Breaking News
February 22, 2019 - Growing number of cancer survivors, fewer providers point to challenge in meeting care needs
February 22, 2019 - Innovative compound offers a new therapeutic approach to treat multiple sclerosis
February 22, 2019 - $1.5 million grant to develop opioid treatment program for jail detainees
February 22, 2019 - FDA’s new proposed rule would update regulatory requirements for sunscreen products in the U.S
February 22, 2019 - Most Hip, Knee Replacements Last Decades, Study Finds
February 22, 2019 - Wellness problems prevalent among ob-gyn residents
February 22, 2019 - In the Spotlight: “The world is your oyster in geriatrics”
February 22, 2019 - Successful testing of multi-organ “human-on-a-chip” could replace animals as test subjects
February 22, 2019 - Analysis of cervical precancer shows decline in two strains of HPV
February 22, 2019 - Sugary stent eases suturing of blood vessels
February 22, 2019 - From surgery to psychiatry: A medical student reevaluates his motivations
February 22, 2019 - Is New App From Feds Your Answer To Navigating Medicare Coverage? Yes And No
February 22, 2019 - New pacemakers powered by heartbeats could reduce need for surgery
February 22, 2019 - The United States records highest drug overdose death rates
February 22, 2019 - Phase 1 data reinforce safety profile of new drug for treating Duchenne muscular dystrophy
February 22, 2019 - Vitamin D supplementation less effective in the presence of obesity, shows study
February 22, 2019 - Sarepta Announces FDA Acceptance of Golodirsen (SRP-4053) New Drug Application for Patients with Duchenne Muscular Dystrophy Amenable to Skipping Exon 53
February 22, 2019 - An institutional effort to reduce the amount of opioids prescribed following lumbar surgery
February 22, 2019 - Failure to take statins leads to higher mortality rates | News Center
February 22, 2019 - New study explains why some patients report phantom sensations after limb amputation
February 22, 2019 - First motor-controlled heart valves implanted by Mainz University Medical Center
February 22, 2019 - Novel preclinical model mimics persistent interneuron loss seen in preterm infants
February 22, 2019 - Global health burden of glaucoma has increased, study reveals
February 22, 2019 - A holistic approach key to minimize treatment complexity in patients with interstitial lung disease
February 22, 2019 - 1 in 10 middle-aged Chinese adults are at high risk for heart disease, finds study
February 22, 2019 - More than half a million breast cancer patient’s lives saved by improvements in treatment
February 22, 2019 - Study finds no evidence that tougher policies prevent teenage cannabis use
February 22, 2019 - New blood test detects genetic disorders in fetuses
February 22, 2019 - Lower Self-Perception Observed in Children With Amblyopia
February 22, 2019 - Up to 15 percent of children have sleep apnea, yet 90 percent go undiagnosed
February 22, 2019 - Rare pulmonary defect prompts parents’ nationwide search for answers | News Center
February 22, 2019 - Lesbian and bisexual women at greater risk of being overweight, study finds
February 22, 2019 - UQ research may explain why vitamin D is essential for brain health
February 22, 2019 - Heart Attacks Rising Among Younger Women
February 22, 2019 - How your smartphone is affecting your relationship
February 22, 2019 - Orthopaedic surgeon receives prestigious award, $10 million grant | News Center
February 22, 2019 - New sepsis test could save thousands of lives
February 22, 2019 - Cervical cancer could be eradicated by 2100
February 21, 2019 - Sustained smoking cessation can lower risk of seropositive RA
February 21, 2019 - Thousands with chronic UTIs are not receiving the treatment they need
February 21, 2019 - Are teens getting high on social media? The surprising study seeking the pot-Instagram link
February 21, 2019 - Stanford expands biobank services | News Center
February 21, 2019 - Scientists identify link between drinking contexts and early onset intoxication among adolescents
February 21, 2019 - Strong social support may reduce cardiovascular disease risk in postmenopausal women
February 21, 2019 - Rapid expansion of interventions could prevent up to 13 million cases of cervical cancer within 50 years
February 21, 2019 - Motif Bio Receives Complete Response Letter From The FDA
February 21, 2019 - Researchers map previously unknown disease in children
February 21, 2019 - A skeptical look at popular diets: Going gluten-free
February 21, 2019 - Podcast: KHN’s ‘What The Health?’ How Safe Are Your Supplements?
February 21, 2019 - Factors associated with increased risk of developing surgical site infections
February 21, 2019 - Anticipatory signals in eye movements can help measure attentive capacity, learning with greater precision
February 21, 2019 - Study explores daily exposure to indoor air pollutants
February 21, 2019 - Evening exercise does not negatively affect sleep, may also reduce hunger
February 21, 2019 - Artificial intelligence technique can be used to identify alcohol misuse in trauma setting
February 21, 2019 - Overweight, obesity in adolescence associated with increased risk of renal cancer later in life
February 21, 2019 - BGU develops new AI platform for monitoring and predicting ALS progression
February 21, 2019 - Researchers discover a new promising target to improve HIV vaccines
February 21, 2019 - Brief Anesthesia in Infancy Does Not Mar Neurodevelopment
February 21, 2019 - Gaming system helps with autism diagnosis
February 21, 2019 - Heart Disease: Six Things Women Should Know
February 21, 2019 - More States Say Doctors Must Offer Overdose Reversal Drug Along With Opioids
February 21, 2019 - Researchers explore case studies focused on industries that kill more people than employed
February 21, 2019 - Only half of GP practice buildings are fit for purpose
February 21, 2019 - Intense exercise, fasting and hormones can enhance waste-protein removal, study shows
February 21, 2019 - Scientists can monitor brain activity to predict epileptic seizures few minutes in advance
February 21, 2019 - Study quantifies hepatic and intestinal mRNA expression of Ugt isoforms in rats
February 21, 2019 - ‘Apple-Shaped’ Body? ‘Pear-Shaped’? Your Genes May Tell
February 21, 2019 - Can we repair the brain? The promise of stem cell technologies for treating Parkinson’s disease
February 21, 2019 - Trump Plan To Beat HIV Hits Rough Road In Rural America
February 21, 2019 - PENTAX Medical introduces new electrosurgical and argon plasma coagulation platforms
February 21, 2019 - Trump plan to beat HIV hits rough road in rural America
February 21, 2019 - Eating blueberries every day could help decrease blood pressure
February 21, 2019 - ‘No Second Chances’ report calls for new measures to combat cardiovascular disease in Australia
February 21, 2019 - Mayo clinic researchers discuss local case studies of leprosy
February 21, 2019 - Scientists demonstrate key role of salt in allergic immune reactions
February 21, 2019 - Experts propose revising the criteria for diagnosis of Parkinson’s disease
February 21, 2019 - The med student and the machine
February 21, 2019 - Hey, Hey! Ho, Ho! Is Striking For School Nurses The Way To Go?
February 21, 2019 - Latest research encourages children to move out and learn through physical activity
February 21, 2019 - Proper oral hygiene and regular visits to dentist can promote heart health
Mutations of IRF2BPL gene associated with previously undiagnosed neurological disorder

Mutations of IRF2BPL gene associated with previously undiagnosed neurological disorder

image_pdfDownload PDFimage_print

An international team of scientists, including researchers from Baylor College of Medicine, has discovered mutations of gene IRF2BPL that are associated with a previously undiagnosed neurological disorder in seven unrelated individuals. The researchers propose that these disease-causing mutations lead to a loss of function of the protein and that the gene IRF2BPL is required for proper neuronal function and maintenance. The study appears in the American Journal of Human Genetics.

“This project began when our colleague and corresponding author of this study Dr. Loren D.M. Pena, associate professor of pediatrics, and Dr. Vandana Shashi, professor of pediatrics at the Duke Clinical Site of the Undiagnosed Disease Network (UDN), connected us to a patient presenting with a severe neurological condition without a diagnosis,” said corresponding author Dr. Hugo Bellen, professor of molecular and human genetics and neuroscience at Baylor College of Medicine and an investigator at the Howard Hughes Medical Institute. “The patient’s and family’s DNA had been sequenced and indicated that the gene IRF2BPL was a candidate that could be causing the disease.”

Unfortunately, the normal function of the candidate gene is poorly known, but the researchers at the Model Organisms Screening Center of the UDN led by Drs. Bellen, Michael Wangler and Shinya Yamamoto, assistant professors of molecular and human genetics at Baylor College of Medicine, were already interested in this gene because it was on a list of autism candidate genes. In addition, first author Dr. Paul Marcogliese, postdoctoral associate of molecular and human genetics at Baylor, was creating reagents to study the gene in the fruit fly.

“I already had some experience with and interest in this gene, so when we received this first case through the UDN, I volunteered to pursue this project because I already had tools to study the gene,” Marcogliese said.

After the first patient, six more came along. Five of them presented with similar neurological characteristics: they were born healthy but, between the ages of 3 to 5 years, they began to display progressive, severe neurodevelopmental regression including lack of coordination, low muscle tone and muscle strength (hypotonia) and loss of full control of bodily movement (ataxia). Around their 10th birthday, most of them were in a wheelchair. The two other cases presented with milder characteristics, displaying global developmental delay and seizures.

Connecting gene IRF2BPL with an undiagnosed neurological disorder

The researchers’ investigations showed that the five individuals presenting with the most severe neurological condition carried a nonsense mutation of IRF2BPL, meaning a mutation that introduces a ‘stop’ signal within the gene’s protein coding region. This type of mutation results in the production of a truncated protein that usually cannot fulfill the function of the normal protein.

The two individuals presenting with milder neurological conditions, on the other hand, carry a missense mutation. In this case, the mutation changed one single ‘letter’ in the protein’s genetic code resulting in the substitution of one amino acid – the building blocks of proteins – for another in the protein made by the gene. Both the nonsense and the missense mutations are de novo, or new in the patients, meaning they are not present in their parents. The mutations also are dominant; only one of the two copies of the gene is defective in the patients, and this is sufficient to cause disease.

To learn more about gene IRF2BPL that could connect it to the human neurological disorder, the researchers carried out experiments in the fruit fly. This animal model expresses a gene called pits, which is the fruit fly’s equivalent of human IRF2BPL.

“Our studies showed that the gene known as pits is broadly expressed in the fruit fly’s brain,” said Bellen, who also is a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. “Complete loss of pits was lethal in the fly’s early development. Interestingly, we found that partially knocking down pits resulted in neurodegeneration that progressively affected motor functions as the flies aged. So, one common characteristic between the human and the fly condition is that both are a progressive type of neurodegeneration.”

The researchers also looked into what was going on at the cellular level, specifically the consequences of knocking down pits only in the light-sensitive neurons or photoreceptors in the fruit fly’s eyes.

“We observed that the photoreceptors are fine while the flies are young, but show signs of degeneration in the aged flies,” Marcogliese said. “Electron microscopy studies revealed a number of altered cellular structures and the accumulation of lipid droplets, which are known to negatively affect neuronal function.”

In addition, the researchers genetically modified fruit flies to express the mutated IRF2BPL genes found in the patients. Expressing the severe nonsense mutations in flies resulted in a drastic loss of function and expression of one of the missense mutations that causes a more subtle neurological condition in humans resulted in a partial loss of function in the flies.

“Taken together, our findings indicate that IRB2BPL and pits are essential genes for the nervous system of both humans and fruit flies and their loss or disruption results in a variety of neurological conditions,” Marcogliese said. “Next, we want to find ways to improve or prevent the condition.”

“The clinician-researcher partnership was particularly exciting, as the work on fruit flies provided additional compelling evidence that IRF2BPL is an important protein for neurological development and maintenance,” said Pena. “The work on fruit flies also was crucial in providing information to classify the variants in IRF2BPL as a likely diagnosis.”

“Our next goals are to work with fruit flies to study the biology of the process that leads to neurodegeneration and to develop a mouse model of the human condition in which we could test potential therapies,” Bellen said.

Source:

https://www.bcm.edu/news/molecular-and-human-genetics/neurological-disorder-linked-gene-mutations

Tagged with:

About author

Related Articles