Sedoheptulokinase deficiency due to a 57-kb deletion in cystinosis patients causes urinary accumulation of sedoheptulose: elucidation of theCARKLgene

Abstract

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.

Infertility Associated with Meiotic Failure in the <i>tremor</i> Rat (<i>tm/tm</i>) is Caused by the Deletion of <i>Spermatogenesis Associated 22</i>

“…Whether the loss of Shpk [28], seven OR genes [25], and a function-unknown gene, LOC100359760 , affects the reproductive system has not been known. Although the functions of the seven OR genes are unknown, olfactory receptors are known to be responsible for the recognition and G protein-mediated transduction of odorant signals in cells, such as olfactory receptor neurons and sperms [25].…”

The 57 kb deletion in cystinosis patients extends into TRPV1 causing dysregulation of transcription in peripheral blood mononuclear cells

“…The consequence of CTNS gene knockout has been extensively documented for cystinosis patients and there has been limited investigation into the knockout of SHPK ,13 the gene immediately upstream of CTNS .…”

Clinical utility gene card for: Cystinosis

“…Increased concentration of sedoheptulose in blood or urine can be used for identifying patients with the homozygous 57-kb deletion. 10,11 The TRPV1 gene encodes for the TRPV1 expressed in the primary sensory neurons and activated by heat and various chemical compounds, including capsaicin. 12 Two first non-coding exons of the TRPV1 are removed by the 57-kb deletion.…”