Abstract
We observed a characteristic shortening of plasma and urinary dolichols in retinitis pigmentosa (RP) patients carrying K42E and T206A mutations in the dehydrodolichol diphosphate synthase (DHDDS) gene, using liquid chromatography-mass spectrometry. Dolichol-18 (D18) became the dominant dolichol species in patients instead of dolichol-19 (D19) in normal individuals. The D18/D19 ratio was calculated and used as an index of dolichol length distribution. K42E/K42E and K42E/T206A patients have significantly higher plasma and urinary D18/D19 ratios than K42E and T206A carriers. The ratios of carriers are significantly higher than normal individuals. Receiver operating characteristic (ROC) analysis shows that plasma and urinary D18/D19 ratios can unambiguously discriminate patients from carriers, and carriers from normal individuals. Dolichol analysis also provides evidence that the T206A mutation is RP-causative. The methodologies and procedures used for dolichol profiling are reliable, high throughput, and cost effective. Dolichol profiling, complementary to genotyping, can be readily adapted as a test in the clinic not only for the diagnosis of patients but also for identification of carriers with DHDDS or other genetic mutations that may impair dolichol biosynthesis.
Highlights
We observed a characteristic shortening of plasma and urinary dolichols in retinitis pigmentosa (RP) patients carrying K42E and T206A mutations in the dehydrodolichol diphosphatesynthase(DHDDS)gene,usingliquidchromatography-mass spectrometry
We recently identified a single-nucleotide c.124A>G mutation in the dehydrodolichol diphosphate synthaseencoding DHDDS gene that changes the highly conserved Lys42 to Glu (K42E) as the cause of autosomal recessive retinitis pigmentosa in a family of Ashkenazi Jewish (AJ) origin [13]
Our results indicate that plasma and urinary dolichol profiles are functional readouts of dolichol biosynthesis and can serve as biomarkers for diagnosis of autosomal recessive retinitis pigmentosa (arRP) and perhaps other diseases caused by abnormal dolichol biosynthesis and metabolism
Summary
We observed a characteristic shortening of plasma and urinary dolichols in retinitis pigmentosa (RP) patients carrying K42E and T206A mutations in the dehydrodolichol diphosphatesynthase(DHDDS)gene,usingliquidchromatography-mass spectrometry. K42E/K42E and K42E/T206A patients have significantly higher plasma and urinary D18/D19 ratios than K42E and T206A carriers. Receiver operating characteristic (ROC) analysis shows that plasma and urinary D18/D19 ratios can unambiguously discriminate patients from carriers, and carriers from normal individuals. Aberrant dolichol chain lengths as biomarkers for retinitis pigmentosa caused by impaired dolichol biosynthesis. Shortened dolichol profile was found in a patient carrying the compound heterozygous T206A/K42E mutations in the DHDDS gene. Our results indicate that plasma and urinary dolichol profiles are functional readouts of dolichol biosynthesis and can serve as biomarkers for diagnosis of arRP and perhaps other diseases caused by abnormal dolichol biosynthesis and metabolism
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