SEP 27, 2018 1:30 PM PDT

Cilia Abnormalities and Developmental Defects in Lowe Syndrome



Lowe Syndrome (LS) is a devastating genetic disease characterized by abnormalities in the eyes, brain and kidneys that unfortunately leads to the premature death of affected children due to renal failure. Despite being described more than 60 years ago, this condition lacks a clear delineation of its mechanism and no specific cure is available. One contributing cause to this slow progress has been the absence of proper disease models for this condition and the inaccessibility of patient cells from the major affected organs. 

However, using patient skin fibroblasts we recently reported the first successful preparation of Lowe syndrome induced Pluripotent Stem Cells (iPSCs) and their reprogramming as renal cells1. This work not only represents a technological advance for the LS research field, but also provided insight as to how the patient’s kidney complications develop.

Specifically, monitoring the process of in vitro kidney cell differentiation provided clues as to how renal deficiency arises in patients. Specifically, we found that in LS kidney cells the transcription factor Six2 (crucial for renal development) was abnormally retained outside the cell nucleus impairing its gene regulatory function. This deficient Six2 activity caused decreased production of the so-called proximal tubular cells which are involved in critical functions of the kidney, such as avoiding the excretion of important serum proteins. 

Misregulation of a differentiation pathway is a novel LS phenotype that is predicted to have great impact in patients’ renal function. Further, this work suggests that developing strategies directed to enhance proper Six2 function or to prevent its retention outside the nucleus constitute viable options to maintain renal function in LS patients.

Learning Objectives: 

1. Understand how Lowe Syndrome can lead to premature death of affected children.
2. Understand how patient skin fibroblasts are helping those affected with Lowe Syndrome.

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SEP 27, 2018 1:30 PM PDT

Cilia Abnormalities and Developmental Defects in Lowe Syndrome

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