About the lab

Our lab investigates molecular and cell biological bases of severe photoreceptor degenerative disorders, such as Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA). Our studies have identified three key ciliary proteins that are involved in protein trafficking to the sensory cilium of photoreceptors (also called outer segment): RPGR (Retinitis Pigmentosa GTPase Regulator), RP2 (Retinitis Pigmentosa 2), and CEP290 (Centrosomal Protein of 290 kDa). We use zebrafish, mouse and mouse embryonic fibroblasts as our model systems to carry out the studies.

Featured research (1)

Mutations in RPGR (retinitis pigmentosa GTPase regulator) cause severe retinal ciliopathy, X-linked retinitis pigmentosa. Although two major alternatively spliced isoforms, RPGRex1-19 and RPGRORF15 are expressed, the relative importance of these isoforms in disease pathogenesis is unclear. Here, we analyzed fibroblast samples from eight patients and found that all of them form longer cilia than normal controls, albeit to different degrees. Although all mutant RPGRORF15 mRNAs are unstable, their steady-state levels were similar or higher than those in the control cells, suggesting there may be increased transcription. Three of the fibroblasts that had higher levels of mutant RPGRORF15 mRNA also exhibited significantly higher levels of RPGRex1-19 mRNA. Four samples with unaltered RPGRex1-19 levels carried mutations in RPGRORF15 that resulted in this isoform being relatively less stable. Thus, in all cases, the RPGRex1-19/RPGRORF15 isoform ratio was increased, and this was highly correlative to the cilia extension defect. Moreover, overexpression of RPGRex1-19 (mimicking the increase in RPGRex1-19 to RPGRORF15 isoform ratio) or RPGRORF15 (mimicking reduction of the ratio) resulted in significantly longer or shorter cilia, respectively. Notably, the cilia length defect appears to be attributable to both the loss of the wild-type RPGRORF15 protein and to the higher levels of the RPGRex1-19 isoform, indicating that the observed defect is due to the altered isoform ratios. These results suggest that maintaining the optimal RPGRex1-9 to RPGRORF15 ratio is critical for cilia growth and that designing strategies that focus on the best ways to restore the RPGRex1-19/RPGRORF15 ratio may lead to better therapeutic outcomes.

Lab head

Hemant Khanna
  • Department of Ophthalmology

Members (4)

Wei Zhang
  • University of Massachusetts Medical School
Bhubanananda Sahu
  • University of Louisville
Laura Moreno Leon
  • University of Massachusetts Medical School
Jack Skelton
  • University of Massachusetts Medical School

Alumni (6)

Linjing Li
  • University of Massachusetts Medical School
Nageswara Rao Kollu
  • University of North Carolina at Chapel Hill
Ruhi Sikka
  • Guru Nanak Dev University
Manisha Anand
  • University of Massachusetts Medical School