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Aniridio: Enzyme Studies in on 11P— Chromosomal Deletion

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Aniridio: Enzyme Studies in on 11P— Chromosomal Deletion 612 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / Moy 1984 Vol. 25 Key words: lipid peroxidation, docosahexenoic acid, posterior 5. Daemen FJM: Vertebrate rod outer segment membranes. subcapsular cataract, tapetoretinal degeneration Biochim Biophys Acta 300:255, 1973. 6. Mead JF: Free radical mechanisms of lipid damage and con- From the University of Texas Health Science Center, Hermann sequences for cellular membranes. In Free Radicals in Biology, Eye Center, Houston, Texas. Supported by National Institute grant Vol 1, Pryor WA, editor. New York, Academic Press, 1976, pp. EY03869 and Retinitis Pigmentosa Foundation grant 7-19523- 51-68. 244092. Submitted for publication: August 25,1983. Reprint requests: 7. Chio K.S and Tappel AL: Inactivation of ribonuclease and other John D. Goosey, MD, LSU Medical Center, LSU Eye Center, 136 enzymes by peroxidizing lipids and by malonaldehyde. Bio- South Roman Street, New Orleans, LA 70112. chemistry 8(7):2827, 1969. 8. Fletcher BL, Dillard CJ, and Tappel AL: Measurement of flu- orescent lipid peroxidation products in biological systems and References tissues. Anal Biochem 52:1, 1973. 9. Feeney L: The phagolysosomal system of the pigment epithelium: 1. Pruett RC: Retinitis pigmentosa, a biomicroscopical study of A key to retinal disease. Invest Ophthalmol 12:635, 1973. vitreous abnormalities. Arch Ophthalmol 93:603, 1975. 10. Young RW: The renewal of rod and cone outer segments of the 2. Heckenlively J: The frequency of posterior subcapsular cataract rhesus monkey. J Cell Biol 49:303, 1971. in the hereditary retinal degenerations. Am J Ophthalmol 93:733, 11. Tappel AL: Measurement of and protection from in vivo lipid 1982. peroxidation. In Free Radicals in Biology, Vol 4, Pryor WA, 3. Francois J: Metabolic tapetoretinal degenerations. Surv editor. New York, Academic Press, 1980, pp. 1-47. Ophthalmol 26(6):293, 1982. 12. Zigler JS, Gery I, and Kinoshita JH: Effects of lipid peroxidation 4. Berliner ML: Biomicroscopy of the Eye, Vol 2. New York, Paul products on the cultured lens. Invest Ophthalmol Vis Sci B. Hoeber, 1949, p. 1439. 22(Suppl):151, 1982. Aniridio: Enzyme Studies in on 11p— Chromosomal Deletion J. Dronwyn Botemon,* Moryellen C. Sporkes.f ond Robert S. Sporkes^ A patient with aniridia and an interstitial deletion of the tivities of genes known to be located on a given chro- bands pl3-pl4 of the short arm of chromosome 11 was mosome may provide such clues. We selected two en- studied to determine the relative locations of the gene(s) zymes, the genes for which are known to be on the encoding for the aniridia-Wilms' tumor association with other short arm of chromosome 11, for study in a patient genes on the same chromosome. Quantitative analysis was with aniridia and an interstitial deletion of the same performed on the red blood cell enzymes lactic acid dehy- drogenase-A (LDH-A) and catalase, the genes for which are chromosome; quantitative analyses of the red cell en- located on the short arm of chromosome 11. The activity of zymes catalase and lactic acid dehydrogenase-A (LDH- LDH-A was normal; the activity of catalase was reduced to A) were performed to determine activity; both of these approximately half normal. This evidence supports loci for enzymes have been shown to exhibit a gene-dose re- the genes encoding for both catalase and the aniridia-Wilms7 lationship. tumor association within the bands pl3-pl4 of the short arm Materials and Methods. A Caucasian girl was iden- of chromosome 11; the normal activity of LDH-A supports tified as having absent pupils at 6 months of age; a a locus outside this region. Invest Ophthalmol Vis Sci 25:612- diagnosis of aniridia was made, and she was referred 616, 1984 to the UCLA Genetics Clinic. The full clinical features will be described in a separate report. Informed human consent was obtained prior to undertaking the study. The association of aniridia, genitourinary malfor- Giemsa and reverse (R) banding of cultured, syn- mations, developmental delay, and Wilms' tumor with chronized lymphocytes of the patient and of her parents interstitial deletions of the short arm of chromosome in late prophase or early metaphase were performed; 11 initially was recognized by Smith and co-workers.' three full karyotypes and six partial karyotypes of pair Although neither the smallest possible deletion re- 11 of the patient were reviewed. sulting in this association nor the number of genes Quantitative analysis of red cell catalase was per- involved is established, a patient with aniridia, Wilms' formed twice on the proband and three unrelated con- tumor, and no demonstrable chromosomal deletion trols by the technique of Beutler3; for each analysis, 2 was reported recently. As Wilms' tumor is life-threat- the degradation of H2O2 was monitored spectropho- ening, methods for identifying those patients with an- tometrically twice on the Gilford 2000 (Gilford In- iridia who are at higher risk for this malignancy would strument Laboratories; Oberlin, OH). be clinically useful. Regional gene mapping by cor- Red cell LDH-A was assayed twice on the proband relating cytogenetic break points with enzymatic ac- and three unrelated controls by electrophoresing a sa- Downloaded from iovs.arvojournals.org on 09/28/2021 No. 5 fXeporrs 613 AH Fig. 1. Early metaphase karyotypes (lym- phocytes) of chromosome 11 of patient. Large arrows on schematic chromosome 11 indicate the break points of our best estimate of the interstitial deletion; the possibility that the break points are within the pi2 and/or p 14 bands cannot be excluded. Small arrows identify the margins of the deletion on the normal chromosome 11; the ab- normal chromosome with the deletion of the bands pl3-pl4 is shown on the right of each pair. 11 ponin-hemolysate of washed red cells on a starch gel over 18 hr (4 V/cm) with a phosphate buffer of pH 7.O.4 The gel was photographed with black and white Polaroid film (55); both the photograph and the gel were scanned in a densitometer equipped with a chart recorder. The peaks of the five isoenzyme patterns of LDH-1 LDH-A and -B polypeptides were compared. The five LDH isoenzymes migrate anodally, 1 faster than 5; as erythrocytes preferentially synthesize LDH-B, isoen- zymes 1 through 3 normally have higher activity than 4 and 5. In this system, superoxide dismutase migrates LDH-2 within the isoenzyme 2 band, which results in the ap- pearance of six bands. Results, An interstitial deletion of the short arm of one chromosome 11 from band pl3-pl4 was present LDH-3 in the patient's lymphocytes (Fig. 1) and skin fibro- LDH-4 blasts; bands lip 12 and pi5 appeared to be intact. Prophase banding of the karyotypes of both parents were normal. Quantitative assay of catalase in the simultaneously run control groups ranged from 137,267 to 249,251 LDH-5 Fig, 2. Polaroid photo of electrophoretic pattern of starch gel stained for LDH-A activity after the separation of the five isozyme bands. Patient's specimen on the right; control on the left. Isoenzyme 2 is divided by superoxide dismutase band (arrow). Downloaded from iovs.arvojournals.org on 09/28/2021 614 INVESTIGATIVE OPHTHALMOLOGY G VISUAL SCIENCE / Moy 1984 Vol. 25 International Units of catalase per gram of hemoglobin There are no observable differences in the intensities (IU per gram of Hb); the patient's activities ranged of the isoenzyme bands 4 and 5 between the patient from 65,513 to 72,065 IU per gram of Hb. The catalase and controls. activity of the first five normals studied in our labo- Discussion. Gene mapping on the basis of interstitial ratory ranged from 133,250 to 188,180 IU per gram chromosomal deletions is useful, but may be imprecise, of Hb with a mean of 162,091. as the identification of the break sites and of the missing The LDH isoenzyme patterns and the recordings of material may be difficult; cumulative evidence, how- the densitometer scans are shown in Figures 2 and 3. ever, may permit the localization of a gene(s) to a i iinrn ;r:i-;-i i i in m; i Fig. 3. Densitometer chart profiles obtained by scanning LDH starch gel of control samples (upper) and of patient (lower). Peaks are labeled with LDH isoenzymes. No relative deficiency of LDH-A (isoenzymes 4 and 5) is evident. Arrows indicate superoxide dismutase band. Downloaded from iovs.arvojournals.org on 09/28/2021 No. 5 Reports 615 specific band. Smith and colleagues originally suggested deletions were not described, all included the pi 3 band; that a gene for aniridia was located on the short arm two had reduced catalase activity.16 An additional pa- of chromosome 11 when they described two patients tient with aniridia and a deletion of the short arm of with aniridia, mental retardation, and genital abnor- chromosome 11 extending from the pi2 through the malities and a partial deletion of this chromosome.1 pi5.1 regions has been found to have reduced catalase Since then, 29 additional aniridia patients with deletion activity.12 Our case, with less than 50% catalase activity, of the short arm of chromosome 11 have been added supports the localization of the catalase gene within to the literature; in those reports with detailed infor- the bands Ilpl3-pl4. mation, all deletions have included the pi3 band of The compilation of available evidence strongly sup- the short arm. ports the localization of the gene(s) for the aniridia/ The genes for two enzymes, catalase and LDH-A, Wilms' tumor association and the catalase gene to the also are located on the short arm of chromosome 11. 1 Ipl3 band. It appears that the LDH-A gene is prox- LDH-A initially was localized to this chromosome by imal to the genes for the aniridia-Wilms' tumor com- somatic cell hybridization studies.
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