Localization of a gene for keratoconus to a 5.6-Mb interval on 13q32.
OBJECTIVE
Keratoconus (KTCN) is a noninflammatory thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive powers, and reduced visual acuity. Several loci responsible for a familial form of KTCN have been mapped, however; no mutations in any genes have been identified for any of these loci. There is also evidence that VSX1 and SOD1 may be involved in the etiology of KTCN. The purpose of this study was to verify the available data and to identify a new keratoconus susceptibility locus.


METHODS
KTCN without other ocular or systemic features was diagnosed in 18 families. VSX1 and SOD1 sequencing was performed on affected individuals and control subjects. Genomewide linkage analysis was then performed in all families using polymorphic microsatellite markers with an average spacing of 5 cM. Next, single-nucleotide polymorphism (SNP) arrays, fluorescence in situ hybridization (FISH) analysis, and a comparative genomic hybridization array were used in one family to assess a candidate region on 13q32.


RESULTS
All previously reported KTCN loci were excluded. VSX1 and SOD1 were sequenced, and no potentially functional variants were found. One KTCN family yielded a maximum multipoint parametric LOD score of 4.1 and multipoint nonparametric linkage (NPL) LOD score of 3.2. Multipoint linkage and haplotype analysis narrowed the locus to a 5.6-Mb region between the SNPs rs9516572 and rs3825523 on 13q32.


CONCLUSIONS
The results exclude VSX1 and SOD1 as potential disease-causing genes in these families and localize a novel gene for keratoconus to a 5.6-Mb interval on 13q32.
Gajecka
Marzena
M
Basic Medical Sciences Program, Washington, Wyoming, Alaska, Montana, and Idaho, Washington State University, Spokane, Washington 99210-1495, USA.
Radhakrishna
Uppala
U
Winters
Daniel
D
Nath
Swapan K
SK
Rydzanicz
Malgorzata
M
Ratnamala
Uppala
U
Ewing
Kimberly
K
Molinari
Andrea
A
Pitarque
Jose A
JA
Lee
Kwanghyuk
K
Leal
Suzanne M
SM
Bejjani
Bassem A
BA
D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D005796:Genes; D008040:Genetic Linkage; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007640:Keratoconus / Q000235:genetics*; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D005136:Eye Proteins; D018398:Homeodomain Proteins; C000606290:SOD1 protein, human; C491583:VSX1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1