Autosomal dominant congenital cataract; linkage relations; clinical and genetic heterogeneity Lund AM, Eiberg H, Rosenberg T. Warburg M. Autosomal dominant cataract; linkage relations; clinical and genetic heterogeneity. Clin Genet 1992: 41: 65-69.
Allan M. Lund', Hans Eibsrg', Thomas Rosenberg3 and Mstts Warburg' 'Oivision of Pediatric Ophthalmology and Handk caps, Gentofte Hospital, Gentofte. 'University Institute of Medical Genetics, Panum Institute. Copenhagen, and 'National Eye Clinic for the Visually Impaired, Hellerup, Denmark
Congenital cataract is a heterogeneous disorder. Approximately one third of the cases are hereditary. A large family with autosomal dominant congenital cataract is described here. Clinical examinations showed variable expressivity, but all affected persons were eventually operated, most of them in the first or second decade of life. Linkage relations with a number of polymorphic marker systems were studied, all of them being negative. Among the 21 systems studied were Fy, HP, D16S4 and CRYG. The present autosomal dominant congenital cataract is termed the Volkman cataract, after the ancestor in the pedigree, and is genotypically different from the Marner cataract found in another large Danish pedigree.
-
Key words: autosomal dominant Cataract c o n genital Cataract haptoglobin - linkage relations
-
Dr. Matte Warburg, Bjenklinikken for MuRihandiCappede. Vangedehuse, Sognevej 40, 2820 Gentofte, Denmark Received 18 January, revised 17 July, accepted for publication 24 July 1991
Congenital cataract is one of the most common major abnormalities of the eye and a frequent cause of blindness in infants; congenital cataracts are responsible for 10% to 30% of all cases of blindness in children (Reese et aI. 1987). In Denmark, Jensen & Goldschmidt (1971) found that 34% of all congenital cataracts were familial. These cataracts may be inherited in an autosomal dominant, autosoma1 recessive or X-linked manner. Autosomal dominant inheritance is most common in outbred communities. To distinguish the various types of cataracts on morphological grounds is difficult: on the one hand, the possible biological reactions of a lens expressing a cataract gene are limited and, on the other hand, the reaction to the same gene is not always the same (Bateman et al. 1986, Marner et al. 1989). Both clinical and genetic heterogeneity exist: at least three different chromosomal loci have been associated with autosomal dominant congenital cataract. In 1963, the Coppock cataract or zonular pulverulent cataract was mapped to chromosome l on the basis of linkage to the Duffy blood groups (Fy), (Renwick & Lawler 1963). Conneally et al. (1978) described a similar cataract, which was also chromosomally localised to the same area as the former. (It was-linked to lqh, a marker on chromoSome 'lose to Fy locus.). A morpholo~callysimilar t Y F 9 studied by Lubsen et aI. (1986h called the Coppock-like cataract, showed linkage with the
gamma-crystalline gene cluster on chromosome 2 (2q33-35). Recently an autosomal dominant cataract segregating in a Danish family was assigned to chromosome 16 on the basis of linkage to haptoTable 1. Linkage relations of autosornal dominant cataract Reference
FY
Renwick et al. Conneally et al. Family 1 Family 2-7 Marner et at. Maumenee Lubsen et al. Moross et al. Reese et al. Hammerstein et al. Huntziger at al.
+ N N
-
HP
Crystallins
+ Iqh
-
+ +
- (19 markers) (LOO =2.1 1) +gamma t(2;14) (p25;q24) t(3;4) (p26.2;pl5) N (20 markers) N (8 markers)
N
-
N
Stabile et at. Bateman et al.
-
Barret et al.
-
N
Bodker et al.
N
-
Present study
- -
Other
- - beta
- gamma - MIP
-
(9 markers) N (15 markers) (6 markers) N (2 markers)
-
(14 markers) N (2 markers) (19 markers)
FY: Dutfy blwd group assigned to chromosome 1 (q21q25). HP: Haptoglobin assigned to chromosome 16. MIP: Major intrinsic protein. N: inconclusive data +: linkage established. -: linkage excluded. nothing: marker not examinedlnot described.
Lund et al. Table 2. Chromosomal localizations of major crystallins in humans Crystallin
I
Localization
alfa A alfa 6 beta 61 beta 62 beta 63 gamma
CRYAl CRYA2 CRY61 CRY62 CRY63 CRYG1-6 CRYGPl +P2
21q22.3 llq 17q11.2-912 22911.2-ql2.1 22q11.2q12.1 2q33-35
gamma
cRWja
3q
n
For references. see Human Gene Mapping 10.
globin (HP) (Eiberg et al. 1988 and 1990, Marner et al. 1989). Haptoglobin is located within band 16q22 (McGill et a]. 1984). Maumenee (1979) and Richards et a]. (1984) obtained a LOD score of 2.1 between HP and a posterior polar cataract, morphologically different from the Marner cataract. Possibly other loci are involved in autosomal dominant cataracts, as shown in Table 1. Some forms may be due to a defect in one of the three major crystallins in the human lens (alfa, beta and gamma), as is probably the case with the Coppocklike cataract. Two autosomal dominant cataracts in mice are presumed to be caused by a defect in a crystallin-gene: the Philly-mouse cataract (Betacrystallin) (Carper et a]. 1982) and the Fraser mouse cataract (gamma-crystallin) (Garber et al. 1985). In 131N guinea-pigs an autosomal dominant cataract is associated with a mutation of the gene for Zeta-crystallin (Huang et al. 1990). Table 2 shows chromosomal localisations for the major human crystallins. Material and methods
The family with congenital cataract considered in this study was first described by Gordon Norrie
Fig. I. First five generations of the Volkmann family. The figure numbers refer to the lineages which have been investigated by
us.
(1 896). later by Kirstine Lehman ( 1918) and most recently by Chr. Rasmussen (1932). The ancestor, Mr. Volkman born in 1730, emigrated from Konigsberg in Germany to Denmark in 1750. The cataract in his descendents is therefore termed the Volkman cataract. Pedigrees were constructed from old medical records kept in the National Eye Clinic for the Visually Impaired, updated by us, and are shown in Fig. 1-4. Most of the family lived and lives in the southern part of Zealand; there are 426 persons in 10 generations. From the turn of the century until now, 285 persons have been born into this family, 144 of them having affected parents; the ratio of affected to unaffected relatives was 60 :72 (the clinical state of 12 persons could not be reliably determined), which is compatible with autosomal dominant inheritance. The ratio of affected males and females born to affected parents
Table 3. Linkage relations of Volkmann cataract with selected markers ~~~
Chromosome
Locus
~~
~
Sex
0.01
Lod-scores at recombination fractions 0.05 0.10 0.20 0.30
0.40
M F
-2.00 -2.17
-0.73 -0.76
-0.29 -0.20
-0.01 0.24
0.04 0.33
0.01 0.23
1
FY
2
CRYG
M+F
-2.51
-1.14
-0.59
-0.14
0.00
0.03
4
MNS
M F
-2.21 -2.80
-0.90 -1.44
-0.42 -0.89
-0.07 -0.39
0.03 -0.151
0.03 -0.04
4
GC
M F
-6.97 0.00
-3.97 0.00
-2.68
-1.4
0.00
-0.73 0.00
-0.29 0.00
M F
-5.52
-2.74 -0.90
0.00 -1.58
-0.57 0.19
-0.15 0.20
0.00 0.08
M F
-0.01 0.00
0.62 0.00
0.42 0.00
0.18 0.00
M F
-1.36 -0.31
-0.17 -0.08
-0.06 -0.03
16 16 22
HP D16S4 Pl
-2.44
-0.24
0.56
0.67
0.00
0.00
-0.68 -0.24
-0.41 -0.17
Linkage could be excluded for ABQ RH, APOH. JK, SE,UI, KEL CQ BF. F13A. F138, ORM and TF.
-0.01 -0.01
Autosomal dominant congenital cataract URSlN
I I1 111
IV
v VI VI 1
YlII
1x x Fig. 2. Subfamily 1 (Ursin).
The pedigrees were plotted with the Pediplot computer program (Baggesen & Baggesen 1989).
was 2913 1. In four cases a generation was skipped (VI-25, VII-18, VII-46 and VII-58 +VIII-65 (two generations skipped)), yielding a penetrance of about 90%. The members of the family have been examined ophthalmologically by us, including determination of acuity, refraction, contrast sensitivity (Cambridge contrast sensitivity tables), slitlamp examination and ophthalmoscopy. Recent and old medical records were obtained from other ophthalmologists and in 4 cases (2 unaffected and 2 affected) examination of these was substituted for our clinical examination. From all family members 50 ml blood was collected by venipuncture. Each sample was analyzed for the following 18 polymorphic blood cell and serum markers: HP, Fy, P1, ABO, RH,MNS, APOH, JK, SE, LU, KEL, CO, BF, GC, F13B, F13A, ORM, TF and the following loci, D16S4 and CRYG. LIPED (Ott 1973) was used for the calculation of LOD-scores and recombination frequencies were scored over the values 1%, 5%, lo%, 20%, 30% and 40%.
We have investigated a total of 35 affected and 58 unaffected individuals (including unaffected partners) in this family. The cataract is progressive; affected members of the family have no symptoms at birth. A progressive visual loss appears during the first decade of life, the majority at 3 4 years of age. The progression rate differs between patients and in a few patients progression has been very slow; one patient developed symptoms in his third decade and operation was not necessary until 20 years later. Eventually all affected members needed operation. Morphologically only two persons were available for examination before cataract operation; as seen from Fig. 5 and 6, their cataracts were very different; this, however, may be related to the difference in age between the two patients, Patient A being 3 years old and Patient B 27 years old. In
BJERREGXARD
JENSEN
,
Results and Discussion
'
I
I1 XI1
I I1 111
V
IV V
v1
VI
VII
VII
VIII
y111
IV
IX
28 29 30 31 52 33
34 35
36
X Fig. 3. Subfamily 2 (Bjerregaard).
37 38
IX
x Fig. 4. Subfamily 3 (Jensen).
67
Lund et al.
Fig. 5. Lens of 3-year-old girl (IX-32). Multiple discrete opacities in the embryonic, fetal and juvenile nucleus are seen.
the lens of Patient A multiple discrete round opacities were seen in the embryonic, fetal and juvenile nucleus. In the elder patient there were two major opacities, which were asymmetric in the two eyes. In the juvenile nucleus, partial circumferential dense opacities were observed; in and around the anterior and posterior Y-suture, opacities were seen as an accentuation of these structures. Furthermore, a discrete opacity was seen in the central
part of the embryonic nucleus. Between the dense opacities of the lens, the three nuclei showed diffuse blurring. The cortex and the capsule had no opacities. Old medical records gave evidence of two family members who were only unilaterally affected. Based on the above two patients, and available medical records and literature, the morphology of the cataract is a central and zonular cataract with a variable expression/progression rate between the two eyes and interpersonally, but mostly resulting in dense cataracts during the first decade of life. As mentioned above, penetrance is approximately 90%: we have examined four children with cataracts whose parents had clear lenses. Skipped generations and slowly progressive cataracts could not be due to genomic imprinting in this family. Linkage results
As a starting point we looked for linkage of the Volkmann cataract with loci thought to be linked to congenital autosomal dominant cataract, first of all haptoglobin and D16S4; both of these loci are located within band 16q22.1 about 5 cM from each other, and both were linked to the Marner
Fig. 6. Lens of 27-year-old girl ( W I - 5 5 ) . Opacifications around the juvenile Y-sutures a n seen together with partial circumferential opacifications of the juvenile nucleus. A dense but diffusely outlined opacification is seen in the embryonic nucleus.
68
Autosomal dominant congenital cataract
cataract. Examinations proceeded with FY, the gamma-crystallin gene cluster (2q33-35) and furthermore chromosomes 4 - involved in a family in which a t(3;4) was co-segregating with an autosomal dominant cataract (Reese et al. 1987) - and 22 on which the beta-2 crystalline gene is located. In Table 3, LOD-scores for Fy, HP, D 16S4, CRYG, P1, MNS and GC are shown. For haptoglobin, LOD-scores for males and females combined are -7.96 at a recombination fraction of 0.01, and thus close linkage with haptoglobin can be firmly rejected. There was no linkage with the other marker systems investigated (Fy, PI ABO, RH, MNS, APOH, JK, SE, LU, KEL, CO, BF, GC, F13B, F13A, ORM, TF, CRYG and D16S4). We conclude that the results of our investigation further support genetic heterogeneity of autosomal dominant congenital cataract. The study will be continued with emphasis on the possible association of this cataract with the other crystallins or with the translocations described on chromosomes 2, 3, 4 and 14 (Moross et al. 1984, Reese et al. 1987). References Baggesen K, Baggesen N. Pediplot: a computer program for drawing pedigrees. Ann Genet 19&9:32: 126-128. Barret DJ, Sparkes RS, Gorin MB, Bhat SP, Spence MA. Marazita ML, Bateman JB. Genetic linkage analysis of autosomal dominant congenital cataracts with lens-specific DNA probes and polymorphic phenotypic markers. Ophthalmology 1988: 95: 538-544. Bateman JB, Spence MA, Marazita ML, Sparkes RS. Genetic linkage analysis of autosomal dominant congenital cataracts. Am J Ophthalmol 1986: 101: 218-225. Bodker FS, Lavery MA, Mitchell TN, Lovrien EW, Maumenee IH. Microphthalmos in the presumed homozygous offspring of a first cousin marriage and linkage analysis of a locus in a family with autosomal dominant Cerulean congenital cataracts. Am J Med Genet 1990: 37: 54-59. Carper D,Shinohara T,Piatigorsky J, Kinoshita JH. Deficiency of functional messenger RNA for a developmentally regulated beta-crystallin polypeptide in a hereditary cataract. Science 1982: 217: 463-464. Conneally PM, Wilson AF, Merritt AD, Helveston EM, Palmer CG, Wang LY. Confirmation of genetic heterogeneity in autosomal dominant forms of congenital cataracts from linkage studies. Cytogenet Cell Genet 1978: 22: 295-297. Eiberg H, Marner E. Rosenberg T, Mohr J. Marner’s cataract (CAM) assigned to chromosome 16: linkage to haptoglobin. Clin Genet 1988: 34: 272-275.
Eiberg H, Marner E, Rosenberg T. Mohr !. RFLP typing of a family with Marner’s cataract. Clin Genet (in press). Garber AT, Winkler C, Shimohara T, King CR, Inana G. Piatigorsky J, Gold RJ. Selective loss of a family of gene transcripts in a hereditary murine cataract. Science 1985: 227: 74-77. Hammerstein W, Scholz W. Familiare Form einer vCataracta centraliscc: klinisch-genetischer Studie mit Koppelungsdaten. Arch Klin Exp Ophthal 1974 189: 9-19. Huang Q,Du X, Stone SH, Amsbaugh DF, Datiles M, Hu T, Zigler JS. Association of hereditary cataracts in strain 13/N guinea-pigs with mutation of the gene for Zetacrystallin. Exp Eye Res 1990 50: 317-325. Human Gene Mapping 10. Cytogenet Cell Genet 1989: 51: 19-21. Huntziger RS, Weitkamp LR, Roca PD. Linkage relations of a locus for congenital total nuclear cataract. J Med Genet 1978: IS: 113-115. Jensen S, Goldschmidt E. Genetic counseling in sporadic cases of congenital cataract. Acta Ophthalmol 1971: 49: 572-576. Lehmann K. Medfedt og arvelig lagstrer i slregten Volkmann. Ugeskrift Lreger 1918: 36: 1407-1417 and 37: 1443-1455. Lubsen NH, Renwick JH. Schoenmakers JGG. Hereditary cataract: perspective for prenatal screening. Ophthal Paediatr Genet 1986: 7: 195-200. Marner E, Rosenberg T,Eiberg H. Autosomal dominant congenital cataract. Acta Ophthalmol 1989: 67: 151-158. Maumenee IH. Classification of hereditary cataracts in children by linkage analysis. Ophthalmology 1979: 86: 1554-1558. McGill JR, Yang F, Baldwin WD, Brune JL, Barnett DR. Bowman BH, Moore CM. Localizatio of the haptoglobin alfa and beta genes (HPA and HPB) to human chromosome 16q22 by in sifu hybridization. Cytogenet Cell Genet 1984: 38: 155-157. Moross T,Vaithilingam SS. Styles S, Gardner HA. Autosomal dominant anterior polar cataracts associated with a familial 2;14 translocation. J Med Genet 1984: 21: 52-53. Norrie G. Ugeskrift LiEger 1896: 937-944. Ott J. A computer program for linkage analysis of general human pedigrees. Am J Hum Genet 1973: 28: 528-529. Rasmussen C. Om arvelig staer hos slacgten Volkmann. Ugeskrift Laeger 1932: 42: 1007-1012. Reese PD, Truck-Muller CM, Maumenee IH. Autosomal dominant congenital cataract associated with chromosomal translocation [t(3;4)(~26.2;~15)].Arch Ophthalmol 1987: 105: 1382-1 384. Renwick JH, Lawler SD. Probable linkage between a congenital cataract locus and the Duffy blood group locus. Ann Hum Genet 1963: 27: 67-84. Richards J, Maumenee IH, Rowe S, Lovrien EW. Congenital cataract possibly linked to haptoglobin. Cytogenet Cell Genet 1984: 37: 570. Stabile M, Amoriello A, Capobianco S, Cavaliere ML, Conte N, De Rosa C, Ruoppo S, Sorrentino V, Ventruto V. Study of a form of pulverulent cataract in a large kindred. J Med Genet 1983: 20: 419-421.
69
Allan M. Lund', Hans Eibsrg', Thomas Rosenberg3 and Mstts Warburg' 'Oivision of Pediatric Ophthalmology and Handk caps, Gentofte Hospital, Gentofte. 'University Institute of Medical Genetics, Panum Institute. Copenhagen, and 'National Eye Clinic for the Visually Impaired, Hellerup, Denmark
Congenital cataract is a heterogeneous disorder. Approximately one third of the cases are hereditary. A large family with autosomal dominant congenital cataract is described here. Clinical examinations showed variable expressivity, but all affected persons were eventually operated, most of them in the first or second decade of life. Linkage relations with a number of polymorphic marker systems were studied, all of them being negative. Among the 21 systems studied were Fy, HP, D16S4 and CRYG. The present autosomal dominant congenital cataract is termed the Volkman cataract, after the ancestor in the pedigree, and is genotypically different from the Marner cataract found in another large Danish pedigree.
-
Key words: autosomal dominant Cataract c o n genital Cataract haptoglobin - linkage relations
-
Dr. Matte Warburg, Bjenklinikken for MuRihandiCappede. Vangedehuse, Sognevej 40, 2820 Gentofte, Denmark Received 18 January, revised 17 July, accepted for publication 24 July 1991
Congenital cataract is one of the most common major abnormalities of the eye and a frequent cause of blindness in infants; congenital cataracts are responsible for 10% to 30% of all cases of blindness in children (Reese et aI. 1987). In Denmark, Jensen & Goldschmidt (1971) found that 34% of all congenital cataracts were familial. These cataracts may be inherited in an autosomal dominant, autosoma1 recessive or X-linked manner. Autosomal dominant inheritance is most common in outbred communities. To distinguish the various types of cataracts on morphological grounds is difficult: on the one hand, the possible biological reactions of a lens expressing a cataract gene are limited and, on the other hand, the reaction to the same gene is not always the same (Bateman et al. 1986, Marner et al. 1989). Both clinical and genetic heterogeneity exist: at least three different chromosomal loci have been associated with autosomal dominant congenital cataract. In 1963, the Coppock cataract or zonular pulverulent cataract was mapped to chromosome l on the basis of linkage to the Duffy blood groups (Fy), (Renwick & Lawler 1963). Conneally et al. (1978) described a similar cataract, which was also chromosomally localised to the same area as the former. (It was-linked to lqh, a marker on chromoSome 'lose to Fy locus.). A morpholo~callysimilar t Y F 9 studied by Lubsen et aI. (1986h called the Coppock-like cataract, showed linkage with the
gamma-crystalline gene cluster on chromosome 2 (2q33-35). Recently an autosomal dominant cataract segregating in a Danish family was assigned to chromosome 16 on the basis of linkage to haptoTable 1. Linkage relations of autosornal dominant cataract Reference
FY
Renwick et al. Conneally et al. Family 1 Family 2-7 Marner et at. Maumenee Lubsen et al. Moross et al. Reese et al. Hammerstein et al. Huntziger at al.
+ N N
-
HP
Crystallins
+ Iqh
-
+ +
- (19 markers) (LOO =2.1 1) +gamma t(2;14) (p25;q24) t(3;4) (p26.2;pl5) N (20 markers) N (8 markers)
N
-
N
Stabile et at. Bateman et al.
-
Barret et al.
-
N
Bodker et al.
N
-
Present study
- -
Other
- - beta
- gamma - MIP
-
(9 markers) N (15 markers) (6 markers) N (2 markers)
-
(14 markers) N (2 markers) (19 markers)
FY: Dutfy blwd group assigned to chromosome 1 (q21q25). HP: Haptoglobin assigned to chromosome 16. MIP: Major intrinsic protein. N: inconclusive data +: linkage established. -: linkage excluded. nothing: marker not examinedlnot described.
Lund et al. Table 2. Chromosomal localizations of major crystallins in humans Crystallin
I
Localization
alfa A alfa 6 beta 61 beta 62 beta 63 gamma
CRYAl CRYA2 CRY61 CRY62 CRY63 CRYG1-6 CRYGPl +P2
21q22.3 llq 17q11.2-912 22911.2-ql2.1 22q11.2q12.1 2q33-35
gamma
cRWja
3q
n
For references. see Human Gene Mapping 10.
globin (HP) (Eiberg et al. 1988 and 1990, Marner et al. 1989). Haptoglobin is located within band 16q22 (McGill et a]. 1984). Maumenee (1979) and Richards et a]. (1984) obtained a LOD score of 2.1 between HP and a posterior polar cataract, morphologically different from the Marner cataract. Possibly other loci are involved in autosomal dominant cataracts, as shown in Table 1. Some forms may be due to a defect in one of the three major crystallins in the human lens (alfa, beta and gamma), as is probably the case with the Coppocklike cataract. Two autosomal dominant cataracts in mice are presumed to be caused by a defect in a crystallin-gene: the Philly-mouse cataract (Betacrystallin) (Carper et a]. 1982) and the Fraser mouse cataract (gamma-crystallin) (Garber et al. 1985). In 131N guinea-pigs an autosomal dominant cataract is associated with a mutation of the gene for Zeta-crystallin (Huang et al. 1990). Table 2 shows chromosomal localisations for the major human crystallins. Material and methods
The family with congenital cataract considered in this study was first described by Gordon Norrie
Fig. I. First five generations of the Volkmann family. The figure numbers refer to the lineages which have been investigated by
us.
(1 896). later by Kirstine Lehman ( 1918) and most recently by Chr. Rasmussen (1932). The ancestor, Mr. Volkman born in 1730, emigrated from Konigsberg in Germany to Denmark in 1750. The cataract in his descendents is therefore termed the Volkman cataract. Pedigrees were constructed from old medical records kept in the National Eye Clinic for the Visually Impaired, updated by us, and are shown in Fig. 1-4. Most of the family lived and lives in the southern part of Zealand; there are 426 persons in 10 generations. From the turn of the century until now, 285 persons have been born into this family, 144 of them having affected parents; the ratio of affected to unaffected relatives was 60 :72 (the clinical state of 12 persons could not be reliably determined), which is compatible with autosomal dominant inheritance. The ratio of affected males and females born to affected parents
Table 3. Linkage relations of Volkmann cataract with selected markers ~~~
Chromosome
Locus
~~
~
Sex
0.01
Lod-scores at recombination fractions 0.05 0.10 0.20 0.30
0.40
M F
-2.00 -2.17
-0.73 -0.76
-0.29 -0.20
-0.01 0.24
0.04 0.33
0.01 0.23
1
FY
2
CRYG
M+F
-2.51
-1.14
-0.59
-0.14
0.00
0.03
4
MNS
M F
-2.21 -2.80
-0.90 -1.44
-0.42 -0.89
-0.07 -0.39
0.03 -0.151
0.03 -0.04
4
GC
M F
-6.97 0.00
-3.97 0.00
-2.68
-1.4
0.00
-0.73 0.00
-0.29 0.00
M F
-5.52
-2.74 -0.90
0.00 -1.58
-0.57 0.19
-0.15 0.20
0.00 0.08
M F
-0.01 0.00
0.62 0.00
0.42 0.00
0.18 0.00
M F
-1.36 -0.31
-0.17 -0.08
-0.06 -0.03
16 16 22
HP D16S4 Pl
-2.44
-0.24
0.56
0.67
0.00
0.00
-0.68 -0.24
-0.41 -0.17
Linkage could be excluded for ABQ RH, APOH. JK, SE,UI, KEL CQ BF. F13A. F138, ORM and TF.
-0.01 -0.01
Autosomal dominant congenital cataract URSlN
I I1 111
IV
v VI VI 1
YlII
1x x Fig. 2. Subfamily 1 (Ursin).
The pedigrees were plotted with the Pediplot computer program (Baggesen & Baggesen 1989).
was 2913 1. In four cases a generation was skipped (VI-25, VII-18, VII-46 and VII-58 +VIII-65 (two generations skipped)), yielding a penetrance of about 90%. The members of the family have been examined ophthalmologically by us, including determination of acuity, refraction, contrast sensitivity (Cambridge contrast sensitivity tables), slitlamp examination and ophthalmoscopy. Recent and old medical records were obtained from other ophthalmologists and in 4 cases (2 unaffected and 2 affected) examination of these was substituted for our clinical examination. From all family members 50 ml blood was collected by venipuncture. Each sample was analyzed for the following 18 polymorphic blood cell and serum markers: HP, Fy, P1, ABO, RH,MNS, APOH, JK, SE, LU, KEL, CO, BF, GC, F13B, F13A, ORM, TF and the following loci, D16S4 and CRYG. LIPED (Ott 1973) was used for the calculation of LOD-scores and recombination frequencies were scored over the values 1%, 5%, lo%, 20%, 30% and 40%.
We have investigated a total of 35 affected and 58 unaffected individuals (including unaffected partners) in this family. The cataract is progressive; affected members of the family have no symptoms at birth. A progressive visual loss appears during the first decade of life, the majority at 3 4 years of age. The progression rate differs between patients and in a few patients progression has been very slow; one patient developed symptoms in his third decade and operation was not necessary until 20 years later. Eventually all affected members needed operation. Morphologically only two persons were available for examination before cataract operation; as seen from Fig. 5 and 6, their cataracts were very different; this, however, may be related to the difference in age between the two patients, Patient A being 3 years old and Patient B 27 years old. In
BJERREGXARD
JENSEN
,
Results and Discussion
'
I
I1 XI1
I I1 111
V
IV V
v1
VI
VII
VII
VIII
y111
IV
IX
28 29 30 31 52 33
34 35
36
X Fig. 3. Subfamily 2 (Bjerregaard).
37 38
IX
x Fig. 4. Subfamily 3 (Jensen).
67
Lund et al.
Fig. 5. Lens of 3-year-old girl (IX-32). Multiple discrete opacities in the embryonic, fetal and juvenile nucleus are seen.
the lens of Patient A multiple discrete round opacities were seen in the embryonic, fetal and juvenile nucleus. In the elder patient there were two major opacities, which were asymmetric in the two eyes. In the juvenile nucleus, partial circumferential dense opacities were observed; in and around the anterior and posterior Y-suture, opacities were seen as an accentuation of these structures. Furthermore, a discrete opacity was seen in the central
part of the embryonic nucleus. Between the dense opacities of the lens, the three nuclei showed diffuse blurring. The cortex and the capsule had no opacities. Old medical records gave evidence of two family members who were only unilaterally affected. Based on the above two patients, and available medical records and literature, the morphology of the cataract is a central and zonular cataract with a variable expression/progression rate between the two eyes and interpersonally, but mostly resulting in dense cataracts during the first decade of life. As mentioned above, penetrance is approximately 90%: we have examined four children with cataracts whose parents had clear lenses. Skipped generations and slowly progressive cataracts could not be due to genomic imprinting in this family. Linkage results
As a starting point we looked for linkage of the Volkmann cataract with loci thought to be linked to congenital autosomal dominant cataract, first of all haptoglobin and D16S4; both of these loci are located within band 16q22.1 about 5 cM from each other, and both were linked to the Marner
Fig. 6. Lens of 27-year-old girl ( W I - 5 5 ) . Opacifications around the juvenile Y-sutures a n seen together with partial circumferential opacifications of the juvenile nucleus. A dense but diffusely outlined opacification is seen in the embryonic nucleus.
68
Autosomal dominant congenital cataract
cataract. Examinations proceeded with FY, the gamma-crystallin gene cluster (2q33-35) and furthermore chromosomes 4 - involved in a family in which a t(3;4) was co-segregating with an autosomal dominant cataract (Reese et al. 1987) - and 22 on which the beta-2 crystalline gene is located. In Table 3, LOD-scores for Fy, HP, D 16S4, CRYG, P1, MNS and GC are shown. For haptoglobin, LOD-scores for males and females combined are -7.96 at a recombination fraction of 0.01, and thus close linkage with haptoglobin can be firmly rejected. There was no linkage with the other marker systems investigated (Fy, PI ABO, RH, MNS, APOH, JK, SE, LU, KEL, CO, BF, GC, F13B, F13A, ORM, TF, CRYG and D16S4). We conclude that the results of our investigation further support genetic heterogeneity of autosomal dominant congenital cataract. The study will be continued with emphasis on the possible association of this cataract with the other crystallins or with the translocations described on chromosomes 2, 3, 4 and 14 (Moross et al. 1984, Reese et al. 1987). References Baggesen K, Baggesen N. Pediplot: a computer program for drawing pedigrees. Ann Genet 19&9:32: 126-128. Barret DJ, Sparkes RS, Gorin MB, Bhat SP, Spence MA. Marazita ML, Bateman JB. Genetic linkage analysis of autosomal dominant congenital cataracts with lens-specific DNA probes and polymorphic phenotypic markers. Ophthalmology 1988: 95: 538-544. Bateman JB, Spence MA, Marazita ML, Sparkes RS. Genetic linkage analysis of autosomal dominant congenital cataracts. Am J Ophthalmol 1986: 101: 218-225. Bodker FS, Lavery MA, Mitchell TN, Lovrien EW, Maumenee IH. Microphthalmos in the presumed homozygous offspring of a first cousin marriage and linkage analysis of a locus in a family with autosomal dominant Cerulean congenital cataracts. Am J Med Genet 1990: 37: 54-59. Carper D,Shinohara T,Piatigorsky J, Kinoshita JH. Deficiency of functional messenger RNA for a developmentally regulated beta-crystallin polypeptide in a hereditary cataract. Science 1982: 217: 463-464. Conneally PM, Wilson AF, Merritt AD, Helveston EM, Palmer CG, Wang LY. Confirmation of genetic heterogeneity in autosomal dominant forms of congenital cataracts from linkage studies. Cytogenet Cell Genet 1978: 22: 295-297. Eiberg H, Marner E. Rosenberg T, Mohr J. Marner’s cataract (CAM) assigned to chromosome 16: linkage to haptoglobin. Clin Genet 1988: 34: 272-275.
Eiberg H, Marner E, Rosenberg T. Mohr !. RFLP typing of a family with Marner’s cataract. Clin Genet (in press). Garber AT, Winkler C, Shimohara T, King CR, Inana G. Piatigorsky J, Gold RJ. Selective loss of a family of gene transcripts in a hereditary murine cataract. Science 1985: 227: 74-77. Hammerstein W, Scholz W. Familiare Form einer vCataracta centraliscc: klinisch-genetischer Studie mit Koppelungsdaten. Arch Klin Exp Ophthal 1974 189: 9-19. Huang Q,Du X, Stone SH, Amsbaugh DF, Datiles M, Hu T, Zigler JS. Association of hereditary cataracts in strain 13/N guinea-pigs with mutation of the gene for Zetacrystallin. Exp Eye Res 1990 50: 317-325. Human Gene Mapping 10. Cytogenet Cell Genet 1989: 51: 19-21. Huntziger RS, Weitkamp LR, Roca PD. Linkage relations of a locus for congenital total nuclear cataract. J Med Genet 1978: IS: 113-115. Jensen S, Goldschmidt E. Genetic counseling in sporadic cases of congenital cataract. Acta Ophthalmol 1971: 49: 572-576. Lehmann K. Medfedt og arvelig lagstrer i slregten Volkmann. Ugeskrift Lreger 1918: 36: 1407-1417 and 37: 1443-1455. Lubsen NH, Renwick JH. Schoenmakers JGG. Hereditary cataract: perspective for prenatal screening. Ophthal Paediatr Genet 1986: 7: 195-200. Marner E, Rosenberg T,Eiberg H. Autosomal dominant congenital cataract. Acta Ophthalmol 1989: 67: 151-158. Maumenee IH. Classification of hereditary cataracts in children by linkage analysis. Ophthalmology 1979: 86: 1554-1558. McGill JR, Yang F, Baldwin WD, Brune JL, Barnett DR. Bowman BH, Moore CM. Localizatio of the haptoglobin alfa and beta genes (HPA and HPB) to human chromosome 16q22 by in sifu hybridization. Cytogenet Cell Genet 1984: 38: 155-157. Moross T,Vaithilingam SS. Styles S, Gardner HA. Autosomal dominant anterior polar cataracts associated with a familial 2;14 translocation. J Med Genet 1984: 21: 52-53. Norrie G. Ugeskrift LiEger 1896: 937-944. Ott J. A computer program for linkage analysis of general human pedigrees. Am J Hum Genet 1973: 28: 528-529. Rasmussen C. Om arvelig staer hos slacgten Volkmann. Ugeskrift Laeger 1932: 42: 1007-1012. Reese PD, Truck-Muller CM, Maumenee IH. Autosomal dominant congenital cataract associated with chromosomal translocation [t(3;4)(~26.2;~15)].Arch Ophthalmol 1987: 105: 1382-1 384. Renwick JH, Lawler SD. Probable linkage between a congenital cataract locus and the Duffy blood group locus. Ann Hum Genet 1963: 27: 67-84. Richards J, Maumenee IH, Rowe S, Lovrien EW. Congenital cataract possibly linked to haptoglobin. Cytogenet Cell Genet 1984: 37: 570. Stabile M, Amoriello A, Capobianco S, Cavaliere ML, Conte N, De Rosa C, Ruoppo S, Sorrentino V, Ventruto V. Study of a form of pulverulent cataract in a large kindred. J Med Genet 1983: 20: 419-421.
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