Aberrant dolichol chain lengths as biomarkers for retinitis pigmentosa caused by impaired dolichol biosynthesis.
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.
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136.
Rong
R
Wen
Byron L
BL
Lam
Ziqiang
Z
Guan
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019883:Alkyl and Aryl Transferases / Q000235:genetics; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism; D002648:Child; D004286:Dolichols / Q000096:biosynthesis* / Q000097:blood / Q000737:chemistry* / Q000652:urine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012174:Retinitis Pigmentosa / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D055815:Young Adult
D015415:Biomarkers; D004286:Dolichols; D019883:Alkyl and Aryl Transferases; C051389:dehydrodolichyl diphosphate synthetase
autosomal recessive; dehydrodolichol diphosphate synthase; dolichol-18:dolichol-19 ratio; human blood; human urine; mass spectrometry