Duska J. Sidjanin, PhD
Associate Professor, Cell Biology, Neurobiology and Anatomy
Specialization: Molecular Genetics of the Eye
Warburg Micro Syndrome (WARBM)
WARBM is a rare autosomal recessive syndromic disorder characterized by brain, eye, and genital abnormalities. Mutations in RAB3GAP1, RAB3GAP2, and RAB18 genes cause WARBM. Recently, our lab in collaboration with a lab from the University of Edinburgh, identified that mutations in TBC1D20 also cause WARBM [OMIM #615663]. Regardless of which of the four WARBM genes harbor the causing mutation, WARBM children present with indistinguishable clinical characteristics. The predominant brain abnormality is polymicrogyria, a cortical malformation disorder characterized by an excessive number of small gyri and shallow sulci. In addition to polymicrogyria, WARBM children present with corpus callosum hypogenesis, myelination defects, and cerebellar vermis hypoplasia. One of our current research goals is to understand the molecular and cellular etiology of WARBM in the brain caused by mutations in TBC1D20. As a part of this effort, in collaboration with Dr. Ebert, we are modeling the disease in TBC1D20-deficient and control iPSC-induced neurons. One of the eye disorders affecting WARBM children are congenital cataracts. In our lab, we are studying how TBC1D20 deficiency disrupts human lens epithelial cells in culture, as well as in lenses of TBC1D20-deficient blind sterile (bs) mice that recapitulate the cataract phenotype in WARBM children. In spite of the progress made, in about 50% of WARBM children the causing mutation is not in RAB3GAP1, RAB3GAP2, RAB18, or TBC1D20. By using the NextGen sequencing technologies, we are currently searching for novel genes that cause WARBM. As a part of these combined research efforts, we are inviting families affected with WARBM (with both known and unknown genetic causes) to participate in our studies. If you are interested in participating in our study or would like more information about the WARBM studies in our lab, please contact Dr. Sidjanin via email or call 414-955-7810
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.