In 1995, the gene was localized to the short arm of chromosome 17. An international collaborative effort finally succeeded in isolating CTNS by positional cloning in 1998.
Gene
CTNS is located on the p arm of human chromosome 17, at position 13.2. It spans base pairs 3,636,468 and 3,661,542, and comprises 12 exons.
Tissue distribution
The gene is expressed in the lysosomes of all organs and tissues. Cystinosin has also been found in melanosomes in melanocytes.
Structure
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. It comprises 367 amino acid residues, and has a molecular mass of 41738 Da. Cystinosin has seven N-glycosylation sites in the N-terminus 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 moiety.
Cystinosin functions as a symporter which actively transports protons and cystine, the oxidized cysteine dimer, out of the lysosome. This is necessary to distribute cystine to the rest of the cell and allow the lysosome to continue to function. Cystinosin has also been discovered in melanosomes and has been linked to the control and regulation of melanin.
Mutations in CTNS can result in cystinosis. Cystinosis 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 tubularcell lines. Non-human protein homologs for cystinosin include ERS1 in Saccharomyces cerevisiae and the Caenorhabditis elegans protein, C41C4.7. Murine ctns has also been used.
