FMR1
Encyclopedia
Human
Humans are the only living species in the Homo genus...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that codes for a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
called fragile X mental retardation protein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development
Cognitive development
Cognitive development is a field of study in neuroscience and psychology focusing on a child's development in terms of information processing, conceptual resources, perceptual skill, language learning, and other aspects of brain development and cognitive psychology compared to an adult's point of...
and female reproductive function. Mutations of this gene can lead to fragile x syndrome
Fragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
, mental retardation, premature ovarian failure
Premature ovarian failure
Premature Ovarian Failure , also known as premature ovarian insufficiency, primary ovarian insufficiency , premature menopause, hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40...
, autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
, Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, developmental delays and other cognitive deficits.
FMR1 Gene Expressions
The FMR1 gene is located on the X chromosomeX chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
and contains a DNA segment called CGG trinucleotide. In most people, the CGG segment is repeated in the gene approximately 5-44 times. Increased expression of the CGG segment on the FMR1 gene is associated with impaired cognitive and reproductive function. If a person has 45-54 repeats this is considered the “gray zone” or borderline risk, 55-200 repeats is called premutation and more than 200 repeats is considered a full mutation of the FMR1 gene according to the American College of Medical Genetics.
The FMR1 gene can be found on the long (q) arm of the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
at position 27.3, from base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
146,699,054 to base pair 146,738,156.
Fragile X syndrome
Almost all cases of fragile X syndromeFragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
are caused by expansion of the CGG trinucleotide repeat in the FMR1 gene. In these cases, CGG is abnormally repeated from 200 to more than 1,000 times, which makes this region of the gene unstable. As a result, the FMR1 gene is methylated, which silences the gene (it is turned off and does not make any protein). Without adequate FMRP, severe learning deficits or mental retardation can develop, along with physical abnormalities seen in fragile X syndrome.
Fewer than 1 % of all cases of fragile X syndrome are caused by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s that delete part or all of the FMR1 gene, or change a base pair, leading to a change in one of the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s in the gene. These mutations disrupt the 3-dimensional shape of FMRP or prevent the protein from being synthesized, leading to the signs and symptoms of fragile X syndrome.
A CGG sequence in the FMR1 gene that is repeated about 55 to 200 times is described as a premutation expansion. Men, and probably some women, with this premutation do not have fragile X syndrome, but are at increased risk of developing a disorder known as fragile X-associated tremor/ataxia syndrome
Fragile X-associated tremor/ataxia syndrome
Fragile X-associated tremor/ataxia syndrome is a late onset neurodegenerative disorder associated with problems with movement, memory, and the autonomic nervous system...
(FXTAS). FXTAS is characterized by progressive movement problems (ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
), tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, memory loss
Memory loss
Memory loss can be partial or total and it is normal when it comes with aging. Sudden memory loss is usually a result of brain trauma and it may be permanent or temporary. When it is caused by medical conditions such as Alzheimers, the memory loss is gradual and tends to be permanent.Brain trauma...
, loss of sensation in the lower extremities (peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
) and mental and behavioral changes. The disorder usually develops late in life.
Although most men and women with the premutation are intellectually normal, some of these individuals have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience emotional problems such as anxiety or depression. About 20 % of women who carry a premutation expansion in the FMR1 gene experience premature ovarian failure (POF). POF is a loss of ovarian function in women younger than age 40, which can result in infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
. However, as Fragile X is an X-linked recessive
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
disorder, most females with premutation or even full mutation do not exhibit symptoms due to a second, normal X-chromosome.
Researchers have found that some children with a premutation expansion in the FMR1 gene have learning disabilities, mental retardation, or disorders in the autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
spectrum, characterized by deficits in communication and social interaction.
Premature Ovarian Aging
In recent years scientists have discovered that the FMR1 gene plays a very important role in ovarian function, independent from cognitive/neurological effects. Minor expansions of CGG repeats that do not cause fragile X syndromeFragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
are associated with an increased risk for premature ovarian aging, also called occult primary ovarian insufficiency, a condition in which women prematurely deplete their ovarian function
Polycystic Ovarian Syndrome
A very specific sub-genoype of FMR1 has been found to be associated with polycystic ovarian syndrome (PCOS). The gene expression, called heterozygous-normal/low may cause PCOS-like excessive follicle-activity and hyperactive ovarian function when women are younger. This leads to premature depletion of ovarian reserve and these women often suffer from premature ovarian aging when they are older.Interactions
FMR1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with FXR2
FXR2
Fragile X mental retardation syndrome-related protein 2 is a protein that in humans is encoded by the FXR2 gene.-Interactions:FXR2 has been shown to interact with FXR1, LCMT1, FMR1 and CYFIP1.-Further reading:...
, CYFIP1
CYFIP1
Cytoplasmic FMR1-interacting protein 1 is a protein that in humans is encoded by the CYFIP1 gene.-Interactions:CYFIP1 has been shown to interact with FXR2 and FMR1.-Further reading:...
, CYFIP2
CYFIP2
Cytoplasmic FMR1-interacting protein 2 is a protein that in humans is encoded by the CYFIP2 gene. Cytoplasmic FMR1 interacting protein is a 1253 amino acid long protein and is highly conserved having a 99% homology to the mouse protein. It is expressed mainly in brain tissues, white blood cells...
, NUFIP1
NUFIP1
Nuclear fragile X mental retardation-interacting protein 1 is a protein that in humans is encoded by the NUFIP1 gene.-Interactions:NUFIP1 has been shown to interact with FMR1, Cyclin T1 and BRCA1.-Further reading:...
, FXR1
FXR1
Fragile X mental retardation syndrome-related protein 1 is a protein that in humans is encoded by the FXR1 gene.-Interactions:FXR1 has been shown to interact with FXR2 and FMR1.-Further reading:...
, and NUFIP2
NUFIP2
Nuclear fragile X mental retardation-interacting protein 2 is a protein that in humans is encoded by the NUFIP2 gene.-Further reading:...
.