202.966.5557 x201
Fax: 202.966.8553
FOR IMMEDIATE RELEASE                                                                              
Contact: Tanya Murza
Genetic Alliance team among PCORI funding recipients to establish the National Patient Centered Clinical Research Network
WASHINGTON, DC (December 18, 2013) A team led by Genetic Alliance has been approved for a funding award by the Patient-Centered Outcomes Research Institute (PCORI) to develop and expand a health data network that will be part of PCORnet: the National Patient-Centered National Clinical Research Network. Community-Engaged Network for All (CENA) is one of 29 networks approved to form this new national resource that aims to boost the efficiency of health research. 
Under the CENA proposal, Genetic Alliance, University of California San Francisco, University of California Davis Health System, and Private Access will collaborate with ten disease advocacy organizations that were competitively selected earlier this year from nearly 100 Genetic Alliance partners that had applied to take part in the pilot. CENA will employ Genetic Alliance’s award-winning Platform for Engaging Everyone Responsibly (PEER) to launch and/or upgrade online registries for each of the ten conditions; and through each, to help engage additional participants in participant-centric biomedical research. Genetic Alliance will provide technical assistance for engaging communities to safely share their information online, as well as community building and collaboration among condition communities, and with other PCORI projects. Dixie Baker, a renowned privacy and security technology expert and senior partner at Martin, Blanck and Associates, will be an advisor on the project.
“We are pleased that CENA will be part of this exciting initiative to build the data structures needed to significantly enhance the speed and efficiency of patient-centered comparative effectiveness research,” said PCORI Executive Director Joe Selby. “The process to select the awardees was very competitive and CENA demonstrated it has the expertise, resources, and commitment to engaging patients and other stakeholders to be an excellent fit in PCORnet.”
The initiative will use and improve upon participant-led governance models that Genetic Alliance has pioneered for more than a decade, bringing leaders and affected individuals from each condition community together to oversee CENA. Explained Genetic Alliance CEO and Principal Investigator Sharon Terry: “We are thrilled. Collaboratively building a participant-centric clinical research network has long been part of Genetic Alliance’s vision. Using PEER, these advocacy organizations and academic partners will collaborate in ways that will align incentives, empower data sharing, and revolutionize clinical research.”
The group plans to test the prospect of recruiting patients from academic medical centers into participant-led models. The ten patient support organizations participating in CENA are Alström Syndrome International, Dyskeratosis Congenita Outreach, Inflammatory Breast Cancer Research Foundation, Hepatitis Foundation International, Joubert Syndrome Foundation, KS&A, MLD Foundation, National Gaucher Foundation, and PXE International. The conditions range from rare to common, and cover a broad demographic spectrum. Additionally, through collaboration with another UCSF proposal selected by the PCORI Board (Health eHeart), the initiative will assess the utility of CENA to recruit for a co-morbidity (cardiovascular disease) that affects patients in each of the ten groups. 
In addition, CENA will pilot new methods of facilitating collaboration among researchers and participants by supporting a broadly accessible online environment where communities and researchers have equal voice in the development of research hypotheses. The condition-specific communities will be supported and grown through inter-community collaboration and sharing best practices. Through the development partnership with Private Access, PEER will allow for extremely cost-effective data capture from participants using technology that enables individualized and dynamic privacy permissions management.  
PEER employs a Traitwise gamified survey interface to present questions in a way that provides immediate feedback to maximize participant engagement, and that provides flexibility for continual fine-tuning or addition of questions, including changes based on input from condition-specific communities and academic research partners. PEER’s novel approach of empowering each participant to determine with whom and for what purpose his or her information may be shared, and its potential to radically accelerate participant engagement and the collection of participant-reported outcomes has been recognized through earning top honors in the Sanofi Collaborate | Activate and Ashoka Changemaker Challenges, as well as being designated by Forbes as one of six business models that are transforming health systems around the world. This initiative will utilize Syapse for Registries, which enables the management of large-scale phenotypic, “omics,” and other relevant patient data, all linked through a flexible platform that can be quickly configured to meet complex needs.
Co-PIs Mini Kahlon at UC San Francisco, and Nick Anderson at UC Davis, will lead the academic partnership, and will invite researchers and their patients into CENA. In addition to testing whether patients at their institutions can be successfully engaged using PEER and other participant-led initiatives, CENA plans to employ a UC San Francisco developed tool called Open Proposals to help support dynamic and meaningful communications among individual participants, leaders of the disease advocacy organizations, and UC San Francisco and UC Davis researchers interested in those conditions.
Commenting on the announcement, Dr. Kahlon, Executive Director of the Clinical and Translational Science Institute at UC San Francisco, stated: “We couldn’t be more delighted! We are firmly committed to facilitating cross-institutional collaboration to share clinical data for research purposes. By involving both UC San Francisco and UC Davis, this initiative ties directly into that objective, and is consistent with the Chancellor’s theme regarding the importance for discovering new ways in which to engage patients in accelerating research.”
Adds Sharon Terry: “Particularly for genetic and chronic conditions, academic medical centers and specialized treatment centers hold great promise as focused points of engagement for recruitment into participant-led networks.” Reflecting on the potential of the initiative, Ms. Terry, who founded and heads a disease advocacy organization for a genetic condition that affects her two children, adds: “CENA will help to identify best practices for engaging participants in advancing research, and we’re all eager to extend these practices to the more than 1000 other condition-specific organizations in Genetic Alliance’s network.”
All awards are approved pending completion of a business and programmatic review by PCORI staff and issuance of a formal award contract.

About Genetic Alliance

Genetic Alliance engages individuals, families and communities to transform health. Founded in 1986, it is the world's largest nonprofit health advocacy organization network. Genetic Alliance's network includes more than 1,200 disease-specific advocacy organizations, as well as thousands of universities, private companies, government agencies, and public policy organizations. For more information about Genetic Alliance, visit www.geneticalliance.org.

About UC San Francisco (UCSF)

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital. More information is available at www.ucsf.edu

About UC Davis Health System

UC Davis Health System improves lives by providing excellent patient care, conducting groundbreaking research, fostering innovative, interprofessional education and creating dynamic, productive community partnerships. It encompasses one of the country's best medical schools, a 619-bed acute-care teaching hospital, a 1,000-member physician practice group and the Betty Irene Moore School of Nursing. Together, they make UC Davis a hub of innovation that is transforming health for all. For information, visit www.healthsystem.ucdavis.edu.

About Private Access

Private Access is striving to make it safe for sensitive personal information such as medical records and genomic data to be accessible over the Internet. Through PrivacyLayer®, the firm ’s core services platform, Private Access empowers individuals to set granular privacy preferences and use dynamic consent tools to address a number of critical privacy concerns and related hurdles that have traditionally impeded privacy-protective sharing of this valuable information. In 2009, Forbes named Private Access as #12 on its list of America’s Most Promising Companies. More information is available at www.privateaccess.com

About PCORI

The Patient-Centered Outcomes Research Institute (PCORI) is an independent, non-profit organization authorized by Congress in 2010. Its mission is to fund research that will provide patients, their caregivers and clinicians with the evidence-based information needed to make better-informed health care decisions. PCORI is committed to continuously seeking input from a broad range of stakeholders to guide its work. More information is available at www.pcori.org.

 


 

Genetics of Dyskeratosis Congenita

Philip J Mason, University of Pennsylvania, Philadelphia, Pennsylvania, USA 
Dara Reeves, University of Pennsylvania, Philadelphia, Pennsylvania, USA 
Nieves Perdigones, University of Pennsylvania, Philadelphia, Pennsylvania, USA 
Published online: February 2013
DOI: 10.1002/9780470015902.a0024269
Full Article on Wiley Online Library
Dyskeratosis congenita (DC) is a rare, inherited, skin and bone marrow failure disease. It is a multisystem disorder which is heterogeneous at the genetic and clinical levels. Genetically, nine genes have so far been identified whose mutation causes DC, and inheritance of the disease can be X linked, autosomal dominant or recessive. Clinically, the disease can present in childhood as classical DC with a characteristic triad of nail dystrophy, leukoplakia and abnormal skin pigmentation along with progressive bone marrow failure. More severe forms presenting in infancy and milder forms in adults, as aplastic anaemia or pulmonary fibrosis, exist. All forms of the disease with known pathogenesis are due to failure of telomere maintenance, often leading to stem cell exhaustion. Recent progress in the identification of mutations in human syndromes has revealed that DC overlaps clinically and genetically with a number of other rare syndromes.
Key Concepts: 
  • The major cause of death in DC is bone marrow failure.​
  • The most common form of DC is X linked.​
  • In the X-linked form, females are not, or very mildly, affected, but they show extremely skewed X-inactivation, with cells expressing the mutated gene being outgrown by cells expressing the wild type gene.​
  • Dyskeratosis congenita is a disease caused by defective telomere maintenance.​
  • Eleven genes have been discovered to cause dyskeratosis congenita when mutated, and their products are involved in telomerase and its assembly or as part of the telomere.​  
  • CTC1
  • DKC1
  • NHP2
  • NOP10
  • RTEL1
  • TERC
  • TERT
  • TINF2
  • WRAP53
  • ACD
  • PARN
  • When the disease is caused by mutations in the core components of telomerase, TERT and TERC families show an increase in severity of the disease in later generations, a phenomenon known as genetic anticipation.​
  • Genetic anticipation is due to shortening of telomeres from one generation to the next.​
  • Some DC mutations are also known causes of pulmonary fibrosis, liver fibrosis and Coats retinopathy.​
  • Now that genes responsible for rare syndromes are being discovered, it is becoming evident that there is overlap between DC and several other rare syndromes that have been described.
​Keywords: telomerase; telomere; dyskerin; TERC; TIN2; Hoyeraal Hreidarsson; anticipation; pulmonary fibrosis; aplastic anaemia; telomere length
 

 

New Gene Announced at ASH

515 Germline Mutations in RTEL1 cause Dyskeratosis Congenita 
Program: Oral and Poster Abstracts
Type: Oral
Session: 508. Bone Marrow Failure - Inherited Disorders I
 
Monday, December 10, 2012: 3:45 PM 
B302-B303, Level 3, Building B (Georgia World Congress Center) 
Bari J Ballew, PhD1*, Kevin B. Jacobs, M.S.2*, Meredith Yeager, PhD2*, Neelam Giri, MD1, Joseph F Boland2*, Belynda D Hicks2*, Laurie Burdett, PhD2*, Amy A Hutchinson2*, Blanche P Alter, MD, MPH1 and Sharon A Savage, MD1
 
1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
2Core Genotyping Facility, National Cancer Institute, SAIC-Frederick, Inc., NCI-Frederick
 

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome that results from impaired telomere maintenance. The classic triad (dysplastic nails, skin pigmentation, and oral leukoplakia) is diagnostic of DC but significant clinical heterogeneity can exist, even within a family. Leukocyte telomere lengths less than the first percentile for age are diagnostic of DC. Patients with DC are at high risk of bone marrow failure (BMF), myelodysplastic syndrome, cancer, pulmonary fibrosis, liver disease and other complications. 

Currently, germline mutations in 1 of 8 telomere biology genes (DKC1, TERC, TERT, TINF2, NOP10, NHP2, WRAP53, and CTC1) are known to cause ~50-60% of DC cases. Our longitudinal cohort study conducts detailed medical record review and clinical examinations of patients with DC and their family members. DC is diagnosed based on the presence of the diagnostic triad or 1 of the triad plus BMF. All DC patients had telomeres <1st percentile. Patients are classified as DC-like if they have telomeres <1st percentile and other features, such as BMF or family history, suggestive of DC. All participants in this study were negative for mutations in the known DC genes. 

 

We performed whole exome sequencing (WES) on two DC families using an enriched multiplexed sequencing library (Nimblegen v2) and sequenced on an Illumina HiSeqTM. Variants were removed from analyses if they did not pass quality control filters or were present more than 3 times in publically available databases (1000Genomes, ESP, Kaviar, and dbSNP). Since DC can be inherited in autosomal dominant, autosomal recessive, and X-linked manners, we evaluated all inheritance models in our families. Additionally, if healthy family members had very short telomeres, they were also evaluated as potential silent carriers, since this approach has facilitated the identification of other DC genes. Nonsynonymous variants were considered deleterious if SIFT, PolyPhen 2, and Condel predictions were consistent. 

 

Family 1 has 2 siblings with the Hoyeraal Hreidarsson syndrome (HH) variant of DC, which includes features of DC plus cerebellar hypoplasia. In that family, WES revealed autosomal dominant inheritance of a nonsense mutation in RTEL1 (Regulator of Telomere Elongation Helicase 1), p.Arg1010Stop. Their mother, who has lymphocyte telomere lengths at the 1st percentile, is a clinically silent carrier of this mutation; the severe phenotypes present in her children are likely an example of genetic anticipation. In family 2, we found 2 RTEL1 mutations, a nonsense (p.Arg998Stop) and a deleterious missense (p.Glu615Asp) mutation, that were inherited from the father and mother, respectively. One clinically healthy child inherited only the missense mutation, but has telomeres <1st percentile. The other child has HH and extremely short telomeres; he is a compound heterozygote, having inherited both the missense and nonsense mutations in RTEL1. 

 

We subsequently performed targeted sequencing of the entire RTEL1 gene in all of our mutation-negative DC (n=11) and DC-like (n=14) families. We identified missense mutations in RTEL1 in 2 additional families. Family 3 has 2 DC-like siblings, but only the proband’s DNA was available for sequencing. He was heterozygous for a deleterious missense mutation (p.Ala645Thr) in a conserved helicase domain of RTEL1. In family 4, a mutation was inherited in an autosomal recessive manner by a proband with HH. This mutation is intronic except for a read-through transcript of RTEL1-TNFRSF6B, which utilizes an alternative exon 34. If translated, this variant results in the amino acid change p.Arg1264His, which is likely deleterious; if not, this mutation may affect nonsense-mediated decay or induce a regulatory change in RTEL1 expression. 

 

RTEL1 is an essential, evolutionarily conserved DNA helicase that is important for DNA replication and telomere elongation. Depletion of mRTEL1 from mouse embryonic stem cells results in telomeric loss and chromosomal instability. All individuals with germline RTEL1 mutations in this study have short telomeres, which underscores the functional importance of RTEL1 in human telomere maintenance. In summary, by employing WES followed by targeted sequencing, we discovered mutations in RTEL1 in 4 DC families, indicating that dysfunctional RTEL1 is a biologically plausible cause of DC. 

 


 

A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells

Rosario Machado-Pinilla1, 
Isabel Sánchez-Pérez1, 
José Ramón Murguía2, 
Leandro Sastre3, and 
Rosario Perona1
 
+ Author Affiliations
 
1Translational Oncology Unit, Instituto de Investigaciones Biomédicas Consejo Superior de Investigaciones, Cientificas/Universidad Autónoma de Madrid (CSIC/UAM), C/ Arturo Duperier, Madrid; 
2Institute of Plant Molecular and Cellular Biology, Universidad Politécnica de Valencia, Valencia; and 
3Department of Control of Gene Expression Regulation, Instituto de Investigaciones Biomédicas, CSIC/UAM, Madrid, Spain 
 

Abstract

 

Dyskerin gene is mutated in patients with X-linked dyskeratosis congenita (X-DC), which results in greatly reduced levels of telomerase activity. A genetic suppressor element (GSE) termed GSE24-2 has been isolated in a screening for cisplatin resistance. GSE24-2–expressing cells presented impaired telomerase inhibition following in vitro exposure to chemotherapies, such as cisplatin, or telomerase inhibitors. The promoter of the telomerase component hTERT was constitutively activated in GSE24-2 cells in a c-myc expression–dependent manner. Deletion analyses and mutagenesis of the human c-myc promoter demonstrated that the target sequence for activation was the nuclease hypersensitive element-III (NHEIII) site located upstream to the P1 region of the promoter. Further, expression of GSE24-2 in cell lines derived from patients with X-DC and in VA13 cells induced increased hTERT RNA and hTR levels and recovery of telomerase activity. Finally, expression of GSE24-2 was able to rescue X-DC fibroblasts from premature senescence. These data demonstrate that this domain of dyskerin plays an important role in telomerase maintenance following cell insults such as cisplatin treatment, and in telomerase-defective cells in patients with X-DC. The expression of this dyskerin fragment has a dominant function in X-DC cells and could provide the basis for a therapeutic approach to this disease. 

Submitted April 8, 2007. 

Accepted November 20, 2007. 

© 2008 by The American Society of Hematology

The full paper can be viewed by clicking here:

http://bloodjournal.hematologylibrary.org/content/111/5/2606.full

For more information about this company and their work you can visit their website at:  http://advmedprojects.com/

 


 

October 5th, 2009

Stockholm, Sweden -- Exciting news everyone! The Nobel Prize for Medicine has gone to three scientists whose work focused on telomere biology, a realm of science at the heart of recent research into Dyskeratosis Congenita (DC). As many of us know, recent work at the National Institutes of Health has led to the recognition that DC is a disorder of telomere biology. While the awarding of a Nobel may not mean a "cure" for DC is just around the corner, we at DC Outreach are glad to see research in this important field elevated to international prominence with this important recognition.

 

Here's the news, as described by the Nobel committee in an Oct. 5, 2009 press release: 

http://nobelprize.org/nobel_prizes/medicine/laureates/2009/press.html

 

Telomeres are structures on the ends of chromosomes that protect the strands of DNA, much like the plastic aglets that protect the ends of your shoelaces. Telomeres shorten naturally in everyone as they age. However, persons with DC have telomeres that are much shorter than expected for their age. While the research is ongoing, scientists over the years have found that DC is caused by a mutation in one of nine genes important in telomere biology However only about one-half of patients with DC have an identifiable mutation in one of these genes. Ongoing research aims to discover more DC-associated gene mutations, and to learn how telomere genes contribute to cancer development and aging.