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Byron L Lam, Ziqiang Guan, Potyra R Rosa, Yiwen Li, Rong Wen; Aberrant Dolichol Chain Length Distribution as Biomarkers for Retinitis Pigmentosa Associated with DHDDS Genotypes. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5011.
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© ARVO (1962-2015); The Authors (2016-present)
In search of quantitative biomarkers for retinitis pigmentosa (RP), we characterized urinary and plasma dolichol profiles in autosomal recessive RP (arRP) patients and carriers with mutations in the DHDDS gene encoding dehydrodolichol diphosphate synthase, a key enzyme in dolichol biosynthesis. Dolichols are long chain polyisoprenoid alcohols composed of 17-21 isoprene units.
Urine and/or plasma were collected from 9 DHDDS arRP patients, 35 DHDDS arRP carriers, 19 normals, and 34 arRP patients with wild-type DHDDS. Lipids were extracted and dolichols were measured by liquid chromatography-mass spectrometry (LC-MS). Dolichol length distribution was quantified as the ratio of dolichol 18 and dolichol 19 (D18/D19 ratio), the two most abundant dolichol species in human.
The mean plasma D18/D19 ratio of arRP K42E/K42E DHDDS patients (2.84±0.38, mean±SD, n=8) is significantly higher than K42E carriers (1.56±0.11, n=25, P<0.001) and normals (0.82±0.12, n=16, P<0.001). The mean urinary D18/D19 ratio of K42E/K42E patients (4.00±0.45, n=7) is also significantly higher than K42E carriers (1.27±0.19, n=30, P<0.001) and normals (0.47±0.06, n=13, P<0.001). Receiver-operating-characteristic (ROC) analysis shows both plasma and urinary D18/D19 ratios discriminate K42E/K42E patients from K42E carriers, and K42E carriers from normals with 100% sensitivity and 100% specificity. The predictive power of the D18/D19 ratio was tested by screening plasma samples from 36 arRP patients with unknown genotypes, and two were identified to carry the K42E/K42E DHDDS mutation. In addition, an arRP patient with novel compound heterozygous T206A/K42E DHDDS mutations was found to have high D18/D19 ratios similar to those of K42E/K42E patients, and the mean plasma and urinary D18/D19 ratios of T206 carriers (1.31±0.06, 1.04±0.04, n=5) were similar to K24E carriers, indicating similar functional defects of these two mutations.
Mutations in the DHDDS gene lead to a characteristic shortening of plasma and urinary dolichols, which can be used as a functional readout of the enzyme. Urinary and plasma D18/D19 ratios reliably determine if a DHDDS genotype is disease-causing. D18/D19 ratio is a viable objective functional biomarker and can be readily adapted as a clinical test for arRP diagnosis and carrier screening with DHDDS or other genetic mutations that impair dolichol biosynthesis.
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