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Human Molecular Genetics Pages 843-847
A gene which causes severe ocular alterations and occipital encephalocele (Knobloch syndrome) is mapped to 21q22.3
Introduction
Results
   Linkage studies
   Haplotype analysis
Discussion
Materials And Methods
   Family
   Methods
   Linkage analysis
Acknowledgements
References

A gene which causes severe ocular alterations and occipital encephalocele (Knobloch syndrome) is mapped to 21q22.3

A gene which causes severe ocular alterations and occipital encephalocele (Knobloch syndrome) is mapped to 21q22.3 A. L. Sertié, M. Quimby1, E. S. Moreira, J. Murray1, M. Zatz, S. E. Antonarakis2 and M. R. Passos-Bueno*

Departamento de Biologia, Universidade de São Paulo, São Paulo, Brazil, 1Department of Pediatrics, University of Iowa, Iowa, USA and 2Division de Génétique Médicale, Université de Genève, Geneva, Switzerland

Received January 4, 1996; Revised and Accepted March 21, 1996

Knobloch syndrome (KS), characterized by high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities and occipital encephalocele, was recently confirmed as autosomal recessive. Here we report the assignment of the gene for this syndrome to 21q22.3 with the marker D21S171 through homozygosity mapping in a highly inbred Brazilian family with 11 affected individuals. A total of nine markers spanning a region of 15.2 cM of the chromosome 21q22.3 were tested and the candidate region was restricted to an interval of 4.3 cM.

INTRODUCTION

Knobloch syndrome (KS) is a condition characterized by high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities and occipital encephalocele (1 -3 ), which was recently confirmed as autosomal recessive (4 ). There is intrafamilial and interfamilial variability, but apparently 100% penetrance (1 -4 ).

The family we have described is a large inbred kindred, living in an isolated geographic region of Brazil. The inbreeding coefficient of this family varied from 1/16 to 1/64; therefore the disease-causing mutation is expected to originate from just one member of the family and the majority of affected chromosomes may share a common haplotype in the proximity of this gene.

The typical cranial and ophthalmological alterations observed among the patients suggested that KS could result from the disruption of a developmental gene or a gene important for cell migration. Therefore, the mapping of this locus may eventually lead to the isolation of the gene involved in this disease. Based on the genotyping of 11 affected individuals from a primary genome wide screen, we report here the assignment of the KS gene to 21q22.3.

RESULTS

Linkage studies

A total of 438 polymorphic DNA markers spread over the 22 autosomes were analysed (full genotyping data are available on request). Only two of them showed homozygosity in all (or in the majority) of the affected individuals: D4S171 and D21S171. Analysis of the complete family material excluded D4S171, since the homozygosity of the affecteds turned out to be due to homozygosity of the parents for the same allele. However, when all the family members were genotyped for D21S171, a maximum lod score of 6.13 at [theta] = 0.03 was estimated, indicating linkage between the disease gene and this locus (Fig. 1 ; Table 1 ). The linkage was further confirmed after the testing of eight other markers surrounding D21S171: D21S1260, D21S212, D21S1225, D21S49, D21S141, D21S1259, PFKL and D21S1446. The two-point lod scores are summarized in Table 1 .

Haplotype analysis

The haplotypes obtained with the nine tested markers are described in Figure 2 . The following marker order and genetic distances were used: D21S1260 - 2.0 cM - D21S212 - 0.3 cM - D21S1225 - 3.0 cM - D21S49 - 2.0 cM - D21S141 - 2.0 cM - D21S1259/PFKL - 1.6 cM- D21S171 - 4.3 cM - D21S1446 (5 ,6 , Antonarakis, pers. comm.). This region spans about 15.2 cM of the genetic map of chromosome 21q22.3.

All the affecteds share a common homozygous haplotype for the markers PFKL and D21S1446. However, the homozygosity observed for these two markers might be due to lack of informativeness since at least two parents are homozygous for these loci (III-5 for both these markers and III-1 for D21S1446; Fig. 2 ). This candidate region (D21S1259/PFKL-D21S1446) spans approximately 5.9 cM.


Figure 1.The amplification of D21S171 is shown in each sibship with the affecteds and their normal relatives of the KS family. The haplotype (the allele numbers correspond to those shown in Figure 2 and Table 2) for each individual is shown just below the pedigree. D21S171 shows partial homozygosity among the affecteds. The allele in homozygosity (allele 4) is 121 bp, with a high frequency (43%) in the normal population.

The following recombinants were important in refining the candidate region within this area: the normal individual V-4 and the affected V-10. The subject V-4 has the same haplotype of his affected sibs for D21S1446; since his parents seem to be heterozygous for this marker, this observation suggest that the gene is proximal to D21S1446. The affected V-10, has received one `non-at-risk' allele for the loci D21S1259 and D21S171, suggesting that the gene might be between D21S1259/PFKL and D21S171 or between D21S171 and D21S1446. Considering these recombinants, the lack of homozygosity in all affecteds and that the genetic distance between D21S1259/PFKL-D21S171 (about 1.6 cM) is smaller than between D21S171-D21S1446 (4.3 cM), we suggest that the most likely position of the KS gene is between D21S171-D21S1446.

Table 1 Two-point linkage analysis between each chromosome 21 marker and the disease locus [theta]maxZmax
Cytogenetic

  

 Recombination fraction

  

  

location

 Locus

 0

 0.01

 0.05

 0.10

 0.20

 0.30
21q22.3

 D21S1260

 -[infinity]

 -3.75

 -0.66

 0.33

 0.80

 0.64

 0.19

 1.10
21q22.3

 D21S212

 -[infinity]

 -2.04

 0.84

 1.59

 1.58

 1.01

 0.14

 1.71
21q22.3

 D21S1225

 -[infinity]

 0.62

 1.11

 1.14

 0.90

 0.54

 0.08

 1.15
21q22.3

 D21S49

 -[infinity]

 3.31

 4.09

 3.93

 2.99

 1.85

 0.06

 4.10
21q22.3

 D21S141

 -[infinity]

 3.86

 4.05

 3.71

 2.72

 1.62

 0.03

 4.09
21q22.3

 D21S1259

 -[infinity]

 1.11

 2.13

 2.25

 1.86

 1.24

 0.09

 2.25
21q22.3

 PFKL

 4.56

 4.47

 4.09

 3.60

 2.57

 1.50

 0.00

 4.56
21q22.3

 D21S171

-[infinity]

 5.98

 6.02

 5.48

 4.08

 2.55

 0.03

 6.13
21q22.3

 D21S1446

 -[infinity]

 2.09

 3.05

 3.08

 2.50

 1.62

 0.07

 3.12

DISCUSSION

We have assigned the gene for Knobloch syndrome to 21q22.3 with the marker D21S171 through homozygosity mapping in a highly inbred Brazilian family with 11 affected individuals. The linkage was confirmed through the analysis of all the available members of the family with this and eight additional markers spanning a region of 15.2 cM of this chromosome.

Homozygosity mapping using DNA polymorphic markers, first proposed by Lander and Botstein (7 ), has been shown to be very powerful for the mapping of autosomal recessive genes (8 -12 ). The present results confirm once more the advantages of this strategy.


Figure 2. Haplotypes of the informative 21q markers which showed linkage with the KS gene. The haplotypes of III-4 and IV-2 were deduced from their descendants. The haplotypes or portions of haplotype presumed to be ancestrally associated with the disease in the family are boxed; an open box was represented when it was not possible to establish with certainty the haplotype at-risk (due to lack of informativeness of at least one of the parents).

Based on the recombinants V-4 and V-10, we suggest that the KS gene might lie between D21S171 and D21S1446, restricting the candidate region to 4.3 cM. If we take into account the prediction of Lander and Botstein (7 ) that first cousins' affected children are expected, on average, to be homozygous for polymorphic markers around the disease locus over a region of 28 cM, this region of partial homozygosity observed in the present kindred is relatively small. This finding might be a consequence of the high rate of recombination observed in the telomeric region of the chromosomes (13 ,14 ). Indeed, Burmeister et al. (15 ) identified a hot spot of recombination at 21q22.3, between CD18 and COL6A1; in addition, a significant higher recombination frequency in the terminal interval of chromosome 21 (between D21S171-D21S1575) in males as compared to females has been reported (16 ). The analysis of new polymorphic markers in this area will be extremely important to refine the critical chromo- somal region. Since we have not yet found a region of homozygosity for all the affecteds, it may be possible to restrict further the critical region to a relatively small genetic distance before testing possible candidate genes within this area.

Human chromosome 21 has been the focus of high resolution genetic and physical mapping, providing an ideal model for the construction of an integrated transcript map (6 ,17 ,18 ). This high interest on chromosome 21 is mainly due to the importance of identifying the genes responsible for the Down syndrome phenotype and its small size (50 Mb long). The KS gene has been mapped to the 21q22.3 band, distal to the main critical region of Down syndrome (19 -21 ). The 21q22.3 band seems to contain many CpG islands suggesting that the gene density is very high (18 ,22 ). Interestingly, patients with clinical findings consistent with holoprosencephaly and deleted for 21q22.3 have been reported (23 -25 ); the candidate region for this form of holoprosencephaly seems to be D21S113-qter (24 -25 ), which encompasses the chromosomal region containing the KS gene.

Three known genes have been mapped within the distal region of 21q22.3, where the KS gene must lie: ITGB2, COL6A1 and COL6A2 (6 ). ITGB2 or integrin [beta]-2 is expressed in leukocytes. Mutations in this gene have been associated with inherited immunodeficiency disease (26 ) which makes it unlikely to be a candidate gene for KS. The genes COL6A1 and COL6A2, which are closely linked (27 ) codify collagen polypeptides which together with COL6A3 form the collagen VI protein (28 ). Type VI collagen forms microfibrillar arrays in extracellular matrix of virtually all tissues and in cultured cells in vitro and apparently has an anchoring function (28 -30 ). Collagen genes have been implicated in some human connective tissue disorders (28 ,31 -33 ). Among these, of particular interest is the Stickler syndrome which is characterized primarily by progressive and severe myopia, vitreal degeneration and retinal detachment (34 ); this syndrome is caused by mutations in collagen genes COL2A1 or COL11A2 (31 -33 ). Although we did not observe any clinical sign highly suggestive of alterations in the connective tissues of the patients from the present KS genealogy, Seaver et al. (3 ) reported maxillary and/or midfacial hypoplasia, generalized mild hyperextensibility and dilated vasculature in the occipital scalp defects in their two KS patients. Therefore, COL6A1 and COL6A2 may be considered plausible candidate genes for KS.

It is important to point out that there is clinical variability within the affected family members, in particular for the encephalocele. Allelic variants of the presumed KS gene might also play a role in not only other forms for the encephaloceles, but also in more common variants of ocular pathologies, like myopia, as well. Therefore, it is possible that isolated cases of KS may be misdiagnosed. Identification of this gene and its mutation will enhance our understanding of the development and differentiation of the nervous and visual systems.

MATERIALS AND METHODS

Family

The complete genealogy of the family, including the clinical data, was reported previously (4 ). All the affecteds showed severe ocular alterations (including high myopia, retinal detachment, the iris diffusely atrophic in both eyes and macular abnormalities), occipital encephalocele and normal intelligence. For linkage analysis blood was collected from 11 affected individuals and 17 normal relatives.

Methods

Genomic DNA was extracted from total blood according to the method of Kunkel et al. (35 ).

Genotype analysis were done using polymorphic markers (microsatellites) spaced about 10-20 cM, from the Cooperative Human Linkage Center, CHLC (36 ) or purchased from Research Genetics. The microsatellites were analyzed by PCR in a total volume of 10 [mu]l using 40 ng of genomic DNA, under two alternative conditions: (i) 10 mM Tris-HCl, pH 9.0, 1.5 mM MgCl2, 50 mM KCl, 0.01% gelatin, 0.1% Triton, 200 [mu]M of dATP, dTTP, dGTP, 2.5 [mu]M of dCTP, 7.5 * 10-4 [mu]Ci [P32]-dCTP, 2.5 pmol of each primer and 0.1 U Taq polymerase (SuperTaq, HT); (ii) 10 mM Tris-HCl pH 8.3, 1.5 mM MgCl2, 50 mM KCl, 0.01% gelatin, 500 [mu]M of each dNTPs, 2.5 pmol of each primer, 0.25 U Taq polymerase (Boehringer). Usually, the following program was used: 94oC for 30 s, 55oC for 30 s and 72oC for 30s (30-35 cycles).

The PCR products were size-fractionated on a 6.0-6.5% denaturing gel electrophoresis. When CTP32 was used in the PCR reaction, the gel was dried and exposed to an X-ray film at room temperature for 2-24 h, while reactions without 32P were visualized using a silver staining procedure previously reported (37 ).

Table 2 . Allele frequencies in the Brazilian population (N = 40 chromosomes) of the marker loci most closely linked to the KS gene D21S1446
 

  

 D21S1259

  

  

 PFKL

  

  

 D21S171

  

  

 

  

 bp

 frequency

  

 bp

 frequency

  

 bp

 frequency

  

 bp

 frequency
A1

  

 208

 0.04

  

 133

 0.13

  

 111

 0.02

  

 212

 0.43
A2

  

 220

 0.5

  

 137

 0.02

  

 117

 0.02

  

 214

 0.09
A3

  

 224

 0.38

  

 139

 0.58

  

 119

 0.12

  

 216

 0.03
A4

  

 228

 0.04

  

 141

 0.08

  

 121

 0.43

  

 218

 0.14
A5

  

 232

 0.04

  

 143

 0.06

  

 123

 0.22

  

 222

 0.09
A6

  

 -

 -

  

 145

 0.13

  

 125

 0.14

  

 224

 0.2
A7

  

 -

 -

  

 -

 -

  

 127

 0.03

  

 228

 0.02
A8

  

 -

 -

  

 -

 -

  

 131

 0.02

  

 -

 -

Linkage analysis

Two-point linkage analysis was done for each marker and the disease gene. The lod-scores were estimated through the LINKAGE program, version 5.1 (38 ). The frequency of the disease allele was assumed as 0.001, with a 100% penetrance. Equal allele frequencies were considered for most of the marker loci; however, allele frequencies in 40 chromosomes from unrelated healthy Brazilians for the loci surrounding the disease gene (Table 2 ) were used for the linkage analysis. Recombination frequencies were assumed to be equal in males and females.

ACKNOWLEDGEMENTS

This research was supported by FAPESP, CNPq, PADCT. We would like to acknowledge: Constancia G. Urbani, Mariz Vainzof, Marta Canovas, Antonia Cerqueira, Simone Campiotto, Dr Sueli K. Marie, Dr Isaac Neustein and Dr Mario Monteiro.

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*To whom correspondence should be addressed

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