Human and Molecular Genetics Center

Faculty

Duska J. Sidjanin, PhD

Associate Professor, Cell Biology, Neurobiology and Anatomy
Specialization: Molecular Genetics of the Eye

 

Sidjanin Lab

Duska J. Sidjanin, PhD

Research Interests

The genetic and molecular etiology of hereditary cataracts
 

Sidjanin Lab Our goal is to understand the genetic basis of cataracts. Cataracts are the leading cause of treatable blindness world-wide. The etiology of the most common forms of cataracts is unknown. To gain a better understanding of molecular mechanisms associated with cataracts we apply molecular, genetic, genomic, and computational approaches to map the cataract loci and ultimately clone genes and mutations responsible for the disease phenotype. Our current focus is on three novel mouse cataract loci: lop13, bs-2 and bs. lop13 is a recessive cataract locus that exhibits nuclear cataracts and fissures of the skin surrounding the eyes. We mapped lop13 to mouse chromosome 15, to a 1.2 Mb region encompassing 23 genes. Evaluation of lop13 candidate genes is currently in progress. Blind sterile locus 2 (bs2) and blind sterile locus 1 (bs) are recessive loci that exhibit congenital cataracts and male-specific sterility. We mapped the bs2 locus to a 5 Mb region on mouse chromosome 2. The blind sterile (bs) locus has been previously mapped to chromosome 2, but to a different genomic region than bs-2. We are currently evaluating if bs and bs-2 are allelic loci. The future goals for this project are to identify genes and mutations responsible for lop13, bs and bs-2 and to understand the molecular pathways associated with the mutant genes.

The development of the anterior segment of the eye

Our long-range goal is to understand the regulatory pathways governing the anterior segment development. Our current work focuses on woe and woe2 mouse models. Both woe and woe2 are autosomal recessive loci that exhibit the eyelid open at birth phenotype, microphthalmia/anophthalmia, cataracts and defects in the anterior segment structures originating from the neural crest (NC) cells such as corneal stroma, corneal endothelium, iris, ciliary body and drainage structures. Both mice also exhibit the wavy fur phenotype. Unlike woe, the woe2 mice also exhibit optic nerve hypoplasia. The phenotype similarities suggest that woe and woe2 may be involved in overlapping during the ocular development. As an initial step in answering these questions, we positionally cloned both mutations. We identified a C794T substitution in the Adam17 gene as responsible for the woe phenotype. The mutation is a Thr265Met substitution that results in a hypomorphic Adam17 function. The positional cloning of woe2 identified a 1308 bp deletion in the Ppp1r13l gene as responsible for the woe2 phenotype. The deletion results in a skipping of exons 9, 10, and 11, a frame-shift and a truncated protein. Adam17 plays a role in the ectodomain shedding of membrane bound ligands essential for signaling, whereas Ppp1r13l has been implicated as a regulator of apoptosis. The roles of Adam17 and Ppp1r13l have never been evaluated during the ocular development. Our current goal is to identify the molecular pathways that Adam17 and Ppp1r13l play a role during the eye development. The ultimate goal is to understand the relationship between Adam17 and Ppp1r13l pathways and how Adam17 and Ppp1r13l gene defects lead to developmental defects observed in woe and woe2.

Recent Publications