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Pages 1667-1672 ©
The gene for Schnyder's crystalline corneal dystrophy maps to human chromosome 1p34.1-p36
Introduction
Results And Discussion
   Two-point linkage analysis
   Multipoint and haplotype analysis
   Candidate genes
Materials And Methods
   Families
   DNA studies
   Linkage analysis
   Radiation hybrid mapping
Acknowledgements
References

The gene for Schnyder's crystalline corneal dystrophy maps to human chromosome 1p34.1-p36

The gene for Schnyder's crystalline corneal dystrophy maps to human chromosome 1p34.1-p36 Amanda M. Shearman1, Thomas J. Hudson2, J. Michael Andresen1, Xiaoyun Wu2, Robert L. Sohn1, Frank Haluska1,3, David E. Housman1 and Jayne S. Weiss4,5,*

1Center for Cancer Research, E17-536, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA, 2Center for Genome Research, Whitehead Institute, Massachusetts Institute of Technology, 1 Kendall Square, Bldg. 300, Cambridge, MA 02139, USA, 3Department of Hematology/Oncology, Massachusetts General Hospital, Fruit Street, Boston, MA 02114, USA and 4Department of Ophthalmology, University of Massachusetts Medical Center, Worcester, MA 01655, USA (previous address) and 5Kresge Eye Institute, Wayne State University School of Medicine, 4717 St Antoine, Detroit, MI 48221, USA

Received April 23, 1996; Revised and Accepted July 11, 1996

Schnyder's crystalline corneal dystrophy (SCCD) is an autosomal dominant eye disease characterized by a bilateral clouding of the central cornea, arcus lipoides and/or visible crystalline deposits of cholesterol in the stroma. There is accumulation of phospholipid, unesterified cholesterol and cholesterol ester in the corneal stroma; this is believed to be due to an imbalance in the local factors affecting lipid/cholesterol transport or metabolism. The cellular mechanism of abnormal lipid transport and metabolism in SCCD is of interest due to its potential involvement in atherosclerosis, and its implications for the pathogenesis of cerebrovascular, coronary and peripheral vascular disease as well as corneal opacification. To determine the chromosomal location of the SCCD locus, genome-wide linkage analysis has been performed in two large Swede-Finn kindreds recently identified in central Massachusetts. After analysing 300 microsatellite markers >90% of the genome was excluded from linkage to the SCCD locus. We now report the chromosomal assignment of the gene for SCCD in both families to be 1p34.1-p36; the maximum multipoint lod-score was 8.48 in the interval between D1S214 and D1S503. From haplotype analysis, the SCCD locus lies in the 16 cM interval between markers D1S2663 and D1S228. Several candidate genes for SCCD have been localized to the 1p34.1-p36 interval.

INTRODUCTION

Schnyder's crystalline corneal dystrophy (SCCD, OMIM number: 121800) is an autosomal dominant eye disease characterized by a bilateral clouding of the central cornea, arcus lipoides and/or visible crystalline deposits of cholesterol in the stroma (Fig. 1 ; 1 ). It is caused by an accumulation of phospholipid, unesterified cholesterol and cholesterol ester in the corneal stroma (2 ,3 ).


Figure 1.SCCD patients. (a) A ring-like deposition of anterior stromal cholesterol crystals. (b) Central stromal disc-like opacity surrounded by a less dense midperipheral haze and dense arcus lipoides in the corneal periphery. (c) The left cornea is clear after corneal transplantation surgery while the right unoperated cornea remains hazy with a prominent arcus lipoides peripherally.

The transparent cornea is composed of a range of cell types that embrace a diversity of physiological functions. A number of corneal dystrophies have been mapped. Two autosomal dominant corneal dystrophies map to the pericentromeric region of chromosome 20; in posterior polymorphous corneal dystrophy (4 ) the corneal endothelium, normally composed of a single layer of cells, becomes multilayered and more reminiscent of the epithelium. In congenital hereditary endothelial dystrophy there is a diffuse corneal oedema and thickening of the Descemet's membrane (5 ). Three autosomal dominant stromal corneal dystrophies map to the same region of 5q (6 ,7 ): lattice corneal dystrophy type I (amyloid deposition), granular dystrophy (irregular aggregates of hyaline) and Avellino dystrophy (which combines the findings of both lattice and granular in the same patient). Lattice corneal dystrophy type II is caused by mutations in the gelsolin gene on chromosome 9 (8 ) and results in amyloid deposition in the skin, viscera and nerves in addition to the cornea. Autosomal recessive cornea plana congenita maps to chromosome 12 (9 ) and is characterised by reduced curvature, hazy corneal limbus, opacities in the corneal stroma and arcus.

Corneal arcus and other corneal opacities may occur in association with abnormal lipid levels and systemic disorders or may occur independently (reviewed in 10 ). Corneal arcus has been associated with coronary artery disease (11 ,12 ) and hypercholesterolemia (13 ). Abnormal serum lipid, lipoprotein or cholesterol levels probably do not explain SCCD since both normal and elevated levels have been detected in SCCD patients (10 ,14 ). Thus in SCCD there is believed to be an imbalance in the local factors affecting lipid/cholesterol transport or metabolism. An alternative model is that the gene for SCCD plays an important role in lipid/lipoprotein metabolism throughout the body and that the corneal arcus in SCCD reflects a global defect.

The corneal defects that occur in SCCD consist of an accumulation of unesterified and esterified cholesterol and phospholipid. The apolipoprotein constituents of HDL (apoA-I, A-II and E) are accumulated in the central cornea while those of LDL (apo B) are absent; this suggests that HDL metabolism may be affected in SCCD (15 ). Alteration in metabolites involved in bile acid synthesis can also induce corneal arcus and the symptoms of SCCD (16 ). HDL concentrations are inversely related to the incidence of coronary atherosclerosis (17 ). The lesions in the corneas of SCCD patients are similar in some aspects to those found in atherosclerosis, making SCCD an appealing model system for the study of atherosclerosis which results in cerebrovascular, coronary and peripheral vascular disease (18 ,19 ).

We now describe the mapping of the gene responsible for the SCCD trait in two large kindreds (1 ; Fig. 2 ) to 1p34.1-p36. Candidate genes within this region will be discussed.


Figure 2.Partial pedigrees of two families with SCCD. Black circles (females) and squares (males) represent affected individuals. Unrelated spouses and unaffected family members are represented as white icons. Down-pointing arrows indicate deceased individuals. Asterisks indicate individuals who were included in the linkage analysis. Generation numbers are shown to the left of each pedigree. Generation I members of pedigree 2 were of unknown diagnosis.

Table 1 . Two-point lod scores between chromosome 1p markers and the SCCD locus Markers are arranged according to their chromosomal location from 1p33-p36. Cumulative lod scores for each marker are in larger type.

RESULTS AND DISCUSSION

Two-point linkage analysis

A genome wide scan was performed using 300 microsatellite markers with an average spacing of 10-20 cM. On chromosome 1, D1S228 gave Zmax = 1.66 at [theta] = 0.12. An additional 40 markers were then typed to examine this and other regions where the original markers had been uninformative, unscorable or had given slightly positive lod scores. Loci on chromosome 1, flanking D1S228 gave significant evidence of linkage (Table 1 ). The markers and distances obtained from the Généthon map (22 ) were: D1S468- (0.10) - D1S214 - (0.07) - D1S503- (0.09) - D1S489 - (0.00)- D1S228-(0.05)-D1S507-(0.15)-D1S478. Assuming fully penetrant inheritance of an autosomal dominant disease locus, either pedigree alone generates significant evidence of linkage to this region with lod scores >3 (for pedigree 1 Zmax = 3.17 at [theta] = 0 using D1S489, for pedigree 2 Zmax = 3.93 at [theta] = 0 using D1S214). A cumulative peak lod score for both families of 6.49 at [theta] = 0 was obtained using D1S214, representing unequivocal evidence of this as the region for the SCCD gene. D1S214 showed no recombinants with the SCCD locus. This region falls within 1p32-p36.

Multipoint and haplotype analysis

To define further the SCCD locus, combined multipoint analyses for the two SCCD kindreds were carried out (Fig. 3 ). The maximum multipoint lod-score was 8.48 in the 7 cM interval between D1S214 and D1S503, a region of 2-2.5 Mb (the location database; 20 ). The 2-unit-of-lod-score support interval spans this region.


Figure 3. Multipoint analyses for SCCD versus five markers on chromosome 1p. The position of the markers is indicated by their D numbers. D1S214 is at position 0. Zmax - 2 is indicated by a horizontal line. The 2-unit-of-lod-score support interval is indicated by vertical dotted lines.

Analysis of recombinants and haplotypes in the pedigrees may further localize SCCD. The marker order is D1S468- D1S214- D1S503-D1S228-D1S489-D1S507-D1S478. For these markers the most centromeric recombinant marker with respect to the SCCD disease phenotype is D1S228. The most telomeric recombinant marker is D1S468. This defines a 26 cM interval on the Généthon map (32 ). The chromosome 1 summary map in the location database (January 1996 version; 20 ) indicates that the physical distance from D1S468-D1S489 is 7-10 Mb, the lower estimate comes from physical map data and the higher from radiation hybrid data. To further map the cross-overs defining the disease interval and allow comparison of the disease haplotype in the two pedigrees more markers were used on a subset of samples. Marker order is D1S468- D1S2845 - D1S2893 - D1S2633 - (D1S508, D1S1596, D1S214) - D1S2633 - D1S2694 - (D1S503, D1S450) - D1S2667 - (D1S434, D1S228, D1S489) - D1S507-D1S478. This allowed the telomeric cross-overs to be defined as between D1S2893 and D1S508, D1S2633 which lies between these markers was uninformative with respect to the cross-overs. The most centromeric crossover was between D1S2667 and D1S228. We note from reconstruction of the haplotypes that both pedigrees have common haplotypes for nine consecutive informative markers D1S2694-(D1S503, D1S450)- D1S2667- (D1S434, D1S228, D1S489)-D1S507-D1S478 that span a 35 cM interval. The markers that make up the common haplotype have observed heterozygosities that range from 0.59 to 0.83, and five to 11 alleles. Further mapping of this region may confirm that it is inherited identical by descent in both families. Combining haplotype and recombination data suggests that the SCCD locus lies in the 16 cM interval between D1S2633 and D1S228.

Candidate genes

It is thought that SCCD is caused by a localized metabolic defect of the cornea which results in a loss of balance between the factors causing gain of cholesterol (e.g. synthesis, uptake via low-density lipoprotein or scavenger receptors, hydrolysis of cholesteryl ester to free cholesterol) and factors causing loss of cholesterol (e.g. steroid synthesis, cholesteryl ester formation and reverse cholesteryl transport via high-density lipoprotein transfer to the liver). Of the many genes listed in the Genome Data Base with localization's overlapping 1p32-p36, several were of particular interest as candidates for the SCCD gene: fatty-acid-binding protein 3 (FABP3), cytidine 5'-triphosphate synthetase (CTPS), sterol carrier protein 2 (SCP2), collagen type VIII alpha-2 polypeptide (COL8A2), UDP galactose-4-epimerase (GALE), and methylene tetrahydrofolate reductase (MTHFR). The microsatellite markers used to define the region of linkage were not cytogenetically mapped or ordered with respect to these cytogenetically mapped candidate genes.

FABP3 is thought to function in membrane transport, cytosolic solubilization and esterification of fatty acids, thus affecting the overall homeostasis of lipid metabolism (21 ). CTPS has a function in the biosynthesis of phospholipids and nucleic acids (22 ). SCP2 is thought to transport many types of lipid molecules, including sterols and phospholipids, between organelles (23 ). However, we have excluded SCP2 and CTPS from the SCCD region by radiation hybrid mapping which places each of them close to framework markers outside the region, with lod scores >3 to support these locations. CTPS has been mapped to 1p34.1 (22 ) and lies proximal to SCCD. This defines the proximal limit of the cytogenetic location of SCCD to be 1p34.1 (Fig. 4 ). Thus FABP at 1p32-p33, proximal to CTPS, should lie outside the SCCD region as well.


Figure 4. Ideogram of 1p31.2-pter, illustrating the localization of SCCD. The sex averaged recombination distances in cM are indicated between the markers. The localization of SCCD is indicated with a vertical bar. Map positions in cR are given for markers placed on the Whitehead Institute/MIT Center for Genome Research Radiation Hybrid Map. On the basis of the genetic, radiation hybrid and cytogenetic map locations of flanking markers and genes the SCCD gene is cytogenetically located in 1p34.1-p36. Cytogenetic localizations of methylene tetrahydrofolate reductase (MTHFR), UDP galactose-4-epimerase (GALE), cytidine 5'-triphosphate synthetase CTPS) and fatty-acid-binding protein 3 (FABP3) are indicated.

In the Human to Mouse Homology map of chromosome 1 (National Center for Biotechnology Information) the order of genes on human 1p32-p36 appears to be conserved in the syntenic region of mouse chromosome 4. ALPL and FUCA1 appear on this map. In the location database which incorporates both genes and microsatellite markers these two genes are proximal to D1S478 and thus should be proximal to the SCCD locus. If this is the case and if the gene order is conserved between human and mouse then the more precise map data in the mouse may be used to suggest exclusion of a number of candidate genes and that SCCD may map to 1p36. For example, COL8A2 (a component of Descemet membrane, the basement membrane of corneal endothelial cells) that was mapped to 1p32.3-p34.3 (24 ) probably maps proximal to the SCCD region.

GALE deficient hamster cells grown in the absence of exogenous galactose and N-acetylglycosamine (25 ) lack normal posttranslational processing of LDL receptors and other glycoproteins and have an LDL receptor-deficient phenotype. GALE maps to 1p35-p36. MTHFR is associated with atherosclerotic changes and thromboembolism (26 ,27 ) and was mapped to 1p36.3. Three uncharacterized expressed sequence tags (ESTs), HSC01G122, HSC0VD072 and EST00164 have been mapped distal to D1S214, the haplotype data suggests that this is outside the SCCD region (28 ).

Further localization of the SCCD locus and candidate genes with respect to each other will be required. Additional markers in the critical region may be used on the existing pedigrees to facilitate this process. Expansion of the pedigrees and analysis of other pedigrees may allow identification of additional recombinants, haplotype analysis and reduction of the candidate interval. Identification and functional characterization of the SCCD gene may provide insight into lipid metabolism.

MATERIALS AND METHODS

Families

The majority of members of both Swede-Finn pedigrees live in central Massachusetts and both trace their ancestry to a 100 km region of the southwest coast of Finland. It is likely that the two kindreds are linked by a common ancestor; however, each kindred was sufficiently large to allow identification of genetic linkage independently of the other. The two families were examined and reported previously (1 ,2 ). Affected status was determined by the presence of a central corneal cloudiness, arcus lipoides and/or a haze between these two. Half of the affected individuals had visible crystalline deposits of cholesterol in the anterior stroma (29 ). Blood samples for genetic analysis were collected after the subjects signed an informed consent form approved by the Human Studies Committee of the University of Massachusetts Medical Center.

DNA studies

DNA studies were carried out using standard methods. Anticoagulated venous blood samples were used for direct DNA preparations and to establish lymphoblastoid cell lines by Epstein-Barr virus transformation (30 ). A set of microsatellite markers (31 ) that cover the genome at an average spacing of 10-20 cM (Screening set version 4, compiled by Jim Weber and his group) was used. Additional markers were selected from the Généthon (32 ) and Cooperative Human Linkage Center (CHLC, 31) maps. Amplifications were carried out using 20 ng of DNA incorporating 32P-dCTP in a total volume of 10 [mu]l. PCR conditions were 35 cycles at 94oC for 30 s, 55oC for 1 min and 72oC for 30 s and finally 10 min at 72oC. The products were separated on 6% denaturing polyacrylamide gels and visualized by autoradiography. Gels were exposed at -70oC without prior drying.

Linkage analysis

For linkage analysis the following parameters were used. Autosomal dominant inheritance, penetrance estimates of 100 and 90%, a mutation rate of zero, equal recombination rates in males and females, marker allele frequencies were defined as equal and the affected allele frequency as 0.0001.

Two-point lod scores were calculated using the MLINK program of LINKAGE (version 5.1) (34 ,35 ). Multipoint analysis was performed using the LINKMAP program of LINKAGE to carry out sequential three-point linkage runs between SCCD and five loci mapping to 1p (pter-D1S468-D1S214-D1S503- D1S489- D1S507- cen) with sex-average recombination fractions of 0.10, 0.07, 0.09 and 0.05 in the respective intervals. The disease penetrance was set at 90%. Recombination fractions were converted to centiMorgans using Kosambi's map function (36 ).

Radiation hybrid mapping

PCR was used to screen the Genebridge 4 Radiation Hybrid screening panel (37 ). The Whitehead Institute/MIT Center for Genome Research's radiation hybrid mapping server was then used to map the candidate genes against a radiation hybrid map of the human genome (38 ).

ACKNOWLEDGEMENTS

We thank the families for their participation. We thank Bob Cottingham for the supply of analysis software. We thank Jim Weber, J. David Brook, Howard Kruth, Donna David and James Trofatter for their help. This work was supported in part by NHLBI 5PO1-HL41484-02 (D.E.H.), NCHGR 5R01-HG00299-12 (D.E.H.), the Healey Endowment Grant (J.S.W.) and the Clason Corneal Research Fund (J.S.W.).

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*To whom correspondence should be addressed at: Kresge Eye Institute, Wayne State University School of Medicine, 4717 St. Antoine, Detroit, MI 48221, USA

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