Centrosomal protein of 290 kDa is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''CEP290''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
CEP290 is located on the Q arm of chromosome 12.
Function
The gene CEP290 is a centrosomal protein that plays an important role in
centrosome
In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle progre ...
and
cilia
The cilium (: cilia; ; in Medieval Latin and in anatomy, ''cilium'') is a short hair-like membrane protrusion from many types of eukaryotic cell. (Cilia are absent in bacteria and archaea.) The cilium has the shape of a slender threadlike proj ...
development. This gene is vital in the formation of the
primary cilium
The cilium (: cilia; ; in Medieval Latin and in anatomy, ''cilium'') is a short hair-like membrane protrusion from many types of eukaryotic cell. (Cilia are absent in bacteria and archaea.) The cilium has the shape of a slender threadlike proj ...
, a small antenna-like projections of the cell membrane that plays an important role in the photoreceptors at the back of the retina (which detect light and color) and in the kidney, brain, and many other organs of the body. Knocking down levels of the CEP290 gene transcript resulted in dramatic suppression of ciliogenesis in retinal pigment epithelial cells in culture, proving just how important CEP290 is to cilia formation.
On a molecular level, CEP290 has been shown to play a critical regulatory and structural role in primary cilium formation. Recent studies have implicated CEP290 as a
microtubule
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nanometer, nm and have an inner diameter bet ...
and
membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
binding protein that might serve as a structural link between the microtubule core of the cilium and the overlying ciliary membrane.
Disruption of CEP290's microtubule binding domain in the rd16 mouse model of CEP290 disease
has been shown to result in rapid and dramatic retinal degeneration, demonstrating the importance of CEP290 microtubule binding in disease. The role of CEP290 in promoting ciliogenesis is inhibited both by auto-regulatory domains found at either end of the CEP290 protein
and through CEP290's interaction with the inhibitory protein CP110.
The discovery of the CEP290 gene has led researchers to find another gene critical in retinal function, LCA5. Clinical trials involving gene replacement of these two genes have started in Philadelphia, where researchers are hopeful that Leber Congenital Amaurosis will one day be cured.
[McGill University Health Centre. "Gene Responsible For Blindness In Infants And Children Identified." ScienceDaily, 4 Jun. 2007. Web. 30 Mar. 2013.]
Structure
This gene encodes a protein with 13 putative
coiled-coil domain
A coiled coil is a structural motif in proteins in which two to seven alpha-helices are coiled together like the strands of a rope. ( Dimers and trimers are the most common types.) They have been found in roughly 5-10% of proteins and have a va ...
s, a region with homology to SMC
chromosome
A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
segregation
ATPase
ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, ATP hydrolase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or ...
s, six
KID motifs, three
tropomyosin homology domain
Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in many animal and fungal cells. In animals, it is an important component of the muscular system which works in conjunction with troponin to regulate muscle contraction. It is ...
s and an
ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for
''N''-glycosylation, tyrosine
sulfation
Sulfation (sometimes spelled sulphation in British English) is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected ...
,
phosphorylation
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writ ...
, N-
myristoylation
Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an ''N''-terminal glycine residue. Myristic acid is a 14-carbon saturated f ...
, and
amidation
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent any group, typically organyl groups or hydrogen atoms. The amide group is called a p ...
.
Clinical significance
Mutations in this gene have been associated with
Joubert syndrome
Joubert syndrome is a rare autosomal recessive genetic disorder that affects the cerebellum, an area of the Human brain, brain that controls balance and coordination.
Joubert syndrome is one of the many genetic syndromes associated with syndromic ...
and
nephronophthisis
Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease. The disorder is inherited in an autosomal recessive
In genetics, dominance is the phenomenon of one variant ...
, and recently with a frequent form of
Leber's congenital amaurosis
Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life.
It affects about 1 in 40,000 newborns. LCA was first described by Theodor Leber in the 19th century. It should not be ...
, called LCA10. The presence of antibodies against this protein is associated with several forms of cancer.
A mutation in this gene leads to infant and child blindness, a disease known as Leber Congenital Amaurosis. As of today, 35 different mutations in CEP290 are responsible for causing LCA. Other mutations in CEP290 have also been identified in causing Meckel Syndrome and Joubert Syndrome, a few among many syndromes. A defective CEP290 gene is usually the cause of these disorders due to abnormal cilia. It is unknown how one mutation in a gene can cause so many different types of syndromes, particularly many of which affect the Central Nervous System.
References
External links
GeneReviews/NIH/NCBI/UW entry on Bardet-Biedl Syndrome*
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Further reading
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{{Ciliary proteins
Centrosome