Abstract
Purpose :
Dehydrodolichyl diphosphate synthase (DHDDS) is a subunit of cis-prenyltransferase, which is required for dolichol synthesis in protein glycosylation. Mutations in DHDDS cause recessive retinitis pigmentosa, RP59. The most common mutation, K42E, frequently causes non-syndromic RP. Polymorphisms in other glycosylation pathway genes have been reported that may exacerbate the phenotypic severity of the disease. We assessed polymorphisms in five potential modifier genes in DHDDS K42E patient samples.
Methods :
Eleven [8 RP59, 3 cone-rod dystrophy (CRD)] DHDDS K42E patients and 3 controls with no known ocular disease were clinically assessed. All patients had only central islands of function by the age of 30 years, so two parameters [visual field area (V-4e) and SD-OCT] were compared at patient ages of 17-30 years. [SD-OCT data were available only for 5 patients.] Patient DNA was purified from peripheral blood draws. UCSC Genome Browser was used to design DNA primers for each potential modifier polymorphism (ALG6 [c.911T>C], ALG8 [c.1068C>G], MPDU1 [c.393C>T], DDSOT [c.679A>G], and TNKS [c.1945G>A]). Following PCR with established methods, DNA specimens were sequenced at the UAB Heflin Center.
Results :
Successful PCR, DNA sequencing of polymorphisms showed normal sequence except in ALG6. Three RP59, two CRD, and two control samples were heterozygous for ALG6 polymorphism. Since the control samples’ status does not rule out a modifier effect, we evaluated the association of the polymorphism with clinical severity. In subjects without the ALG6 polymorphism, visual field (VF) area was 63% and 38% of normal in 2 patients while 4 patients had only a central VF island. In heterozygous patients, 4 had relatively large VF areas (74, 56, 40, and 11%), and N=1 had only a central VF island. SD-OCT analysis showed 2 normal patients to have standard outer nuclear layer (ONL) thickness centrally, but no detectable ONL outside this region. In 3 heterozygous patients, there was limited (10°, N=1) or no detectable (N=2) ONL thickness.
Conclusions :
No association was found with any of the five potential modifier gene polymorphisms and disease severity. The great diversity in phenotypic expression suggests a modifier may exist that remains elusive. The new diagnosis of CRD in these RP59 patients is novel and indicates a greater macular involvement and more diverse function of cis-prenyltransferase than previously appreciated.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.