Cystinosin
   HOME

TheInfoList



OR:

''CTNS may also refer to the
Center for Theology and the Natural Sciences The Graduate Theological Union (GTU) is a consortium of eight private independent American theological schools and eleven centers and affiliates. Seven of the theological schools are located in Berkeley, California. The GTU was founded in 1962 ...
.'' ''CTNS'' is the
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
that encodes the
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
cystinosin in humans. Cystinosin is a
lysosomal A lysosome () is a membrane-bound organelle found in many animal Cell (biology), cells. They are spherical Vesicle (biology and chemistry), vesicles that contain Hydrolysis, hydrolytic enzymes that can break down many kinds of biomolecules. A ly ...
seven-transmembrane protein that functions as an active transporter for the export of cystine molecules out of the lysosome. Mutations in ''CTNS'' are responsible for
cystinosis Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine. It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosom ...
, an autosomal
recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
lysosomal storage disease.


Gene

''The CTNS'' gene is located on the
p arm In genetics, a locus (plural loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the total ...
of human
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
17, at position 13.2. It spans base pairs 3,636,468 and 3,661,542, and comprises 12
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s. In 1995, the gene was localized to the
short arm In genetics, a locus (plural loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker A genetic marker is a gene or DNA sequence with a known location on a chromosome that can be used to identify individuals or ...
of chromosome 17. An international collaborative effort finally succeeded in isolating ''CTNS'' by positional cloning in 1998. The CTNSN323K, CTNSK280R, and CTNSN288K mutations completely stop the movement of CySS out of the lysosome via cystinosin. /sup> interestingly, CTNSN323K and CTNSK280R are related to juvenile nephropathic cystinosis while CTNSN288K mutations are found in cases with infantile nephropathic cystinosis.


Tissue distribution

The gene is expressed in the lysosomes of all organs and tissues. Cystinosin has also been found in melanosomes in
melanocyte Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and heart. ...
s.


Structure

Cystinosin is a seven-transmembrane domain receptor embedded in the lysosomal membrane, and is a member of the
lysosomal cystine transporter family The lysosomal cystine transporter (LCT) familyTC# 2.A.43 is part of the TOG Superfamily and includes secondary transport proteins that are derived from animals, plants, fungi and other eukaryotes. They exhibit 7 putative transmembrane α-helical sp ...
of transport proteins. It comprises 367
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
residues, and has a molecular mass of 41738 Da. Cystinosin has seven
N-glycosylation ''N''-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein), ...
sites in the
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
region, spanning a range of 128 amino acid residues. The receptor also has two sorting motifs; a GYDQL motif in the C-terminus region, and a YFPQA motif, known as the 'PQ loop,' on the fifth inter-transmembrane
α-helix The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...
moiety. Cystinosin embeds in the lysosomal membrane with the C-terminus region facing the cytosol and the N-terminus region facing the lumen.


Mechanism

The protein obeys Michaelis-Menton kinetics and has an associated KM of 278 ± 49 μM. The GYDQL and YFPQA motifs on the C-terminal binds cystinosin to the lysosome. Mutations in the GYDQL motif cause a repositioning of cystinosin to being partially on the plasma membrane and partially on the lysosome. Mutations in both GYDQL and YFPQA motifs cause cystinosin to position itself to the plasma membrane instead of lysosomes An increase in acidity in the lumen of the lysosome initiates the reaction of CySS and H+ being transported into the cytosol.


Function

Cystinosin functions as a
symporter A symporter is an integral membrane protein that is involved in the transport of two (or more) different molecules across the cell membrane in the same direction. The symporter works in the plasma membrane and molecules are transported across the ...
which actively transports protons and cystine, the oxidized
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
dimer, out of the
lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
. Cystinosin only transports L-CySS while other cystine transporters will work on various amino acids. If cystine builds up in the lysosome it will inhibit the normal functioning of the organelle making the transport function important in the regular functioning of cells. Cystinosin has also been discovered in melanosomes and has been linked to the control and regulation of
melanin Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...
.


Clinical significance


Cystinosis

Mutations in ''CTNS'' gene can result in cystinosis.
Cystinosis Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine. It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosom ...
is a type of lysosomal transport disorder, a subset of lysosomal storage disorders. Variation in the encoded cystinosin protein results in an inhibition or loss in its ability to transport cystine out of the lysosome. Cystine molecules accumulate and form crystals within the lysosome, impairing its function.


Mutations

Cystinosis is presented in patients with a range of ''CTNS'' mutations; as of 2017, over 100 have been identified. The most common mutation is a 57,257 base pair deletion commonly referred to as the 57 kb deletion. This was formally known as the 65 kb deletion; a misnomer originating from early incorrect estimates. Other reported mutations include other deletions, missense mutations, and in-frame deletions and insertions. The type and extent of mutation determines the type and severity of cystinosis in the carrier. This is a result of the degree of transport inhibition caused by the misfolding of cystinosin. For example, mild cystinosis is typically associated with mutations that do not affect the amino acids in the transmembrane domains of cystinosin. In contrast, infantile nephropathic cystinosis, the most severe form of the disease, is most commonly associated with a total loss of activity. Gene deletion resulting in the absence of either of the sorting motifs results in the delocalization of cystinosin to the cellular plasma membrane.


Model systems

Human models for cystinosin are typically derived from cystinotic
renal tubular The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
cell lines. Non-human protein homologs for cystinosin include ERS1 in ''Saccharomyces cerevisiae'' (yeast cells) and the ''Caenorhabditis elegans'' protein, C41C4.7. Murine ctns has also been used.


See also

*
Cystinosis Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine. It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosom ...
*
Lysosomal storage disorders Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
*
Lysosomal Cystine Transporter Family The lysosomal cystine transporter (LCT) familyTC# 2.A.43 is part of the TOG Superfamily and includes secondary transport proteins that are derived from animals, plants, fungi and other eukaryotes. They exhibit 7 putative transmembrane α-helical sp ...


References


Further reading

* * * * * * * * * * *


External links


GeneReviews/NCBI/NIH/UW entry on Cystinosis
* {{UCSC gene info, CTNS
Genetics Home Reference
page on ''CTNS''.
Genetic Testing Registry