Cataract, the most common cause of blindness worldwide, and retinal degenerations, commonly termed retinitis pigmentosa, are frightening and debilitating. In the pediatric age group, the emotional and economic tolls of congenital cataracts are substantial; congenital cataracts can prevent normal visual development causing further handicaps. With the advent of the rubella vaccine, the most common etiology of congenital cataracts now is genetic. To find improved treatment modalities for hereditary cataracts and retinal degenerations, we need to locate the responsible genes and understand the causative mutations.
Our laboratory focuses on identifying genetic loci and mutations in genes responsible for autosomal dominant cataracts (ADC). We have identified numerous, large, informative families located throughout the United States and Latin America that are willing to participate in our studies. After collecting samples for DNA extraction and assembling pedigree information to verify the mode of inheritance, we perform linkage analysis. Using our screening panel of informative genetic markers we first determine whether the ADC gene in a family cosegregates with any of the previously mapped loci (13 are known). If the cataract locus is a new one, we initiate a complete genome wide screen to identify the likely chromosomal assignment; additional markers are selected to refine the chromosomal region and confirm the linkage. Thereafter, we select candidate genes known to reside in the linked region and screen them for mutations by sequencing. Using these methods, we mapped a new ADC locus to chromosome 12 (Johannes et al., 1998 and Bateman et al., submitted) and identified a new mutation for an ADC locus on chromosome 17 (Geyer et al., 1998 and Bateman et al., submitted).
In addition, we have regionally localized important lens genes such as the human MP70 gene to specific chromosomal locations (Geyer et al., 1997). For new ADC loci, we make and validate transgenic mouse models to study etiology and possible treatments. Our laboratory incorporates new techniques and methodologies as they are developed such as the use of fluorescently labeled primers for genotyping (Johannes et al 1998). The identification of disease-causing mutations will enhance our understanding of normal lens function and the pathogenesis of cataract formation, improve accuracy of genetic counseling and potentially permit more effective treatment of this costly visual disorder.
While our main emphasis is on the study of ADC, we also have mapped the disease locus in a large family with autosomal dominant retinitis pigmentosa to human chromosome 17 (Kojis et al., 1996) and are now pursuing the identification of the disease causing gene in this [DEMO]orm (RP13).
Johannes M, Geyer DD, Masser DS, Flodman P, Spence MA, Clancy K, Bateman JB. Identification of an autosomal dominant cataract locus on chromosome 12. Am J Hum Genet, S63:A294, 1698, 1998.
Bateman JB, Johannes M, Flodman P, Geyer D, Clancy K, Heinzmann C, Kojis T, Spence MA. A new locus for autosomal dominant cataract on chromosome 12q13. Submitted: IOVS, 1999
Geyer DD, Clancy KP, Johannes M, Masser D, Flodman P, Moreira A, Spence MA, Bateman JB. DNA sequence studies of the candidate beta-A3/A1 crystallin gene in an autosomal dominant cataract family (ADC10). Am J Hum Genet, S63:A361, 2094, 1998.
Bateman JB, Geyer D, Flodman P, Johannes M, Sikela J, Walter N, Moreira A, Clancy K, Spence MA. A new (A1-crystallin splice junction mutation for autosomal dominant cataracts. Submitted: IOVS, 1999.
Geyer D, Church RL, Steele EC, Heinzmann C, Kojis TL, Klisik I, Sparkes RS, Bateman JB. Regional mapping of the human MP70 (Cx50; connexin 50) gene by fluorescence in situ hybridization to 1q21.1. Molecular Vision 3:12, 1997. (On line: http://www.emory.edu/molvis/v3/geyer)
Johannes M, Geyer DD, Berry R, Walter NAR, Sikela JM, Bateman JB. Comparison of fluorescent dUTP incorporation and labeled primers in genotype analysis. Anal Biochem, 262:193-195, 1998.
Kojis TL, Heinzmann C, Flodman P, Ngo JT, Sparkes RS, Spence MA, Bateman JB, Heckenlively JR. Map refinement of locus RP13 to human chromosome 17p13.3 in a second family with autosomal dominant retinitis pigmentosa. Am J Hum Genet, 58:347-355, 1996