CLN6 Cloning

Announcement: Cloning of the CLN6 Gene

From: McDonald Laboratory, Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA

Variant late infantile neuronal ceroid lipofuscinosis (vLINCL) is a devastating inherited neurodegenerative disease that claims young people after a protracted course of disease that features blindness, seizures and loss of cognition that leaves the patients completely incapacitated. Tragically treatment is palliative and there is nothing that can stop the onset of the disorder or slow its inexorably worsening symptoms. However, a fundamental starting point for understanding the molecular basis of the disease has been reached: the CLN6 gene has been cloned, using a genetic strategy to isolate it based on its location on human chromosome 15. This work, a collaboration with Dr. Rose-Mary Boustany at Duke University Medical Center, is reported in a paper” Mutations in a novel CLN6 encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse”. Our paper will appear in The American Journal of Human Genetics (February 2002), with an indep!
endent report on the cloning of CLN6 that comes from the laboratory of Dr. S. Mole in Britain.

We have shown that different CLN6 mutations are found in vLINCL patients from different unrelated families, although all of these seem likely to eliminate the function of the CLN6 gene. CLN6 encodes for a novel protein (dubbed linclin), not related to any other known protein. Linclin may be integral to cellular membranes, perhaps in an organelle called the mitochondrian that is important to the energy supply so important to the neuronal cells. The discovery of the CLN6 gene provides the means to determine how prevalent the disease gene is in the population and importantly, to accurately diagnosis vLINCL, which may be confused with late infantile and juvenile NCLs, providing improved disease management for patients and their families. The discovery will also provide the starting point for unraveling the normal function of linclin, critical to understanding the disease mechanism and future efforts aimed at restoring the function that is critical to the brain cells that are los!
t in the disease. Most of the cases we have identified have been of Costa Rican, Portuguese or Venezuelan decent, complementing mutations that have been described by Dr. Mole and colleagues. We will pursue research designed to identify additional CLN6 mutations that cause variant LINCL, assisting Dr. Katherine Sims at the MGH Neurogenetics Diagnostic Lab, who will offer DNA testing to those cases with an atypical late infantile course that remain undiagnosed.

We would like to take this opportunity to thank all the vLINCL families who participated in the genetic studies that identified the CLN6 gene. We also thank the families who continue to participate in our genetic studies that are now aimed at understanding how defects in the CLN6 gene cause this devastating disease.

Editors note: This project was partially funded by BDSRA.

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