American Journal of Medical Genetics 3254-59 (1990)
Microphthalmos in the Presumed Homozygous Offspring of a First Cousin Marriage and Linkage Analysis of a Locus in a Family With Autosomal Doiminant Cerulean Congenital Cataracts Fred S. Bodker, Mary Ann Lavery, Thomas N. Mitchell, Everett W. Lovrien, and Irene H. Maumenee Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, Maryland (F.S.B., T.N.M., I.H.M.); Department of Ophthalmology, University of Texas, Galveston (M.A.L.); Linkage Laboratory, University of Oregon, Portland (E.W.L.) ~~
~
A family with autosomal dominant congenital cataracts was studied to determine clinical variability. A total of 159 relatives was ascertained; 17 affected and 19 normal individuals were evaluated and their blood sampled for inclusion in the linkage analysis. The disease was compatible with normal to mildly decreased visual acuity until adult life in all affected except the product of a consanguineous marriage of affected first cousins who was born with bilateral microphthalmos and dense congenital cataracts, attributed to homozygosity of the cataract gene. There were no extraocular abnormalities; the patient was of normal intelligence. Twenty-three markers were typed, 18 of which were informative. Linkage could be excluded for all 18 markers at short distances.
KEY WORDS: autosomal dominant cataracts, consanguineous, homozygous, cerulean, murine cataract loci, linkage, lens crystallin protein, red cell and enzymatic markers, linkage, lod score. INTRODUCTION Hereditary congenital cataracts are estimated to be responsible for up to a third of the cases of blindness in the pediatric population [Fransois, 19631. Much interest has focused on the correlation of phenotype and mode of transmission since autosomal dominant, autosomal reReceived for publication August 11,1989; revision received January 26, 1990. Address reprint requests to Irene H. Maumenee, M.D. Wilmer Ophthalmological Institute, The Johns Hopkins Hospital, 321 Maumenee, 600 N. Wolfe Street, Baltimore, MD 21205.
0 1990 Wiley-Liss, Inc.
cessive, and X-linked inheritance have all been observed in cataracts and syndromes with cataracts [Reese et al., 19871. Cerulean cataract (CC) was first described by Vogt [1922a,b] and consists of predominantly peripheral bluish and white opacifications organized in concentric layers with occasional coexisting central lesions arranged radially. The opacities are observed in the superficial layers of the fetal nucleus as well as the adult nucleus of the lens. The eyes are commonly affected bilaterally and visual acuity is only mildly reduced in childhood. The severity changes little until adulthood at which time the opacifications may progress and lens extraction becomes necessary. Histologically the lesions are described as fusiform cavities between lens fibers which contain a deeply staining granular material. Grossly the lesions take on various colors, most commonly dull blue [Franqois, 1963; Waardenburg et al., 19611. To our knowledge, linkage analysis has not been previously performed in this condition. Association has been noted between CC and Down syndrome [Scheer, 1919a,b; Igersheimer, 19521, myotonic dystrophy [Heine, 19231, and many forms of senile and presenile cataracts. Two affected first cousins in a family with autosomal dominant congenital cataracts married and produced a daughter with microphthalmia, microcornea, and total congenital cataract. This clinical finding is of particular interest since the patient is presumed to have received the dominant mutant allele from each parent and is likely to be homozygous for markers flanking the CC locus [Lander and Botstein, 19871.Here we attempt to link the gene for CC to known chromosome markers. MATERIALS AND METHODS The propositus first consulted the Johns Hopkins Center for Hereditary Eye Diseases because of his cataracts. The extended family included 159 members, 36 of whom received full ophthalmologic examinations. The sex distribution among affected relatives was equal with
Microphthalmos in Homozygosity of Cerulean Cataracts
55
I I1 111 I
I
I
I
1
IV V VI VII Fig. 1. Pedigree of family with autosolmal ‘dominant congenital cataracts.
16 males and 19 females. Thirty-five affected individuals and 124 normal members were ascertained. Thirty six relatives were typed using 23 marker systems. The following 18 markers were informative in the family: ABO, FY, HP, RH, MNS, KKK, JK, GC, BF, ACP, AK, PGD, PGM-1, ESD, PGP, GLO, C-3, and ADA. The pedigree was analyzed for linkage by lod scores a s described by Morton [19551 and implemented in the LIPED computer program [Ott, 19763.
RESULTS The pedigree was constructed as shown (Fig. 11, and autosomal dominant inheritance was obvious. Most affected persons were aphakic. Cataract extractions became necessary in the affected subjects between ages 20-40 years and resulted in good visual acuities. The cataracts in younger affected exhibited numerous peripheral blue flakes with occasional central opacifications resembling spokes of a wheel (Fig. 2a,b). The visual acuities were only mildly reduced a t a young age. In contrast, affected first cousins married and had a daughter with bilateral microphthalmos and microcornea. She had nystagmus at birth but light and color perception were present. A photograph taken a t age 4 years showed slight microcornea, leukocoria, and enophthalmos (Fig. 3). At age 5 years, she underwent cataract extractions at the Mayo Clinic, consisting of iridectomy, forceps extraction, and mild anterior vitrectomy. The operative note commented t hat each lens was “a tiny membranous remnant about 3 mm in diameter.” The posterior pole of each eye was grossly normal postoperatively. All visual perception was gradually lost over the next 10 years. On physical examination in 1989, she was a 55-year-old woman without extraocular abnormalities except for hypothyroidism treated for 40 years. External examination showed bilateral sunken microphthalmic eyes (Fig. 4a-d). The corneal diameters measured 5 x 6 mm and 4 x 6 mm in the right and left eye, respectively. Slit lamp examination documented band keratopathy in the inferior part of both eyes with flat anterior chambers. The corneas were hazy with neovascularization. No lens or lens-capsule remnants were identified. Pupils were irregular and possibly contained proliferated pigment. In neither eye could a red reflex be elicited. Extraocular movements were random with full horizontal and vertical range OU. An ultrasound was not available. Globe
size appeared small. Tensions with Schiotz tonometry were 12 mm Hg OD and 21 mm Hg 0s. The exact course of vision loss could not be ascertained. Horizontal corneal diameters in the parents were 12 mm OD and 11 mm 0 s in the mother and 12 mm 0 s in the father (OD enucleated 1960 after failed detachment procedures). The results of the linkage analysis are given in Table I for the entire pedigree. Linkage could be excluded
Fig. 2. a , b Qpical examples of cerulean cataracts with peripheral flakes and central radial opacification as seen in the proband (a)and his sister (b).Visual acuity was 20140 in each eye at the time of photography.
56
Bodker et al.
favoring linkage between the cataract and any markers tested.
Fig. 3. Microcornea, leukocoria, and enophthalmos in the daughter of a consanguineous marriage of affected individuals.
(z 5 - 2.0) for all informative marker loci to include BF, ESD, HP, PGP, and C-3 a t 8 = 0.01; for PGD, GLO, and JK at 8 = 0.05; for PGM-1, RH, ACP, MNS, ABO, and AK at e = 0.10; and for GC a t e = 0.20. FY, KKK, and ADA could not be excluded.The lod score for FY reached a peak of 0.54 at 8 = 0.20. The presumed homozygous affected individual was heterozygous for FY as were her parents. There were 8 instances of homozygosity at the marker locus in the presumed homozygous affected patient and heterozygosity in her parents, but inclusion of affected relatives made linkage for these markers unlikely even a t larger distances. There is no evidence
DISCUSSION The pedigree is clearly indicative of autosomal dominant inheritance of the cerulean cataract. We propose that the consanguineous marriage of 2 heterozygotes produced homozygosity at that particular locus, resulting in bilateral microphthalmos and totally opaque dysplastic lenses leading to leukocoria in early childhood. The existence of a homozygous autosomal dominant genotype which lacks systemic malformations and mental retardation is of particular interest. To date, viable examples of homozygosity of a dominant gene are limited. Previous linkage studies have identified chromosome loci for autosomal dominant congenital cataracts in humans. In 1963, the zonular pulverulent cataract was linked to the Duffy blood group gene and later localized to chromosome 1 [Renwick and Lawler, 1963; Donahue et al., 19681. Posterior polar cataract was linked to the haptoglobin gene on chromosome 16 [Richard et al., 19841. A few pedigrees of X-linked cataracts have been reported [Capella et al., 1963; Krill et al., 1969; Pavone et al., 1981; Walsh and Wegman, 19371. Cataracts in these pedigrees may be part of the Nance-Horan syndrome. In one pedigree, the Nance-Horan syndrome has been weakly linked to the DXS85 locus [Zhu and Maumenee, 1988;Zhu et al., 19891and in another to the DXS43 locus [Bond et al., 19891on the distal short arm of the chromosome X in patients with the Nance-Horan syndrome. Many reports of linkage analysis of autosoma1 dominant congenital cataracts exist in the literature [Renwick and Lawler, 1963; Conneally et al., 1978; Huntzinger et al., 1978; Lyon et al., 1981; Carper et al., 1982; Cebon and West, 1982; Richard et al., 1984; Garber et al., 1985; Bateman et al., 1986; Green and Johnson, 1986; Muggleton-Harris et al., 1987; Barrett et al., 19881;however, none describe the cerulean cataract. No
TABLE I. Lod Scores for Linkage Between Congenital Cataract and Marker Loci Chromosome
Locus
1 1 1 1 2 4 4 6 6 9 9 13 16 16 18 19 20 Unassimed
FY PGD PGM-1 RH ACP
Gc MNS BF GLO ABO AK ESD HP PGP JK c-3 ADA KK
0.00
0.01
0.05
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.02 -0.30
-1.97 -4.21 -7.08 -8.75 -9.42 -13.12 -9.68 -2.66 -4.17 -8.51 -3.19 -2.11 -2.52 -2.45 -4.15 -2.07 0.02 -0.31
-0.17 -2.59 -3.61 -4.06 -4.71 -7.08 -4.36 -0.84 -2.07 -4.44 -2.49 -0.88 -1.04 -1.22 -2.13 -0.79 0.02 -0.31
Recombination frequency 0.10 0.15 0.20 0.37 -1.66 -2.19 -2.23 -2.84 -4.68 -2.29 -0.29 -1.21 -2.78 -2.07 -0.47 -0.42 -0.79 -1.33 -0.34 0.01 -0.24
0.53 -1.10 -1.42 -1.30 -1.84 -3.40 -1.23 -0.10 -0.74 -1.88 -1.69 -0.28 -0.11 -0.59 -0.92 -0.13 0.01 -0.16
0.54 -0.73 -0.93 -0.74 -1.21 -2.54 -0.60 -0.05 -0.46 -1.29 -1.35 -0.16 0.05 -0.47 -0.68 -0.03 0.01 -0.09
0.25
0.30
0.40
0.48 -0.47 -0.60 -0.39 -0.77 -1.90 -0.20 -0.03 -0.27 -0.87 -1.04 -0.08 0.13 -0.39 -0.51 0.02 0.01 -0.04
0.38 -0.28 -0.37 -0.17 -0.47 -1.37 0.03 -0.03 -0.14 -0.56 -0.76 -0.03 0.15 -0.33 -0.40 0.04 0.00 -0.01
0.17 -0.07 -0.09 0.02 -0.12 -0.56 0.18 -0.00 -0.02 -0.17 -0.32 0.02 0.10 -0.21 -0.21 0.03 0.00 0.01
Microphthalmos in Homozygosity of Cerulean Cataracts
57
Fig. 4. a-d External examination revealed bilateral sunken microphthalmiceyes (a,b), and slit lamp examinationwas notable for band keratopathy,corneal haziness, and neovascularizationOD ( c ) and 0s (d) in the daughter of a consanguineous marriage of affected individuals.
case involved a consanguineous marriage of affected individuals. Studies of mice have linked a total congenital cataract with the lens opacity (Lop) gene on chromosome 10 [Lyon et al., 1981;Muggleton-Harris et al., 19871as well as associating cataractogenesis with abnormalities in the lens crystallin families. The Philly mouse strain develops a cataract due to a deficiency in functional 27 kilodalton (K) 6-crystallin messenger RNA in vitro [Carper et al., 19821, while the F’raser mouse strain cataracts are caused by reduced messenger RNA for y-crystallin protein [Garber et al., 19851. The human y-crystallin gene is localized to 2q33-q35 and has since been linked to a Coppock-like cataract
[Lubsen et al., 19871. The mouse correlate to y-crystallin protein is found on chromosome 1 at the Len-1 gene locus [Skow, 19821.A mutation for abnormal lens formation resulting in microphthalmia has been described in mice in association with the eye lens obsolescence (El01 gene in the close vicinity of Len-1 [Oda et al., 1980bl. The relationship between Len-1 and Elo has yet to be elucidated. Although crystallin synthesis was present in the necrotic areas of the central lens of the microphthalmic Elo mice [Watanabe et al., 19801, abnormal regulation of expression and production of trophic factors associated with crystallin synthesis should not be discounted as explanations for microphthalmia. Cytologic changes of
58
Bodker et al.
the in vitro models included the appearance of numerous lysosomal bodies and a deficiency of mitochondria by day 13based on electron microscopy [Oda et al., 1980al. Mechanisms proposed might include 1)selfdestruction of cellular components via lysosomal proliferation, 2) insuficient energy production required for synthesis, post-translational modification,or regulation of cytoskeletal components and crystallins, and 3) abnormal production of extracellular matrix material [Zwaan and Webster, 19841. Another mouse gene, the recessive “ocular retardation” (or),has a role in causing microphthalmia and may combine lens opacification and microphthalmia as a single mutation. When expressed in the homozygous form, the gene may exhibit strong or weak expressivity. The former is characterized by inhibition of optic vesicle growth causing anophthalmia or microphthalmia with aphakia while the latter is associated with retardation of the “anlage” of the retina, causing microphthalmia with cataract. Genetic modifiers presumably account for this variability; however, no localization of or and its modifier has yet been reported [Osipov and Vakhrusheva, 19831. We conclude that cerulean cataract as observed in this kindred is clinically and genetically distinct from other known forms of hereditary cataract. Analysis using DNA markers is in progress.
ACKNOWLEDGMENTS This study was supported in part by the Krieble and Walter Edel Funds of the Johns Hopkins Center for Hereditary Eye Diseases. REFERENCES Barrett DJ, Sparkes RS, Gorin MB, Bhat SP, Spence MA, Marazita ML, Bateman J B (1988): Genetic linkage analysis of autosomal dominant congenital cataracts with lens-specific DNA probes and polymorphic phenotypic markers. Ophthalmology 95538-544. Bateman JB, Spence MA, Marazita ML, Sparkes RS (1986): Genetic linkage analysis of autosomal dominant congenital cataracts. Am J Ophthalmol 101:218-225. Bond A, Lewis RA, Grimes PA, Nussbaum RL, Stambolian D (1989): Mapping of X-linked cataract-dental syndrome. Invest Ophthalmol Vis IARVO Suppll Sci 30:403. Capella JA, Kaufman HE, Lill FJ, Cooper G (1963):Hereditary cataracts and microphthalmis. Am J Ophthalmol 56:454-458. Carper D, Shinohara T, Piatigorsky J, Kinoshita J H (1982): Deficiency of functional messenger RNA for a developmentally regulated P-crystallin polypeptide in a hereditary cataract. Science 217:463464. Cebon L, West RH (1982): A syndrome involvingcongenita1cataractsof unusual morphology, microcornea, abnormal irides, nystagmus and congenital glaucoma, inherited as a n autosomal dominant trait. Aust J Ophthalmol 10:237-242. Conneally PM, Wilson AF, Merritt AD, Helveston EM, Palmer CG, Wang LY (1978): Confirmation of genetic heterogeneity in autosoma1 dominant forms of congenital cataracts from linkage studies. Cytogenet Cell Genet 22:295-297. Donahue RP, Bias WB, Renwick JH, McKusick VA (1968): Probable assignment of the Duffy blood group locus to chromosome 1in man. Proc Natl Acad Sci USA 61:949-955. FranGois J (1963): “Congenital Cataract.” Assen, The Netherlands: Royal VanGorcum, Publisher. pp 1-2, 226-227. Garber AT, Winkler C, Shinohara T, King CR, Inana G, Piatigorsky J (1985): Selective loss of a family of gene transcripts in a hereditary murine cataract. Science 227:74-77.
Green JS, Johnson GJ (1986): Congenital cataract with microcornea and Peters’ anomaly as expressions of one autosomal dominant gene. Ophthalmic Paediatr Genet 7:187-194. Heine L (1923): a e r Tetanie-und Myotoniekatarakte. Z Exp Med 31:84. Huntzinger RS, Weitkamp LR, Roca PD (1978): Linkage relations of a locus for congenital total nuclear cataract. J Med Genet 15:113-115. Igersheimer J (1952):The relationship of lenticular changes to mongolism. Trans Am Ophthalmol SOC49:595-624. Krill AE, Woodbury G, Bowman J (1969): X-chromosomal-linked sutural cataracts. Am J Ophthalmol 68:867-872. Lander ES, Botstein (1987): Homozygosity mapping: A way to map human recessive traits with the DNA of inbred children. Science 236:1567-1569. Lubsen NH, Renwick JH, Tsui L-C, Breitman ML, Schoenmakers JGG (1987): A locus for a human hereditary cataract is closely linked to the y-crystallin gene family. Proc Natl Acad Sci USA 84:489-492. Lyon MF, Jarvis SE, Sayers I, Holmes RS (1981):Lens opacity: A new gene for congenital cataract on chromosome 10 of the mouse. Genet R ~ s38:337-341. Morton NE (1955): Sequential tests for the detection of linkage. Am J Hum Genet 7:277-318. Muggleton-HarrisAL, Jesting MFW, Hall M (1987):A gene location for the inheritance of the cataract Fraser (CatFk) mouse congenital cataract. Genet Res 49:235-238. Oda S, Watanabe K, Fujisawa H, Kameyama Y (1980a): Impaired development of lens fibers in genetic microphthalmia, eye lens obsolescence, Elo, of the mouse. Exp Eye Res 31:673-681. Oda S, Wantanabe T, Kondo K (1980b): A new mutation, eye lens obsolescence, Elo, on chromosome 1 in the mouse. Jpn J Genet 55:71-75. Osipov VV, Vakhrusheva MP (1983): Variation in the expressivity of the gene ocular retardation in mice. Tsitol Genet 17:39-43. Ott J (1976): A computer program for linkage analysis of general human pedigrees. Am J Hum Genet 282128429. Pavone L, LaRosa M, Sorge G, Scaletta S, LiVolti S, Mollica S (1981): Ocular manifestations in a family with probable X-linked cataracts. Clin Genet 20:243-246. Reese PD, Tuck-Muller CM, Maumenee IH (1987): Autosomal dominant congenital cataract associated with chromosomal translocation [t(3;4)(~26.2;~15)]. Arch Ophthalmol 1051382-1384. Renwick JH, Lawler SD (1963): Probable linkage between a congenital cataract locus and the Duffy blood group locus. Ann Hum Genet 27:67-84. Richard J , Maumenee IH, Rowe S, Lovrien EW (1984): Congenital cataract possibly linked to haptoglobin. (Abstract) Cytogenet Cell Genet 37570. Scheer, WMvd (1919a):Cataracta lentis bei mongoloider Idiotie. Klin Mbl Augenheilk 62155-170. Scheer, WMvd (1919b): Verscheidene genvallen van mongoloide idiotie in een gezin. Ned Tijdschr Geneeskd 328. Skow LC (1982): Location of a gene controlling electrophoretic variation in mouse y-crystallins. Exp Eye Res 34509-516. Vogt A (1922a):Die Spezifitat angeborener und erworbener Starformen fur die einzelnen Linsenzonen. Graefes Arch Clin Exp Ophthalmol 108:219-228. Vogt A (1922b):Weitere Ergebnisse der Spaltlampenmikroskopie des vorderen Bulbusabschnittes. 111. (Abschnitt-Fortsetzung). Angeborene und fruh aufgetretene Linsenveranderungen. Graefes Arch Clin Exp Ophthalmol 108:182-191. Waardenburg PJ, Franceschetti A, Klein D (1961): “Genetics and Ophthalmology.” Assen, The Netherlands: Royal VanGorcum Publisher, p 890. Walsh FB, Wegman ME (1937): A pedigree of hereditary cataract, illustrating sex-limited type. Bull Johns Hopkins Hosp 61:125135. Watanabe K, fijisawa H, Oda S, Kameyama Y (1980): Organ culture and immunohistochemistry of the genetically malformed lens, in eye lens obsolescence, Elo, of the mouse. Exp Eye Res 31:683-689. Zhu D, Alcorn DM, Antonarakis SE, Levin LS, Mitchell TN, Maumenee
Microphthalmos in Homozygosity of Cerulean Cataracts IH (1989):Assignment of Nance-Horan syndrome to the distal short arm of the X-chromosome. Hum Genet (in press). Zhu D, Maumenee IH (1988): Linkage of congenital cataracts. Invest Ophthalmol Vis Sci [ARVO Suppll 29:94.
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Zwaan J, Webster EH, Jr (1984):Histochemical analysis of extracellular matrix material during embryonic mouse lens morphogenesis in an aphakic strain of mice. Dev Biol 104380-389.
Microphthalmos in the Presumed Homozygous Offspring of a First Cousin Marriage and Linkage Analysis of a Locus in a Family With Autosomal Doiminant Cerulean Congenital Cataracts Fred S. Bodker, Mary Ann Lavery, Thomas N. Mitchell, Everett W. Lovrien, and Irene H. Maumenee Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, Maryland (F.S.B., T.N.M., I.H.M.); Department of Ophthalmology, University of Texas, Galveston (M.A.L.); Linkage Laboratory, University of Oregon, Portland (E.W.L.) ~~
~
A family with autosomal dominant congenital cataracts was studied to determine clinical variability. A total of 159 relatives was ascertained; 17 affected and 19 normal individuals were evaluated and their blood sampled for inclusion in the linkage analysis. The disease was compatible with normal to mildly decreased visual acuity until adult life in all affected except the product of a consanguineous marriage of affected first cousins who was born with bilateral microphthalmos and dense congenital cataracts, attributed to homozygosity of the cataract gene. There were no extraocular abnormalities; the patient was of normal intelligence. Twenty-three markers were typed, 18 of which were informative. Linkage could be excluded for all 18 markers at short distances.
KEY WORDS: autosomal dominant cataracts, consanguineous, homozygous, cerulean, murine cataract loci, linkage, lens crystallin protein, red cell and enzymatic markers, linkage, lod score. INTRODUCTION Hereditary congenital cataracts are estimated to be responsible for up to a third of the cases of blindness in the pediatric population [Fransois, 19631. Much interest has focused on the correlation of phenotype and mode of transmission since autosomal dominant, autosomal reReceived for publication August 11,1989; revision received January 26, 1990. Address reprint requests to Irene H. Maumenee, M.D. Wilmer Ophthalmological Institute, The Johns Hopkins Hospital, 321 Maumenee, 600 N. Wolfe Street, Baltimore, MD 21205.
0 1990 Wiley-Liss, Inc.
cessive, and X-linked inheritance have all been observed in cataracts and syndromes with cataracts [Reese et al., 19871. Cerulean cataract (CC) was first described by Vogt [1922a,b] and consists of predominantly peripheral bluish and white opacifications organized in concentric layers with occasional coexisting central lesions arranged radially. The opacities are observed in the superficial layers of the fetal nucleus as well as the adult nucleus of the lens. The eyes are commonly affected bilaterally and visual acuity is only mildly reduced in childhood. The severity changes little until adulthood at which time the opacifications may progress and lens extraction becomes necessary. Histologically the lesions are described as fusiform cavities between lens fibers which contain a deeply staining granular material. Grossly the lesions take on various colors, most commonly dull blue [Franqois, 1963; Waardenburg et al., 19611. To our knowledge, linkage analysis has not been previously performed in this condition. Association has been noted between CC and Down syndrome [Scheer, 1919a,b; Igersheimer, 19521, myotonic dystrophy [Heine, 19231, and many forms of senile and presenile cataracts. Two affected first cousins in a family with autosomal dominant congenital cataracts married and produced a daughter with microphthalmia, microcornea, and total congenital cataract. This clinical finding is of particular interest since the patient is presumed to have received the dominant mutant allele from each parent and is likely to be homozygous for markers flanking the CC locus [Lander and Botstein, 19871.Here we attempt to link the gene for CC to known chromosome markers. MATERIALS AND METHODS The propositus first consulted the Johns Hopkins Center for Hereditary Eye Diseases because of his cataracts. The extended family included 159 members, 36 of whom received full ophthalmologic examinations. The sex distribution among affected relatives was equal with
Microphthalmos in Homozygosity of Cerulean Cataracts
55
I I1 111 I
I
I
I
1
IV V VI VII Fig. 1. Pedigree of family with autosolmal ‘dominant congenital cataracts.
16 males and 19 females. Thirty-five affected individuals and 124 normal members were ascertained. Thirty six relatives were typed using 23 marker systems. The following 18 markers were informative in the family: ABO, FY, HP, RH, MNS, KKK, JK, GC, BF, ACP, AK, PGD, PGM-1, ESD, PGP, GLO, C-3, and ADA. The pedigree was analyzed for linkage by lod scores a s described by Morton [19551 and implemented in the LIPED computer program [Ott, 19763.
RESULTS The pedigree was constructed as shown (Fig. 11, and autosomal dominant inheritance was obvious. Most affected persons were aphakic. Cataract extractions became necessary in the affected subjects between ages 20-40 years and resulted in good visual acuities. The cataracts in younger affected exhibited numerous peripheral blue flakes with occasional central opacifications resembling spokes of a wheel (Fig. 2a,b). The visual acuities were only mildly reduced a t a young age. In contrast, affected first cousins married and had a daughter with bilateral microphthalmos and microcornea. She had nystagmus at birth but light and color perception were present. A photograph taken a t age 4 years showed slight microcornea, leukocoria, and enophthalmos (Fig. 3). At age 5 years, she underwent cataract extractions at the Mayo Clinic, consisting of iridectomy, forceps extraction, and mild anterior vitrectomy. The operative note commented t hat each lens was “a tiny membranous remnant about 3 mm in diameter.” The posterior pole of each eye was grossly normal postoperatively. All visual perception was gradually lost over the next 10 years. On physical examination in 1989, she was a 55-year-old woman without extraocular abnormalities except for hypothyroidism treated for 40 years. External examination showed bilateral sunken microphthalmic eyes (Fig. 4a-d). The corneal diameters measured 5 x 6 mm and 4 x 6 mm in the right and left eye, respectively. Slit lamp examination documented band keratopathy in the inferior part of both eyes with flat anterior chambers. The corneas were hazy with neovascularization. No lens or lens-capsule remnants were identified. Pupils were irregular and possibly contained proliferated pigment. In neither eye could a red reflex be elicited. Extraocular movements were random with full horizontal and vertical range OU. An ultrasound was not available. Globe
size appeared small. Tensions with Schiotz tonometry were 12 mm Hg OD and 21 mm Hg 0s. The exact course of vision loss could not be ascertained. Horizontal corneal diameters in the parents were 12 mm OD and 11 mm 0 s in the mother and 12 mm 0 s in the father (OD enucleated 1960 after failed detachment procedures). The results of the linkage analysis are given in Table I for the entire pedigree. Linkage could be excluded
Fig. 2. a , b Qpical examples of cerulean cataracts with peripheral flakes and central radial opacification as seen in the proband (a)and his sister (b).Visual acuity was 20140 in each eye at the time of photography.
56
Bodker et al.
favoring linkage between the cataract and any markers tested.
Fig. 3. Microcornea, leukocoria, and enophthalmos in the daughter of a consanguineous marriage of affected individuals.
(z 5 - 2.0) for all informative marker loci to include BF, ESD, HP, PGP, and C-3 a t 8 = 0.01; for PGD, GLO, and JK at 8 = 0.05; for PGM-1, RH, ACP, MNS, ABO, and AK at e = 0.10; and for GC a t e = 0.20. FY, KKK, and ADA could not be excluded.The lod score for FY reached a peak of 0.54 at 8 = 0.20. The presumed homozygous affected individual was heterozygous for FY as were her parents. There were 8 instances of homozygosity at the marker locus in the presumed homozygous affected patient and heterozygosity in her parents, but inclusion of affected relatives made linkage for these markers unlikely even a t larger distances. There is no evidence
DISCUSSION The pedigree is clearly indicative of autosomal dominant inheritance of the cerulean cataract. We propose that the consanguineous marriage of 2 heterozygotes produced homozygosity at that particular locus, resulting in bilateral microphthalmos and totally opaque dysplastic lenses leading to leukocoria in early childhood. The existence of a homozygous autosomal dominant genotype which lacks systemic malformations and mental retardation is of particular interest. To date, viable examples of homozygosity of a dominant gene are limited. Previous linkage studies have identified chromosome loci for autosomal dominant congenital cataracts in humans. In 1963, the zonular pulverulent cataract was linked to the Duffy blood group gene and later localized to chromosome 1 [Renwick and Lawler, 1963; Donahue et al., 19681. Posterior polar cataract was linked to the haptoglobin gene on chromosome 16 [Richard et al., 19841. A few pedigrees of X-linked cataracts have been reported [Capella et al., 1963; Krill et al., 1969; Pavone et al., 1981; Walsh and Wegman, 19371. Cataracts in these pedigrees may be part of the Nance-Horan syndrome. In one pedigree, the Nance-Horan syndrome has been weakly linked to the DXS85 locus [Zhu and Maumenee, 1988;Zhu et al., 19891and in another to the DXS43 locus [Bond et al., 19891on the distal short arm of the chromosome X in patients with the Nance-Horan syndrome. Many reports of linkage analysis of autosoma1 dominant congenital cataracts exist in the literature [Renwick and Lawler, 1963; Conneally et al., 1978; Huntzinger et al., 1978; Lyon et al., 1981; Carper et al., 1982; Cebon and West, 1982; Richard et al., 1984; Garber et al., 1985; Bateman et al., 1986; Green and Johnson, 1986; Muggleton-Harris et al., 1987; Barrett et al., 19881;however, none describe the cerulean cataract. No
TABLE I. Lod Scores for Linkage Between Congenital Cataract and Marker Loci Chromosome
Locus
1 1 1 1 2 4 4 6 6 9 9 13 16 16 18 19 20 Unassimed
FY PGD PGM-1 RH ACP
Gc MNS BF GLO ABO AK ESD HP PGP JK c-3 ADA KK
0.00
0.01
0.05
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.02 -0.30
-1.97 -4.21 -7.08 -8.75 -9.42 -13.12 -9.68 -2.66 -4.17 -8.51 -3.19 -2.11 -2.52 -2.45 -4.15 -2.07 0.02 -0.31
-0.17 -2.59 -3.61 -4.06 -4.71 -7.08 -4.36 -0.84 -2.07 -4.44 -2.49 -0.88 -1.04 -1.22 -2.13 -0.79 0.02 -0.31
Recombination frequency 0.10 0.15 0.20 0.37 -1.66 -2.19 -2.23 -2.84 -4.68 -2.29 -0.29 -1.21 -2.78 -2.07 -0.47 -0.42 -0.79 -1.33 -0.34 0.01 -0.24
0.53 -1.10 -1.42 -1.30 -1.84 -3.40 -1.23 -0.10 -0.74 -1.88 -1.69 -0.28 -0.11 -0.59 -0.92 -0.13 0.01 -0.16
0.54 -0.73 -0.93 -0.74 -1.21 -2.54 -0.60 -0.05 -0.46 -1.29 -1.35 -0.16 0.05 -0.47 -0.68 -0.03 0.01 -0.09
0.25
0.30
0.40
0.48 -0.47 -0.60 -0.39 -0.77 -1.90 -0.20 -0.03 -0.27 -0.87 -1.04 -0.08 0.13 -0.39 -0.51 0.02 0.01 -0.04
0.38 -0.28 -0.37 -0.17 -0.47 -1.37 0.03 -0.03 -0.14 -0.56 -0.76 -0.03 0.15 -0.33 -0.40 0.04 0.00 -0.01
0.17 -0.07 -0.09 0.02 -0.12 -0.56 0.18 -0.00 -0.02 -0.17 -0.32 0.02 0.10 -0.21 -0.21 0.03 0.00 0.01
Microphthalmos in Homozygosity of Cerulean Cataracts
57
Fig. 4. a-d External examination revealed bilateral sunken microphthalmiceyes (a,b), and slit lamp examinationwas notable for band keratopathy,corneal haziness, and neovascularizationOD ( c ) and 0s (d) in the daughter of a consanguineous marriage of affected individuals.
case involved a consanguineous marriage of affected individuals. Studies of mice have linked a total congenital cataract with the lens opacity (Lop) gene on chromosome 10 [Lyon et al., 1981;Muggleton-Harris et al., 19871as well as associating cataractogenesis with abnormalities in the lens crystallin families. The Philly mouse strain develops a cataract due to a deficiency in functional 27 kilodalton (K) 6-crystallin messenger RNA in vitro [Carper et al., 19821, while the F’raser mouse strain cataracts are caused by reduced messenger RNA for y-crystallin protein [Garber et al., 19851. The human y-crystallin gene is localized to 2q33-q35 and has since been linked to a Coppock-like cataract
[Lubsen et al., 19871. The mouse correlate to y-crystallin protein is found on chromosome 1 at the Len-1 gene locus [Skow, 19821.A mutation for abnormal lens formation resulting in microphthalmia has been described in mice in association with the eye lens obsolescence (El01 gene in the close vicinity of Len-1 [Oda et al., 1980bl. The relationship between Len-1 and Elo has yet to be elucidated. Although crystallin synthesis was present in the necrotic areas of the central lens of the microphthalmic Elo mice [Watanabe et al., 19801, abnormal regulation of expression and production of trophic factors associated with crystallin synthesis should not be discounted as explanations for microphthalmia. Cytologic changes of
58
Bodker et al.
the in vitro models included the appearance of numerous lysosomal bodies and a deficiency of mitochondria by day 13based on electron microscopy [Oda et al., 1980al. Mechanisms proposed might include 1)selfdestruction of cellular components via lysosomal proliferation, 2) insuficient energy production required for synthesis, post-translational modification,or regulation of cytoskeletal components and crystallins, and 3) abnormal production of extracellular matrix material [Zwaan and Webster, 19841. Another mouse gene, the recessive “ocular retardation” (or),has a role in causing microphthalmia and may combine lens opacification and microphthalmia as a single mutation. When expressed in the homozygous form, the gene may exhibit strong or weak expressivity. The former is characterized by inhibition of optic vesicle growth causing anophthalmia or microphthalmia with aphakia while the latter is associated with retardation of the “anlage” of the retina, causing microphthalmia with cataract. Genetic modifiers presumably account for this variability; however, no localization of or and its modifier has yet been reported [Osipov and Vakhrusheva, 19831. We conclude that cerulean cataract as observed in this kindred is clinically and genetically distinct from other known forms of hereditary cataract. Analysis using DNA markers is in progress.
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