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Autosomal Dominant Aniridia: Probable Linkage to Acid

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Autosomal Dominant Aniridia: Probable Linkage to Acid Proc. Natl. Acad. Sci. USA Vol. 77, No. 3, pp. 1580-1582, March 1980 Genetics Autosomal dominant aniridia: Probable linkage to acid phosphatase-1 locus on chromosome 2 (genetic heterogeneity/LIPED computer program/variable expressivity) ROBERT E. FERRELL*, ARAVINDA CHAKRAVARTI*, HELEN MINTZ HITTNERt*, AND VINCENT M. RICCARDIt§ *Center for Demographic and Population Genetics, University of Texas Health Science Center, Houston, Texas 77030; and tDepartment of Ophtht tDepartment of Pediatrics, §Department of Medicine, and IKleberg Genetics Center, Baylor College of Medicine, Houston, Texas 77030 ol~y, Communicated by James V. Neel, December 19, 1979 ABSTRACT Maximum likelihood analysis for linkage be- RESULTS tween autosomal dominant aniridia and 12 biochemical and serological markers in a single large family showed a probable The pedigree of the available family members is given to Fig. linkage between autosomal dominant aniridia and the enzyme 1, with ADAN and ACP1 phenotypes indicated. The pedree acid phosphatase-1. The presence of an autosomal dominant is consistent with autosomal dominant inheritance of the ADAN aniridia gene linked to acid phosphatase- on chromosome arm mutation, and segregation analysis with respect to diw status 2p and the existence of an aniridia syndrome resulting from and sex confirms this impression. In addition to this deletion of band 13 of the short arm of chromosome 11 estab- AOAN, lishes a chromosome basis for genetic heterogeneity of aniridia family was found to be segregating for the erythrocyte Antigen phenotypes. systems ABO, MNS, Rh, Fy, Jk, and K, and the polyniotphic protein loci ACP1, ESD, GLO1, GPT, PGM1, and HPAXable Hittner et al. (1) have recently described a large kindred with 1 presents the results of maximum likelihood analysis forlukage autosomal dominant aniridia (ADAN) characterized by variable between ADAN and these segregating serological and bo- expression. This paper presents the results of a study of linkage chemical markers. Significant positive lod scores wereo.ained between ADAN and 12 polymorphic biochemical and sero- only for linkage between ADAN and the erythrocyteenzyme logical markers in that kindred. The results indicate a probable ACP1, respecting the convention that a lod score of grer tan linkage between a gene responsible for ADAN and the gene 1.5 suggests linkage (6). Large negative lod scores wieEound coding for acid phosphatase-1 on the short arm of human with the erythrocyte antigens ABO, Jk, K, MNS, Aadis and chromosome 2. the proteins GLO1, GPT, HPA, and PGM1. Table 1 gives the results of two analyses that df4wh respect to the disease status assigned to individual 1iU15d the MATERIALS AND METHODS pedigree shown in Fig. 1. Inspection of the pedigree sh.p, that A detailed clinical description of this family has been presented ADAN is segregating with the B allele at the ACP1 locus In- by Hittner et al. (1). Blood samples were drawn from 41 family dividual I112o is phenotypically normal with respect t*ADAN members, including spouses, using an acid/citrate/dextrose but has inherited the B allele of ACP1 from her aftifted anticoagulant. Erythrocytes were typed for antigens of the mother. LIPED analysis assigning a normal phenotype, akence ABO, Rh, MNS, Kell (K), Duffy (Fy), P, and Kidd (Jk) blood of the ADAN mutation, to individual 11120 yielded a peitive group systems, and the erythrocyte enzymes adenylate kinase-1, lod score of 1.81 at a recombination fraction of 0.05-(d for adenosine deaminase, acid phosphatase-1 (ACP1), esterase D linkage 65:1). LIPED analysis excluding Ill2o yielded a W sore (ESD), phosphoglucomutase-1 (PGM1) and phosphogluco- of 3.15 (odds for linkage 1412:1) at zero recombination value, mutase-2, glutamnate-pyruvate transaminase (GPT), glyoxa- whereas lod scores for other loci were essentially utt pd. lase-1 (GLO1), peptidases A, B, C, and D, superoxide dismu- We propose that the latter analysis gave a better estimabe of the tase-1, glucose-6-phosphate dehydrogenase, phosphoglucose likeliiood of linkage, and that the phenotype of indivdua 11120 isomerase, 6-phosphogluconate dehydrogenase, and hemo- speciously misclassified her with respect to ADAN genotype, globin. Plasmas were typed fQr the proteins albumin, hapto- reflecting the extreme variability of expression of ADAN id this globin (HPA), transferrin, and ceruloplasmin. Sample prepa- family. LIPED analysis assigning individual 11120 an ADAN ration and typing were essentially as described by Ferrell et al. phenotype yielded a higher lod score (Z = 3.45, 0:tM-l.10) was carried out the maximum likeli- without changing the lod scores with respect to other umfnkers. (2). Linkage analysis by The large effect of ADAN genotype assignment onlod scores hood method of Ott (3), using the computer program LIPED for linkage to ACP1 without significantly affecting the lod provided by J. Ott, University of Washington, Seattle. The Rh is consistent with locus was treated by using the convention suggested by Ott (4) scores for any other markers linkagebeieen for analyzing human leukocyte antigen serological typing data ADAN and ACP1. in order to include all segregating haplotypes. Lod scores at DISCUSSION various values for recombination fraction [Z(O)s] are presented, using the convention of Keats et al. (5). Phenotypic variability is a consistent feature of ADAN (7-17). Hittner et 41. (1) have documented the extreme varibilif of The publication costs of this article were defrayed in part by page expression of ADAN in the family studied here. Briefly many charge payment. This article must therefore be hereby marked "ad- vertisement" in accordance with 18 U. S. C. §1734 solely to indicate Abbreviations: ADAN, autosomal dominant aniridia; ACPI, acid this fact. phosphatase-1. 1580 -. Genetics: Ferrell et al. Proc. Natl. Acad. Sci. USA 77 (1980) 1581 I !1 Il~l * A a AS a A 0 Female *Affected female \Deceased Male EAffected male Not examined FIG.}1~Pedigree of family with ADAN, showing disease phenotype (filled or empty symbols) and ACP1 phenotypes (A, B, or AB). Phenotypes with rect to all other polymorphic loci are available from R.E.F. upon request. affede-iiiily members were unaware of any ocular abnor- ADAN, but is at the near-normal end of the distribution of mality~jkouse they had round pupils and vision of 20/40 or ADAN phenotypes expressed in this family. The finding of a betteritIt leat one eye (1114, III6, 1117, I116, and IVS). Prior maximum value for Z at values of 0 = 0.00-0.05 indicates that exam of four of these individuals for esotropia and one recombination is not likely, and no evidence for nonpaternity for emWpoia had failed to detect their abnormally thinned ir- was detected at any of the loci examined. Given the variable ides. Lndividujal III20 has probably inherited the gene for expressivity observed in this family, we argue that individual III20 has inherited the ADAN mutation but is phenotypically Table" I. LIPED analysis for linkage of ADAN with serological normal. The fact that her exclusion from the LIPED analysis and biochemical markers changes the lod score by 1.34 units is consistent with, and argues Z at recombination fraction for, linkage. In this context, then, the data presented here in- L-1 ts- L-2 2 0 0.05 0.1 0.2 0.3 0.4 dicate linkage between ADAN and the ACP1 locus, which has been assigned to distal chromosome arm 2p (18). In addition, AJMAN>.`,AGP1 1.81 0.05 1.81 1.75 1.31 0.72 0.19 we have reanalyzed the phenotype data presented by Beattie 3.15 0.00 2.81 2.45 1.71 0.94 0.27 (19), Mohr (20), and Reed and Falls (21), using LIPED, to test for evidence for heterogeneity within the ADAN group. This ADLAN -&BO 0.00 0.50 -3.40 -2.42 -1.41 -0.80 -0.35 analysis is in Table 2. No scores 0.00 0.50 -3.40 -2.42 -1.41 -0.80 -0.35 presented significant positive lod were observed for any of the loci examined. The cumulative ADAN S 0.00 0.50 -0.91 -0.42 -0.06 -0.03 -0.02 results of these studies argues strongly against linkage between 0.00 0.50 -1.15 -0.64 -0.22 -0.06 -0.01 ADAN and Rh locus (Z = -11.94, 0 = 0.50) on chromosome 1 and MNS (Z = -10.59, 0 = 0.50) on chromosome 4. ADANi -PV 0.00 0.50 -1.10 -0.41 0.03 0.08 0.03 The heterogeneity of aniridia, aniridia syndromes, and even 0.00 0.50 -1.38 -0.66 -0.15 -0.10 -0.00 autosomal dominant aniridia is well established in general terms ADAN pLO1 0.00 0.50 -1.84 -1.06 -0.41 -0.15 -0.03 0.00 0.50 -1.84 -1.06 -0.41 -0.15 -0.03 Table 2. LIPED analysis for linkage of ADAN with polymorphic genetic markers, using phenotype data of (a) Beattie (19), (b) ADAN - OPT 0.00 0.50 -4.60 -2.93 -1.40 -0.65 -0.24 Mohr (20),* and (c) Reed and Falls (21) 0.00 0.50 -4.53 -2.95 -1.46 -0.69 -0.25 Z at recombination fraction L-1 L-2 2 6 0.05 0.1 0.2 0.3 0.4 ADAN HPA 0.00 0.50 -4.43 -2.80 -1.35 -0.65 -0.25 0.00 0.50 -4.71 -3.05 -1.53 -0.75 -0.27 ADAN ABO (a) 0.06 0.30 -0.87 -0.40 -0.03 0.06 0.02 ADAN FY (b) 0.08 0.20 -0.30 -0.07 0.08 0.07 0.30 ADAN JK 0.00 0.50 -2.45 -1.37 -0.43 -0.06 -0.03 ADAN LE (b) 0.49 0.15 0.35 0.48 0.44 0.26 0.08 0.00 0.50 -2.22 -1.22 -0.36 -0.02 -0.08 ADAN LU (b) 0.00 0.50 -0.72 -0.44 -0.19 -0.07 -0.02 ADAN MNS (a) 0.00 0.50 -1.03 -0.55 -0.18 -0.04 -0.01 ADANu--K- 0.00 0.50 -4.72 -3.24 -1.79 -0.96 -0.41 MNS (b) 0.00 0.50 -1.96 -1.10 -0.38 -0.11 -0.02 0.00 0.50 -4.72 -3.24 -1.79 -0.96 -0.41 MNS (c) 0.00 0.50 -2.70 -1.80 -0.71 -0.22 -0.04 ADAN P (a) 0.26 0.20 -0.01 0.14 0.26 0.17 0.00 ADAN -NS 0.00 0.50 -4.90 -2.99 -1.29 -0.51 -0.12 P (b) 0.00 0.50 -0.04 -0.03 -0.02 -0.01 -0.00 0.00 0.50 -4.90 -2.99 -1.29 -0.51 -0.12 ADAN PTC (a) 0.00 0.50 -1.52 -0.94 -0.41 -0.16 -0.04 PTC (b) 0.00 0.50 -1.02 -0.67 -6.31 -0.12 -0.03 ADAN: PGMI 0.00 0.50 -2.61 -1.85 -1.02 -0.48 -0.15 ADAN RH (a) 0.00 0.50 -3.41 -1.84 -0.58 -0.13 -0.03 0.00 0.50 -2.61 -1.85 -1.02 -0.48 -0.15 RH (b) 0.00 0.50 -1.44 -0.89 -0.39 -0.15 -0.04 RH (c) 0.00 0.50 -3.90 -2.72 -1.20 -0.43-0.09 ADAN RH 0.00 0.50 -3.19 -2.08 -1.07 -0.57 -0.26 In cases of small positive lod scores we have not attempted the in- 0.00 0.50 -3.19 -2.08 -1.07 -0.57 -0.26 terpolation necessary to obtain the true Z and 6 values.
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