CTNS may also refer to the Center for Theology and the Natural Sciences.
CTNS is the gene that encodes the protein cystinosin in humans. Cystinosin is a lysosomal seven-transmembrane protein that functions as an active transporter for the export of cystine molecules out of the lysosome. [5]
Mutations in CTNS are responsible for cystinosis, an autosomal recessive lysosomal storage disease. [6]
The CTNS gene is located on the p arm of human chromosome 17, at position 13.2. [6] It spans base pairs 3,636,468 and 3,661,542, and comprises 12 exons. [6] [7]
In 1995, the gene was localized to the short arm of chromosome 17. [8] An international collaborative effort finally succeeded in isolating CTNS by positional cloning in 1998. [6]
The CTNSN323K, CTNSK280R, and CTNSN288K mutations completely stop the movement of CySS out of the lysosome via cystinosin.[2] interestingly, CTNSN323K and CTNSK280R are related to juvenile nephropathic cystinosis while CTNSN288K mutations are found in cases with infantile nephropathic cystinosis. [5]
The gene is expressed in the lysosomes of all organs and tissues. [9] Cystinosin has also been found in melanosomes in melanocytes. [10]
Cystinosin is a seven-transmembrane domain receptor embedded in the lysosomal membrane, and is a member of the lysosomal cystine transporter family of transport proteins. [11] It comprises 367 amino acid residues, and has a molecular mass of 41738 Da. [11] Cystinosin has seven N-glycosylation sites in the N-terminus region, spanning a range of 128 amino acid residues. [12]
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 moiety. [13]
Cystinosin embeds in the lysosomal membrane with the C-terminus region facing the cytosol and the N-terminus region facing the lumen. [14]
The protein obeys Michaelis-Menton kinetics and has an associated KM of 278 ± 49 μM. [12] [15]
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 [14]
An increase in acidity in the lumen of the lysosome initiates the reaction of CySS and H+ being transported into the cytosol. [14]
Cystinosin functions as a symporter which actively transports protons and cystine, the oxidized cysteine dimer, out of the lysosome. [12] Cystinosin only transports L-CySS while other cystine transporters will work on various amino acids. [14] 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. [10]
Mutations in CTNS gene can result in cystinosis. Cystinosis is a type of lysosomal transport disorder, a subset of lysosomal storage disorders. [16] 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. [9]
Cystinosis is presented in patients with a range of CTNS mutations; as of 2017, over 100 have been identified. [17] [18] 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. [19] [20] Other reported mutations include other deletions, missense mutations, and in-frame deletions and insertions. [21] [22]
The type and extent of mutation determines the type and severity of cystinosis in the carrier. [23] This is a result of the degree of transport inhibition caused by the misfolding of cystinosin. [21] For example, mild cystinosis is typically associated with mutations that do not affect the amino acids in the transmembrane domains of cystinosin. [7] In contrast, infantile nephropathic cystinosis, the most severe form of the disease, is most commonly associated with a total loss of activity. [21]
Gene deletion resulting in the absence of either of the sorting motifs results in the delocalization of cystinosin to the cellular plasma membrane. [24] [12]
Human models for cystinosin are typically derived from cystinotic renal tubular cell lines. [25] [26]
Non-human protein homologs for cystinosin include ERS1 in Saccharomyces cerevisiae (yeast cells) and the Caenorhabditis elegans protein, C41C4.7. [27] Murine ctns has also been used. [28]
A lysosome is a single membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that digest many kinds of biomolecules. A lysosome has a specific composition, of both its membrane proteins and its lumenal proteins. The lumen's pH (~4.5–5.0) is optimal for the enzymes involved in hydrolysis, analogous to the activity of the stomach. Besides degradation of polymers, the lysosome is involved in cell processes of secretion, plasma membrane repair, apoptosis, cell signaling, and energy metabolism.
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 autosomal recessive disorder resulting from accumulation of free cystine in lysosomes, eventually leading to intracellular crystal formation throughout the body. Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group. Fanconi syndrome occurs when the function of cells in renal tubules is impaired, leading to abnormal amounts of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium and phosphates.
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