Breaking News
March 19, 2018 - ‘Tummy Tuck’ Relieved Postpartum Back Pain/Incontinence
March 19, 2018 - New biomarkers for neuroblastoma, a type of cancer in children
March 19, 2018 - Hookah Smoking Carries a Poisoning Risk
March 19, 2018 - Do Mood and Anxiety Affect MS Disability?
March 19, 2018 - Mean depth of ultrasonographic penetration greater in autism
March 19, 2018 - Platypus milk may help combat antibiotic resistance
March 19, 2018 - U.S. IDE study of THERMOCOOL SMARTTOUCH SF Catheter completes patient enrollment
March 18, 2018 - E-cigarette use exposes adolescents to potentially cancer-causing chemicals
March 18, 2018 - GOP Senator: Solve Opioid Crisis Through Community, Not Policy
March 18, 2018 - Why is ADHD more common in boys than girls?
March 18, 2018 - Measles alert after two passengers with the disease fly into US
March 18, 2018 - FDA looks to remove nicotine from cigarettes
March 18, 2018 - FDA moves to cut nicotine in cigarettes, helping smokers kick habit
March 18, 2018 - Athenex Announces Phase II Clinical Study Results for KX2-391 Ointment for the Treatment of Actinic Keratosis
March 18, 2018 - Surgery Tied to Better Outcomes in Kids with T2D
March 18, 2018 - Scientists use nanotechnology to detect molecular biomarker for osteoarthritis
March 18, 2018 - Research establishes use of chimeric cells as potential therapy for Duchenne muscular dystrophy
March 18, 2018 - Researcher working to develop improved endoscopic probe for colonoscopies
March 18, 2018 - Researchers develop way to sequence entire fetal genome by modifying prenatal testing method
March 18, 2018 - FDA Approves PDUFA Fee Waiver for Gimoti New Drug Application
March 18, 2018 - P2Y12 Tx Subsidy Yields Positive Response from Docs, Patients
March 18, 2018 - Are Proteins in Formula Linked to Type 1 Diabetes?
March 18, 2018 - Exercise does not seem to increase bone marrow edema in healthy people
March 18, 2018 - Researchers delineate architecture of nuclear pore complex in yeast cells
March 18, 2018 - ‘It’s Just Ghetto-izing People’: What We Heard This Week
March 18, 2018 - Alzheimer’s disease: Neuronal loss very limited
March 18, 2018 - Study reveals impact of intense, changing work schedules experienced by medical interns
March 18, 2018 - Jobs That Keep the Mind Sharp … Even Into Retirement
March 18, 2018 - Facial Scarring Improved with Botulinum Toxin
March 18, 2018 - Data detectives shift suspicions in Alzheimer’s to inside villain
March 18, 2018 - Shorter Preventive TB Tx Effective for HIV+ Patients
March 18, 2018 - New technique for identifying alcoholism puts treatment options at patients’ and providers’ fingertips
March 18, 2018 - Researchers uncover four microRNAs as potential biomarkers for atrial fibrillation
March 18, 2018 - IRX Therapeutics Announces Initiation of Phase 2 Clinical Trial of IRX-2 in Squamous Cervical or Vulvar Intraepithelial Neoplasia 3
March 18, 2018 - OncoBreak: Learning from Silence; ‘Rigged’ Drug System; NCCN Guidelines Questioned
March 18, 2018 - The coffee cannabis connection
March 18, 2018 - Novel centrifugal-flow pump for heart failure patients provides improved long-term outcomes
March 18, 2018 - U.S. FDA Accepts New Drug Application for Prucalopride (SHP555) for Chronic Idiopathic Constipation
March 18, 2018 - Cath Lab Recap: iFR vs FFR $$; Ridaforolimus-Eluting Stent
March 18, 2018 - Tree care workers need better training to handle dangers on the job, study finds
March 18, 2018 - Dementia patients do not undergo diagnostic evaluation at onset of disease, study finds
March 18, 2018 - Transplanting enhanced interneurons restores brain rhythms in mouse model of Alzheimer’s
March 18, 2018 - Gene Therapy Flops for Critical Limb Ischemia
March 17, 2018 - Study spotlights risks in anesthesiologist handoffs
March 17, 2018 - Verb fluency test may be useful tool for differential diagnosis of cognitive failure
March 17, 2018 - Health Tip: Suggestions to Improve Your Cholesterol
March 17, 2018 - Fructans Suspect in Non-Celiac Gluten Sensitivity
March 17, 2018 - Aspirin therapy appears safe before thyroid surgery
March 17, 2018 - Minimally invasive surgical device may one day provide lasting heart repair
March 17, 2018 - UIH and RaySearch enter into new partnership
March 17, 2018 - Is BMI Too Inexact? | Medpage Today
March 17, 2018 - Sleep apnea study finds male-female differences in cerebral cortex thickness, symptoms
March 17, 2018 - Leicester research could help identify people with asthma of different severities
March 17, 2018 - Biosense Webster enrolls and treats first AF patient in clinical study of new RF balloon catheter
March 17, 2018 - Participants in rogue herpes vaccine research take legal action
March 17, 2018 - Imara Doses First Patient in Phase 2a Clinical Trial of IMR-687 for Sickle Cell Disease
March 17, 2018 - AAP: Prevent Medication Errors by Improving Processes
March 17, 2018 - Severe sleep apnea during REM sleep tied to acute CV events
March 17, 2018 - Alzheimer’s disease also affects small blood vessels
March 17, 2018 - Jazz Pharmaceuticals Announces FDA Acceptance of NDA for Solriamfetol (JZP-110) for Excessive Sleepiness Associated with Narcolepsy or Obstructive Sleep Apnea
March 17, 2018 - Switching Biologics in Psoriasis Care
March 17, 2018 - Polygenic risk score may identify alzheimer’s risk in younger populations
March 17, 2018 - Genetic heart mutations account for fewer sudden and unexplained infant deaths
March 17, 2018 - Clinical trial to test efficacy of stem cell transplants in stopping ALS muscle deterioration
March 17, 2018 - Researchers team up to improve life for children with microcephaly
March 17, 2018 - Health guide for young women regarding labiaplasty
March 17, 2018 - Inhaled Nitrite Flops as HFpEF Therapy
March 17, 2018 - California mental health tax providing services to needy in L.A. County, study finds
March 17, 2018 - Cancer survivors become fatigued more quickly than their peers, study finds
March 17, 2018 - Study finds common presence of nightmares among U.S. military personnel
March 17, 2018 - Yellow fever outbreak in Brazil necessitates vaccination for travelers
March 17, 2018 - Health Tip: Waist Size May Help Predict Heart Attack
March 17, 2018 - Low-Dose Combo Pill Successfully Takes Down High BP
March 17, 2018 - Most children with sickle cell anemia not receiving key medication to stay healthy
March 17, 2018 - YCC launches new Yale Center for Immuno-Oncology
March 17, 2018 - My Job Isn’t to Move Patients Quickly
March 17, 2018 - Achoo! Cold, Flu, or Something Else?
March 17, 2018 - For girls who mature early, psychological problems last into adulthood
March 17, 2018 - Researchers find new method to restore movement sensation in patients with prosthetic arms
March 17, 2018 - Older patients with colorectal cancer at increased risk of cardiovascular morbidity
A cluster of mutations in neurofibromatosis is important risk factor for severe symptoms

A cluster of mutations in neurofibromatosis is important risk factor for severe symptoms

image_pdfDownload PDFimage_print
Ludwine Messiaen. Credit: UAB

Research led by Ludwine Messiaen, Ph.D., professor of genetics at the University of Alabama at Birmingham, shows that missense mutations in a cluster of just five codons in the NF1 gene are an important risk factor for severe symptoms of the genetic disease neurofibromatosis type 1.

Such information is vital to help guide clinical management and genetic counseling in this complex disease that can be caused by more than 3,000 different mutations found in every part of this large NF1 gene. It shows a potential need for increased disease surveillance of patients with missense mutations in that cluster—specifically, codons 844 to 848.

Individuals with such mutations, the researchers found, have a high incidence of benign tumors of peripheral nerves or the spinal cord, tumors of the optic nerve, and skeletal abnormalities. They also have a high predisposition to develop malignancies, compared with the general neurofibromatosis population.

A missense mutation is a change in one nucleotide in DNA that results in a codon for a different amino acid in the protein made by the gene. The protein encoded by NF1 is a string of 2,818 amino acids that folds into the protein shape. Although the NF1 gene was cloned in 1990, the cellular functions performed by the huge, multi-domain protein encoded by the gene, and called neurofibromin, are still incompletely understood. As such, the specific function of the NF1 codons 844-848 remains so far unknown.

This new study is just the fourth clinically relevant association between specific mutations and specific symptoms that have been discovered for neurofibromatosis type 1. Such an association is known as a genotype-phenotype correlation.

Finding these correlations is important because whether patients will have mild or severe disease cannot—in most cases—be predicted when the neurofibromatosis type 1 first appears, often only with café-au-lait skin markings in infants. As the patients grow, they show a broad clinical variability, especially beginning at puberty, when many develop benign skin tumors called neurofibromas that erupt as bumps across the body.

Patients vary widely in their symptoms, which can include freckles near skin folds of the body, nodules in the eyes, tumors along the optic nerve, heart defects, bone anomalies, developmental delay, intellectual disability and learning problems.

“It is important for people to know what may happen,” Messiaen said. “When a child is born with neurofibromatosis type 1, café-au-lait spots appear very shortly after birth. But other problems, more specifically the development of skin neurofibromas, typically appear around puberty. If a genotype-phenotype correlation exists for a particular mutation, it will help these families have some perspective of what the future will bring, and it will help families cope with the disease.”

Massive effort

To look for correlations, Messiaen and her team collect detailed clinical information on all symptoms found in each of the neurofibromatosis individuals who had their mutation identified through clinical testing at the UAB Medical Genomics Laboratory. Data are compared to large clinical cohorts previously reported in the literature, as well as to the internal Medical Genomics Laboratory dataset on more than 8,100 unrelated mutation-positive individuals.

The initial characterization of 78 individuals in the Medical Genomics Laboratory cohort with mutations affecting the amino acids 844-848 led to the identification of a genotype correlation and the study was further expanded to include another 84 individuals from collaborating centers. This study, published in the American Journal of Human Genetics, involved 75 researchers and clinicians from 46 hospitals and universities in the United States, Belgium, Italy, Spain, the Netherlands, the United Kingdom, Australia, Brazil, Canada, Israel and Singapore. The study included 129 unrelated people who were the first in their family with the disorder, called probands, and 33 affected relatives.

Neurofibromatosis type 1 is a common genetic disorder with highly variable symptoms, and it occurs in one out of every 2,000 to 3,000 births. The kaleidoscope of clinical signs in neurofibromatosis type 1 is mirrored by an abundance of different mutations in the NF1 gene.

The UAB Medical Genomics Laboratory has collected DNA and identified a pathogenic mutation on the more than 8,100 unrelated neurofibromatosis type 1 patients. These include more than 3,000 different mutations, and the mutational spectrum involves microdeletions, deletions or duplications of one or more exons, frameshift and nonsense mutations, and splice or missense mutations.

The missense mutations affecting codons 844-848 in the NF1 gene are found in about 0.8 percent of the mutation-positive probands in the UAB MGL cohort. Although only four groups of recurrent mutations with clear genotype-phenotype correlations have so far been reported, each of them affecting only a small percentage of NF1-affected individuals, they together affect between 5 and 10 percent of the neurofibromatosis type 1 population. While this is already a significant fraction of patients, Messiaen said the “surface has only been scratched.”

While the present study suggests a potential need for increased disease surveillance in individuals with missense mutations affecting amino acids 844-848, it also may herald a potential for genotype-driven personalized medicine. A renewed interest in genotype-phenotype correlations is needed to achieve a timely unfolding of additional correlations, and this will require close collaboration between NF1 clinicians and molecular geneticists.

The study is published in the American Journal of Human Genetics.

Explore further:
Diagnostic mutations ID’d in chronic kidney disease patients

More information:
“Genotype-phenotype correlation in NF1 individuals: evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848,” American Journal of Human Genetics, DOI: 10.1016/j.ajhg.2017.12.001

Journal reference:
American Journal of Human Genetics

Provided by:
University of Alabama at Birmingham

Tagged with:

About author

Related Articles