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Association of a Novel Mutation in the Retinol Dehydrogenase 12 (RDH12) Gene with Autosomal Dominant Retinitis Pigmentosa

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Association of a Novel Mutation in the Retinol Dehydrogenase 12 (RDH12) Gene with Autosomal Dominant Retinitis Pigmentosa OPHTHALMIC MOLECULAR GENETICS SECTION EDITOR: JANEY L. WIGGS, MD, PhD Association of a Novel Mutation in the Retinol Dehydrogenase 12 (RDH12) Gene With Autosomal Dominant Retinitis Pigmentosa John H. Fingert, MD, PhD; Kean Oh, MD; Mina Chung, MD; Todd E. Scheetz, PhD; Jeaneen L. Andorf, BS; Rebecca M. Johnson, BS; Val C. Sheffield, MD, PhD; Edwin M. Stone, MD, PhD Objective: To identify the gene causing retinitis pig- gene. A frameshift mutation (776delG) was detected in mentosa (RP) in an autosomal dominant pedigree. all affected family members and was not detected in 158 control subjects. Methods: Family members with RP were studied with linkage analysis using single-nucleotide polymorphism Conclusions: Heterozygous mutations in RDH12 can and short tandem repeat polymorphic markers. Candi- cause autosomal dominant RP with a late onset and rela- date genes in the linked region were evaluated with DNA tively mild severity. This phenotype is dramatically dif- sequencing. ferent from the other disease associated with mutation in this gene, autosomal recessive Leber congenital Results: Nineteen family members had a mild form of amaurosis. RP. Multipoint linkage analysis of single-nucleotide poly- morphism genotypes yielded a maximum nonparamet- Clinical Relevance: The demonstration that muta- ric linkage score of 19.97 with markers located on chro- tions in a gene previously associated with recessive Leber mosome 14q. LOD scores higher than 3.0 were obtained congenital amaurosis can also cause dominant RP illus- with 20 short tandem repeat polymorphic markers, and trates the wide phenotypic variability of retinal degen- recombinants defined a 21.7-centimorgan locus on chro- eration genes. mosome 14q. The retinol dehydrogenase 12 (RDH12) gene lies within this locus and was evaluated as a candidate Arch Ophthalmol. 2008;126(9):1301-1307 ETINITIS PIGMENTOSA (RP) IS .sph.uth.tmc.edu/Retnet/). The 14 known a collection of inherited, ADRP genes are CA4,4,5 CRX,6,7 FSCN2,8 progressive retinal degen- GUCA1B,9 IMPDH1,10-12 NR2E3,13 NRL,14 erations of the photorecep- PRPF3,15,16 PRPF8,17,18 PRPF31,19,20 RDS,21,22 tors with typical clinical RHO,23-26 ROM1,27 RP1,28-31 RP9,32,33 and Rfeatures including attenuated retinal ar- SEMA4A.34 These genes have a range of terioles, intraretinal bone spiculelike pig- functions, including phototransduction mentation, and posterior subcapsular cata- (RHO); RNA splicing (PRPF3, PRPF8, ract. Retinitis pigmentosa is characterized PRPF9, and PRPF31); signaling (SEMA4A); by marked reduction of both rod and cone and retinal structure (RDS/peripherin, responses in the electroretinogram, pe- FSCN2, and RP1). Mutations associated Author Affiliations: Departments of Ophthalmology ripheral visual field defects, and reduc- with ADRP are most commonly detected and Visual Sciences tion of central vision later in the course in rhodopsin (RHO), RDS/peripherin, and (Drs Fingert, Scheetz, and of the disease. The prevalence of RP is ap- PPRF31, which account for approxi- Stone, and Mss Andorf and proximately 1 in 4000 and more than 1 mately 25%, 10%, and 8% of ADRP, re- Johnson) and Pediatrics million individuals may be affected with spectively. The other genes are associated (Dr Sheffield), Carver College RP worldwide.1 with smaller fractions of disease.35 Over- of Medicine, University of Iowa, Details of the genetic features of RP have all, mutations in these known disease- and the Howard Hughes been recently reviewed.1-3 Retinitis pigmen- causing genes can be detected in nearly half Medical Institute (Drs Sheffield tosa may have an autosomal dominant of all ADRP cases, which suggests that many and Stone), Iowa City; (30%-40%), autosomal recessive (50%- more ADRP genes remain to be identified. Associated Retinal Consultants, 60%), or X-linked (5%-15%) inheritance There is considerable overlap be- Traverse City, Michigan 1 (Dr Oh); and Department of pattern. At present, 16 genetic loci for au- tween the inheritance patterns and the spe- Ophthalmology, University of tosomal dominant RP (ADRP) have been cific types of retinal dystrophies that are Rochester, Rochester, NY identified and the genes at 14 of the loci associated with mutations in a particular (Dr Chung). have been discovered (RetNet: http://www gene. For example, mutations in RHO, (REPRINTED) ARCH OPHTHALMOL / VOL 126 (NO. 9), SEP 2008 WWW.ARCHOPHTHALMOL.COM 1301 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 NRL, and RP1 were initially associated with dominantly ously identified ADRP genes including rhodopsin (OMIM inherited RP,14,23-26,28-31 while different sets of mutations 180380), RDS/peripherin (OMIM 179605), and RP1 (OMIM in these same genes were later shown to cause autoso- 603937). Genotyping with STRP genetic markers was con- 47 mal recessive RP.36-38 Similarly, some of the same genes ducted using standard methods as previously described. A that cause ADRP (CRX, IMPDH1, RDS, RHO, and genome-wide scan was next performed with Affymetrix microarrays (Sty1 array of the GeneChip Human Mapping SEMA4A) have also been associated with a number of 500K Array Set, Affymetrix, Santa Clara, California), which other retinal phenotypes, including pattern dystrophy, interrogated 238 000 single-nucleotide polymorphisms Leber congenital amaurosis, cone dystrophy, and con- (SNPs). Sample processing and labeling were performed using genital stationary night blindness.39-42 Consequently, genes the manufacturer’s instructions. The arrays were hybridized, known to cause one retinal dystrophy are excellent can- washed, and scanned in the University of Iowa DNA core didates for causing others. facility. Array images were processed with GeneChip DNA In this study, we report the genetic analysis of a 6-gen- Analysis software. eration family from North Carolina with ADRP. The gene Microarray data were analyzed and multipoint nonpara- that causes ADRP in this family was mapped to chromo- metric linkage scores were calculated using the Genespring GT some 14q with linkage studies and recombination analy- software package (Agilent Technologies, Palo Alto, Califor- nia). Pairwise linkage analysis using STRP markers was per- sis. Family members were tested for disease-causing mu- formed with the MLINK and LODSCORE programs as imple- tations in candidate genes contained within this new mented in the FASTLINK (v2.3) version48,49 of the LINKAGE ADRP locus. A novel mutation in the retinol dehydro- software package.50 Penetrance and disease gene frequency were genase 12 (RDH12) gene was detected that cosegregates set to 99% and 0.1%, respectively. For each STRP marker, the with ADRP in this large pedigree. Mutations in RDH12 allele frequencies were assumed to be equal. True allele fre- have been previously associated with recessively inher- quencies could not be reliably estimated from the small num- ited retinal dystrophies described clinically as early- ber of spouses in the pedigree. To show that the assumption of onset retinal degeneration or Leber congenital amauro- the equal allele frequencies would not significantly affect our sis.43-45 However, this study presents the first case, to our linkage results, we recalculated the LOD scores using allele fre- knowledge, of ADRP associated with mutations in RDH12. quencies for the “affected” allele of the most tightly linked marker (D14S587) ranging from 0.01 to 0.5. The Zmax for D14S587 was 4.5 when the affected allele frequency was arbitrarily set METHODS to 50%. In the 10 spouses who were studied, the actual fre- quencies of the affected alleles of D14S587 were much lower The research study was approved by the internal review board than 50%. In this small sample, the frequency of the affected of the University of Iowa and informed consent was obtained allele of D14S587 was 10%, which provides additional evi- from study participants. dence that our use of equal allele frequencies for D14S587 (11%) was reasonable. PATIENT RESOURCES CANDIDATE ADRP Family GENE SCREENING Thirty-five family members had complete eye examinations and Candidate genes were selected from among the genes in the chro- 19 were judged to have ADRP. Visual fields were assessed with mosome 14q–linked interval based on their function, expres- Goldmann perimetry and ISCEV standard electroretinograms sion pattern, and prior association with retinal disease. DNA were obtained from a subset of family members. Patients were samples from 2 affected family members and from 2 healthy judged to be affected if they had classic signs of RP, including control subjects were tested for mutations in candidate genes bone spiculelike pigmentation of the retina, attenuation of reti- using bidirectional sequencing of polymerase chain reaction nal arterioles, waxy pallor of the optic nerve, characteristic ring products that encompassed the entire coding sequence. The first, scotomas, and attenuated electroretinograms. and only, candidate to be evaluated was retinol dehydroge- nase 12 (RDH12, OMIM 608830). Sequencing was performed Cohort of Patients With Photoreceptor using dye-terminator chemistry on an ABI 3730 DNA se- Degeneration and Controls quencer (Applied Biosystems, Foster City, California). Poly- merase chain reaction amplification was performed with a stan- 51 All patients (n=273) and healthy control subjects (n=158) were dard protocol using primer sequences that are available on ascertained from the same outpatient ophthalmology clinic popu- request. Potential mutations were identified by comparing the lation
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