The promoter of a lysosomal membrane transporter gene, CTNS, binds Sp-1, shares sequences with the promoter of an adjacent gene, CARKL, and causes cystinosis if mutated in a critical region

Am J Hum Genet. 2001 Oct;69(4):712-21. doi: 10.1086/323484. Epub 2001 Aug 14.


Although >55 CTNS mutations occur in patients with the lysosomal storage disorder cystinosis, no regulatory mutations have been reported, because the promoter has not been defined. Using CAT reporter constructs of sequences 5' to the CTNS coding sequence, we identified the CTNS promoter as the region encompassing nucleotides -316 to +1 with respect to the transcription start site. This region contains an Sp-1 regulatory element (GGCGGCG) at positions -299 to -293, which binds authentic Sp-1, as shown by electrophoretic-mobility-shift assays. Three patients exhibited mutations in the CTNS promoter. One patient with nephropathic cystinosis carried a -295 G-->C substitution disrupting the Sp-1 motif, whereas two patients with ocular cystinosis displayed a -303 G-->T substitution in one case and a -303 T insertion in the other case. Each mutation drastically reduced CAT activity when inserted into a reporter construct. Moreover, each failed either to cause a mobility shift when exposed to nuclear extract or to compete with the normal oligonucleotide's mobility shift. The CTNS promoter region shares 41 nucleotides with the promoter region of an adjacent gene of unknown function, CARKL, whose start site is 501 bp from the CTNS start site. However, the patients' CTNS promoter mutations have no effect on CARKL promoter activity. These findings suggest that the CTNS promoter region should be examined in patients with cystinosis who have fewer than two coding-sequence mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Transport Systems, Neutral
  • Base Sequence
  • Child
  • Child, Preschool
  • Conserved Sequence / genetics*
  • Cystinosis / genetics*
  • DNA / genetics
  • DNA / metabolism
  • DNA Mutational Analysis
  • Female
  • Gene Order / genetics
  • Genotype
  • Glycoproteins*
  • HeLa Cells
  • Humans
  • Infant
  • Membrane Proteins / genetics*
  • Membrane Transport Proteins
  • Molecular Sequence Data
  • Mutation / genetics*
  • Phenotype
  • Phosphotransferases (Alcohol Group Acceptor)
  • Phosphotransferases*
  • Promoter Regions, Genetic / genetics*
  • Protein Binding
  • Response Elements / genetics
  • Sp1 Transcription Factor / metabolism*
  • Transcription Factors / genetics*


  • Amino Acid Transport Systems, Neutral
  • CTNS protein, human
  • Glycoproteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • Sp1 Transcription Factor
  • Transcription Factors
  • DNA
  • Phosphotransferases
  • Phosphotransferases (Alcohol Group Acceptor)
  • SHPK protein, human

Associated data

  • OMIM/219800
  • OMIM/605060