New Gene Mutation Found to Cause Retinitis Pigmentosa in SW USA Hispanics

MedicalResearch.com Interview with:

Stephen P. Daiger, PhD TS Matney Professor of Environmental and Genetic Sciences Human Genetics Center, School of Public Health and Mary Farish Johnston Distinguished Chair of Ophthalmology Ruiz Dept. of Ophthalmology and Visual Science The Univ. of Texas HSC at Houston

Dr. Daiger

Stephen P. Daiger, PhD
Professor, Human Genetics Center
Thomas Stull Matney, Ph.D. Professor in Environmental and Genetic Sciences
Mary Farish Johnston Distinguished Chair in Ophthalmology
The University of Texas Health Science Center at Houston

 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Thanks for your questions about our research.  My research group and I have a long-term interest in finding genes and mutations causing inherited retinal diseases.  Our main focus is on retinitis pigmentosa (RP) and, more specifically, the autosomal dominant form of RP.

Inherited retinal diseases are progressive, degenerative diseases of the retina.  Onset can be very early in life, even at birth, or much later in life.  As the degeneration develops an affected person may first experienced limited loss of vision, progressing to severe loss of vision, ending, in many cases, in legal or complete blindness.  About 300,000 Americans are affected by inherited retinal disease and 50% of these have RP.  RP, like most hereditary conditions, can be inherited in an autosomal dominant, autosomal recessive or X-linked fashion.

One of the surprising, and in some sense, disturbing findings in studying  retinitis pigmentosa is that mutations in many different genes can cause this disease.  We now know that mutations in more than 80 genes can cause RP and thousands of different mutations have been found in these genes.  With next-generations sequencing it is possible to find the cause of RP in from 50% to 80% of cases, depending on the underlying mode of inheritance.For example, in our research we can find the disease-causing mutation in about 75% of families with autosomal dominant RP.  Needless to say, a primary aim of our research is to find the cause in the remaining 25%.

In looking for the cause of retinitis pigmentosa in the remaining 25%, that is, those in whom mutations were not detected by earlier methods, we found a potential dominant-acting mutation in the arrestin-1 gene (gene symbol “SAG”) using whole-genome sequencing.  Molecular modeling suggests this mutation is damaging.  This was unexpected because previously-reported mutations in this gene were associated with Oguchi disease, a recessive retinal disease with symptoms distinct from RP.  On further testing our cohort of patients with autosomal dominant RP, we found this mutation in nearly 4% of families.  Even more surprisingly, when we looked closely at the affected families, and worked with our collaborators to test other patients, we discovered that all of the families with the dominant-acting SAG mutation — 12 total — were of Hispanic origin.  By interviewing informative family members we learned that these families have their roots in the Southwestern United States.  Historically, the mutation may have arisen hundreds of years ago, consistent with genetic variation tracking with the mutation.

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Study Finds Link Between Genetic Variant, Opioid Addiction and Binge Eating

MedicalResearch.com Interview with:

Camron D. Bryant Ph.D Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry Boston University, Boston, MA

Dr. Bryant

Camron D. Bryant Ph.D
Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry
Boston University, Boston, MA

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We previously used genome-wide linkage analysis, fine mapping, gene validation, and pharmacological targeting to identify a negative regulatory role for the gene casein kinase 1-epsilon (Csnk1e) in behavioral sensitivity to drugs of abuse, including psychostimulants and opioids.

Parallel human candidate genetic association studies identified an association between multiple genetic variants in CSNK1E with heroin addiction in multiple populations. Drug addiction is a multi-stage process that begins with the initial acute subjective and physiological responses that can progress to chronic administration, tolerance, and withdrawal. The recovery process begins with abstinence from drug taking but can quickly be derailed by relapse to drug taking behavior. Preclinical pharmacological studies also support a role for CSNK1E in reinstatement of opioid self-administration and relapse to alcohol drinking.

Despite the evidence that disruption of Csnk1e gene and protein function can affect various behaviors associated with drug and alcohol addiction, it is unclear what stage of the addiction process these genetic and pharmacological manipulations modulate. In this study, we show that disruption of the Csnk1e gene resulted in an enhancement of the rewarding properties of the highly potent and addictive opioid, fentanyl.  Unexpectedly, we also discovered that disruption of Csnk1e also enhanced binge eating – but only in female mice.

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Gene Linked To Decreased Plasma Amyloid and Lower Alzheimer’s Disease Risk

MedicalResearch.com Interview with:

Mikko Hiltunen, PhD Professor of Tissue and Cell Biology University of Eastern Finland School of Medicine, Institute of Biomedicine Kuopio,  Finland

Dr. Hiltunen

Mikko Hiltunen, PhD
Professor of Tissue and Cell Biology
University of Eastern Finland
School of Medicine, Institute of Biomedicine
Kuopio,  Finland 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:  We wanted to assess among the population-based METSIM (METabolic Syndrome In Men) cohort whether protective variant in APP gene (APP A673T) affects the beta-amyloid levels in plasma. The rationale behind this was that previous genetic studies have discovered that the APP A673T variant decreases the risk of having Alzheimer’s disease (AD).

However, the protective functional outcome measures related to this variant were lacking and thus we anticipated that the elucidation of plasma samples in terms of beta-amyloid levels would provide the much needed link between APP A673T variant and potential protective functions.

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Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

MedicalResearch.com Interview with:

Antonis Antoniou PhD Reader in Cancer Risk Prediction Academic Course Director MPhil in Epidemiology Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care Strangeways Research Laboratory Cambridge University of Cambridge

Dr. Antoniou

Antonis Antoniou PhD
Reader in Cancer Risk Prediction
Academic Course Director MPhil in Epidemiology
Centre for Cancer Genetic Epidemiology
Department of Public Health and Primary Care
Strangeways Research Laboratory Cambridge
University of Cambridge

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Several studies demonstrated that women with genetic faults in the BRCA1 and BRCA2 genes are at increased risk of developing breast and ovarian cancer. Having accurate age-specific cancer risk estimates for women with mutations is essential for their optimal clinical management.

Most studies to date that estimated cancer risks for BRCA1 and BRCA2 mutation carriers have been “retrospective”, in other words they look at what happened in the past. Estimates from such studies are prone to biases because they rely on the experience of women who have already developed cancer and on self-reported cancer family history information on relatives – which may have inaccuracies.

The ideal epidemiological study design for estimating cancer risks are prospective studies.  In prospective studies, healthy women with genetic faults are followed over time and overcome these potential biases. However, to date, published  prospective studies have been very small.

In the present study we used data from a prospective cohort of women with BRCA1 and BRCA2 mutations who were recruited from 1997 to 2011 and were followed over time. The study included almost 10,000 women who were included in the analyses, and was made possible through collaborations between scientists from Europe, North America and Australia.  The prospective study design explains why it has taken 20 years of hard work to get these results. Most importantly, it took an enormous long-term contribution and commitment from the women themselves to allow the scientists to be able to assemble this dataset.

Here, we were able to estimate more precisely the breast and ovarian cancer risks for women with faults in BRCA1 and BRCA2.  These risk estimates will provide more confidence in the counseling and clinical management of women with faults in the BRCA1 and BRCA2  genes.

A novel finding in this study is that breast cancer risk for women with faults in BRCA1 and BRCA2  increases rapidly at a young age then remains at a constant high level for the rest of their lives. It peaks in the 40’s for BRCA1 mutation carriers and in the 50’s for BRCA2 carriers, but  carriers of mutations in both genes  are at about the same high risk in later life. This is important information to inform the clinical management of older mutation carriers.

This study also shows clearly that for women with a mutation, there are other factors that are important in modifying the breast cancer risk. The study has demonstrated that the extent of the woman’ family history of cancer and the exact place on the gene where her mutation is located are very important in determining the actual risk.

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Rapid Improvements Coming to Gene Editing Techniques

MedicalResearch.com Interview with:

Michael Farzan PhD Co-chair and Professor Department of Immunology and Microbiology  Florida Campus  The Scripps Research Institute Jupiter, Florida

Dr. Farzan

Michael Farzan PhD
Co-chair and Professor
Department of Immunology and Microbiology
Florida Campus
The Scripps Research Institute
Jupiter, Florida

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: CRISPR is system for immune protection of bacteria.  It has now been widely adopted for use in editing mammalian cells.  The most commonly used CRISPR effector protein is Cas9.  Cas9 binds a guide RNA to recognize a DNA target, for example an incoming virus infecting a bacterium, or a gene in a human chromosome.  In bacteria, Cas9 requires a second protein to clear the guide RNA from a longer “CRISPR array”, basically a string of guide RNAs.

We have been studying a CRISPR effector protein related to Cas9 called Cpf1.  In bacteria it was know that, unlike Cas9, Cpf1 could cleave a CRISPR array by itself, without assistance from a second protein.  We knew that if it could do the same thing in human cells, it would help to simplify a number of gene-editing applications.  We were able to show that Cas9 could indeed excise multiple guide RNAs from a single message RNA in human cells.  We further showed that this approach was more efficient than the previous ways that guide RNAs were generated for gene editing, even more so when multiple guide RNAs were needed.

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Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing’s disease

MedicalResearch.com Interview with:

Constantine A. Stratakis, MD, DMSci Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Bethesda

Dr. Stratakis

Constantine A. Stratakis, MD, DMSci
Section on Endocrinology and Genetics
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health, Bethesda

MedicalResearch.com: What is the background for this study?

Response: The pituitary and adrenal glands operate on a kind of feedback loop. In response to stress, the pituitary release ACTH (Adrenocorticotropic hormone), which signals the adrenal glands to release cortisol. Rising cortisol levels then act on the pituitary, to shut down ACTH production. In a previous study, Jacque Drouin of the Institute for Clinical Research in Montreal and colleagues had determined that the CABLES1 protein was a key player in this feedback mechanism, switching off pituitary cell division in cultures exposed to cortisol. Since this feedback mechanism appears to be impaired in many corticotropinomas, we investigated the presence of Cables1 gene mutations and copy number variations in a large group of patients with Cushing’s disease.

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Mind–Body Interventions Reduce Inflammatory Activity of Genes

MedicalResearch.com Interview with:

Ivana Buric Brain, Belief, and Behaviour Lab Centre for Psychology, Behaviour, and Achievement, Faculty of Health and Life Sciences Coventry University, Coventry, United Kingdom Donders Institute for Brain, Cognition and Behaviour Radboud University, Nijmegen, Netherlands

Ivana Buric

Ivana Buric
Brain, Belief, and Behaviour Lab
Centre for Psychology, Behaviour, and Achievement, Faculty of Health and Life Sciences
Coventry University, Coventry, United Kingdom
Donders Institute for Brain, Cognition and Behaviour
Radboud University, Nijmegen, Netherlands

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:  Genes that we inherited can change their activity – the​y can be active and produce proteins, but they can also stop producing proteins and remain silent. We are now beginning to understand what aspects of our environment affect the activity of which genes.

In this study, we analysed all the existing studies that examined the effects of mind-body interventions on the expression of our genes and found that mind-body techniques reduce the activity of genes that produce inflammatory proteins.

This pattern was found in all studies despite the fact that they vary in the amount of physical activity: Tai Chi, yoga, breathing techniques and different types of meditation. We believe that this effect is observed due to reduced stress.

When we experience something stressful, the brain regions associated with pain get activated and send that signal further to sypmathetic nervous system that produces epinephrine and norepinefrine, and activates nuclear factor kappa B – a molecule that travels to and activated the genes that produce inflammatory proteins. When we do yoga or meditation, we learn to perceive situations differently and consequently experience less stress, which then prevents the production of inflammatory proteins.

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Genetic Cause of Cushing’s Disease Detected

MedicalResearch.com Interview with:

Constantine A. Stratakis, MD, DMSci Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Bethesda

Dr. Stratakis

Constantine A. Stratakis, MD, DMSci
Section on Endocrinology and Genetics
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health, Bethesda 

MedicalResearch.com: What is the background for this study?

Response: The pituitary and adrenal glands operate on a kind of feedback loop.  In response to stress, the pituitary release ACTH (Adrenocorticotropic hormone), which signals the adrenal glands to release cortisol.  Rising cortisol levels then act on the pituitary, to shut down ACTH production. In a previous study, Jacque Drouin of the Institute for Clinical Research in Montreal and colleagues had determined that the CABLES1 protein was a key player in this feedback mechanism, switching off pituitary cell division in cultures exposed to cortisol. Since this feedback mechanism appears to be impaired in many corticotropinomas, we investigated the presence of Cables1 gene mutations and copy number variations in a large group of patients with Cushing’s disease.

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Which Diet Is Best For You? It Depends On Your Genes

MedicalResearch.com Interview with:

Kaixiong (Calvin) Ye, PhD Post-doctoral Associate Dept. of Biological Statistics & Computational Biology Cornell University thaca, NY

Dr. Kaixong Ye

Kaixiong (Calvin) Ye, PhD
Post-doctoral Associate
Dept. of Biological Statistics & Computational Biology
Cornell University
thaca, NY

MedicalResearch.com: What is the background for this study?

Response: Omega-6 and omega-3 fatty acids are critical for human brain development, cognitive function, immune response, and cardiovascular health. Physiologically active forms of omega-6 and omega-3 fatty acids, such as AA, EPA, and DHA, are readily available in meat and seafood, but are absent in most plant-based foods (e.g. fruits and vegetables). Instead, plant-based foods contain two precursor fatty acids, LA and ALA, which could be metabolized in our body and converted into physiologically active forms. Fatty acid desaturase (FADS) genes encode key enzymes for this biosynthesis.

We hypothesized that genetic variations in FADS genes that enhance the biosynthesis efficiency were adaptive to plant-based diets in traditional farming populations and thus became more frequent over time. Our study compiled a huge data set of genetic information (DNA) from both present-day and ancient individuals. For the first time, we examined the action of natural selection on humans for the past 30,000 years in Europe.

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Epigenetic Changes Identified In Children Who Develop Early Onset Conduct Problems

MedicalResearch.com Interview with:
Charlotte Cecil, PhD

ESRC FRL Fellow
Edward Barker, PhD
Lab Director, DEVELOPMENTAL PSYCHOPATHOLOGY LAB

Department of Psychology
Institute of Psychiatry, Psychology& Neuroscience
King’s College London

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Conduct problems (CP) are the most common reason for child treatment referral in the UK, costing an estimated £22 billion per year. Children with CP engage in a range of aggressive and antisocial behaviours (e.g. fighting, stealing, lying), that affect their ability to follow rules and adapt to society, do well in school, and form healthy relationships. Those who do not receive treatment are also at increased risk for many negative outcomes in adulthood, including lower job prospects and earnings, more contact with the police and a lower quality of life. Therefore, it is important to understand how CP develop in the first place, in order to create more effective prevention and intervention strategies.

Studies have found that children who develop conduct problems before the age of 10 (early-onset CP) are at greatest risk for poor outcomes across the lifespan. Compared to other children, those showing early-onset CP tend to have experienced more adversity in early life (e.g. prenatal stress, poverty) as well as having more genetic risk. However, little is known about about how genetic factors interact with environmental influences – especially during foetal development – to increase the risk for early-onset conduct problems.

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