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Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55,while about two thirds of affected females are intellectually disabled. Physical features may include a long and narrow face,large ears,flexible fingers,and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common,and seizures occur in about 10%. Males are usually more affected than females.
Repeated sequences are short or long patterns of nucleic acids that occur in multiple copies throughout the genome. In many organisms,a significant fraction of the genomic DNA is repetitive,with over two-thirds of the sequence consisting of repetitive elements in humans. Some of these repeated sequences are necessary for maintaining important genome structures such as telomeres or centromeres.
FMR1 is a human gene that codes for a protein called fragile X messenger ribonucleoprotein,or FMRP. This protein,most commonly found in the brain,is essential for normal cognitive development and female reproductive function. Mutations of this gene can lead to fragile X syndrome,intellectual disability,premature ovarian failure,autism,Parkinson's disease,developmental delays and other cognitive deficits. The FMR1 premutation is associated with a wide spectrum of clinical phenotypes that affect more than two million people worldwide.
In molecular biology,G-quadruplex secondary structures (G4) are formed in nucleic acids by sequences that are rich in guanine. They are helical in shape and contain guanine tetrads that can form from one,two or four strands. The unimolecular forms often occur naturally near the ends of the chromosomes,better known as the telomeric regions,and in transcriptional regulatory regions of multiple genes,both in microbes and across vertebrates including oncogenes in humans. Four guanine bases can associate through Hoogsteen hydrogen bonding to form a square planar structure called a guanine tetrad,and two or more guanine tetrads can stack on top of each other to form a G-quadruplex.
A trinucleotide repeat expansion,also known as a triplet repeat expansion,is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication,also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions,'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However,if the loop out structure is formed on the parent strand,a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally,the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.
Eukaryotic translation initiation factor 4E,also known as eIF4E,is a protein that in humans is encoded by the EIF4E gene.
Fragile X mental retardation syndrome-related protein 1 is a protein that in humans is encoded by the FXR1 gene.
Fragile X mental retardation syndrome-related protein 2 is a protein that in humans is encoded by the FXR2 gene.
AF4/FMR2 family member 2 is a protein that in humans is encoded by the AFF2 gene. Mutations in AFF2 are implicated in cases of breast cancer.
Robert Bernard Darnell is an American neurooncologist and neuroscientist,founding director and former CEO of the New York Genome Center,the Robert and Harriet Heilbrunn Professor of Cancer Biology at The Rockefeller University,and an Investigator of the Howard Hughes Medical Institute. His research into rare autoimmune brain diseases led to the invention of the HITS-CLIP method to study RNA regulation,and he is developing ways to explore the regulatory portions—known as the "dark matter"—of the human genome.
X-linked intellectual disability refers to medical disorders associated with X-linked recessive inheritance that result in intellectual disability.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder most frequently seen in male premutation carriers of Fragile X syndrome (FXS) over the age of 50. The main clinical features of FXTAS include problems of movement with cerebellar gait ataxia and action tremor. Associated features include parkinsonism,cognitive decline,and dysfunction of the autonomic nervous system. FXTAS is found in Fragile X "premutation" carriers,which is defined as a trinucleotide repeat expansion of 55-200 CGG repeats in the Fragile X mental retardation-1 (FMR1) gene. 4-40 CGG repeats in this gene is considered normal,while individual with >200 repeats have full Fragile X Syndrome.
Harvey Franklin Lodish is a molecular and cell biologist,professor at the Massachusetts Institute of Technology (MIT),Founding Member of the Whitehead Institute for Biomedical Research,and lead author of the textbook Molecular Cell Biology. Lodish's research focused on cell surface proteins and other important areas at the interface between molecular cell biology and medicine.
Fragile X-associated Primary Ovarian Insufficiency (FXPOI) is the most common genetic cause of premature ovarian failure in women with a normal karyotype 46,XX. The expansion of a CGG repeat in the 5' untranslated region of the FMR1 gene from the normal range of 5-45 repeats to the premutation range of 55-199 CGGs leads to risk of FXPOI for ovary-bearing individuals. About 1:150-1:200 women in the US population carry a premutation. Women who carry an FMR1 premutation have a roughly 20% risk of being diagnosed with FXPOI,compared to 1% for the general population,and an 8-15% risk of developing the neurogenerative tremor/ataxia disorder (FXTAS). FMR1 premutation women are also at increased risk of having a child with a CGG repeat that is expanded to >200 repeats. Individuals with a full mutation,unlike the premutation,produce little to no mRNA or protein from the FMR1 gene and are affected with Fragile X syndrome.
Ying-Hui Fu is a Taiwanese-American biologist and human geneticist who has made important contributions to understanding the genetics of many neurological disorders. Her chief discoveries include describing Mendelian sleep phenotypes,identifying causative genes and mutations for circadian rhythm disorders,and characterizing genetic forms of demyelinating degenerative disorders. Fu is currently a professor of neurology at the University of California,San Francisco. She was elected to the US National Academy of Sciences in 2018.
Nagwa Abdel Meguid is an Egyptian geneticist and 2002 winner of the L’Oreal UNESCO Award for Women in Science for Africa and the Middle East. Her research has "identified several genetic mutations that cause common syndromes such as the fragile X syndrome and Autism".
Randi J. Hagerman,M.D.,is the medical director of MIND Institute at the University of California,Davis. She works for the pediatrics department under the division of child development and behavior. She is an internationally recognized researcher in the field of genetics of autism spectrum disorder with special focus on genomic instability. Along with her husband Paul Hagerman,she discovered the Fragile X-associated tremor/ataxia syndrome (FXTAS),a neurological disorder that affects older male and rare female carriers of fragile X.
Jeannie T. Lee is a Professor of Genetics at Harvard Medical School and the Massachusetts General Hospital,and a Howard Hughes Medical Institute Investigator. She is known for her work on X-chromosome inactivation and for discovering the functions of a new class of epigenetic regulators known as long noncoding RNAs (lncRNAs),including Xist and Tsix.
Jean-Louis Mandel,born in Strasbourg on February 12,1946,is a French medical doctor and geneticist,and heads a research team at the Institute of Genetics and Molecular and Cellular Biology (IGBMC). He has been in charge of the genetic diagnosis laboratory at the University Hospitals of Strasbourg since 1992,as well as a professor at the Collège de France since 2003.
David L. Nelson is an American human geneticist,currently an associate director at the Intellectual and Developmental Disabilities Research Center (1995),and professor at the Department of Molecular and Human Genetics at Baylor College of Medicine BCM since 1999. Since 2018,he is the director at the Cancer and Cell Biology Ph.D program,and the director of Integrative Molecular and Biomedical Sciences Ph.D since 2015 at BCM.
References
- 1 2 3 "Stephen T Warren, Ph.D., FACMG".
- ↑ "Compensating for a faulty gene".
- ↑ "NICHD Honors Outstanding Scientists During 40th Anniversary Year".
- ↑ "Stephen T. Warren".
- ↑ "Dr. Stephen T. Warren Named to American Academy of Arts and Sciences".
- 1 2 3 4 5 6 7 "Profile of Stephen T. Warren".
- ↑ "Steps - A Jacob's Ladder Publication" (PDF).
- ↑ "Fragile X Researcher Honored By March of Dimes".
- ↑ "Dean's Distinguished Faculty Lecture and Award".
- ↑ "Award for Excellence in Molecular Diagnostics Past Recipients".
- ↑ "Dr. Stephen T. Warren Named to American Academy of Arts and Sciences".
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