Sedoheptulokinase deficiency due to a 57-kb deletion in cystinosis patients causes urinary accumulation of sedoheptulose: elucidation of the CARKL gene.
The most common mutation in the nephropathic cystinosis (CTNS) gene is a homozygous 57-kb deletion that also includes an adjacent gene carbohydrate kinase-like (CARKL). The latter gene encodes a protein that is predicted to function as a carbohydrate kinase. Cystinosis patients with the common 57-kb deletion had strongly elevated urinary concentrations of sedoheptulose (28-451 mmol/mol creatinine; controls and other cystinosis patients <9) and erythritol (234-1110 mmol/mol creatinine; controls and other cystinosis patients <148). Enzyme studies performed on fibroblast homogenates derived from patients carrying the 57-kb deletion revealed 80% reduction in their sedoheptulose phosphorylating activity compared to cystinosis patients with other mutations and controls. This indicates that the CARKL-encoded protein, sedoheptulokinase (SHK), is responsible for the reaction: sedoheptulose + ATP --> sedoheptulose-7-phosphate + ADP and that deletion of CARKL causes urinary accumulation of sedoheptulose and erythritol.
Wamelink
Mirjam M C
MM
Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands. M.Wamelink@vumc.nl
Struys
Eduard A
EA
Jansen
Erwin E W
EE
Levtchenko
Elena N
EN
Zijlstra
Fokje S M
FS
Engelke
Udo
U
Blom
Henk J
HJ
Jakobs
Cornelis
C
Wevers
Ron A
RA
D000293:Adolescent; D000328:Adult; D026921:Amino Acid Transport Systems, Neutral / Q000172:deficiency / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002874:Chromosome Mapping; D003554:Cystinosis / Q000201:enzymology* / Q000235:genetics* / Q000652:urine; D004896:Erythritol / Q000652:urine; D005347:Fibroblasts / Q000201:enzymology; D005808:Genes, Recessive; D006539:Heptoses / Q000652:urine*; D006801:Humans; D007223:Infant; D008954:Models, Biological; D010427:Pentose Phosphate Pathway; D010770:Phosphotransferases / Q000172:deficiency* / Q000235:genetics*; D017853:Phosphotransferases (Alcohol Group Acceptor); D017384:Sequence Deletion; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*
D026921:Amino Acid Transport Systems, Neutral; C111445:CTNS protein, human; D006539:Heptoses; D014157:Transcription Factors; C003011:sedoheptulose; D010770:Phosphotransferases; D017853:Phosphotransferases (Alcohol Group Acceptor); C404793:SHPK protein, human; D004896:Erythritol