MRC award to better understand leukoencephalopathy with calcification and cysts
Prof Yanick Crow’s recent award from the Medical Research Council will be used to gain a better understanding of the molecular pathology of a rare disease of the brain called leukoencephalopathy with calcification and cysts (LCC). Nov 20.
Leukoencephalopathy with calcification and cysts (LCC) is a rare Mendelian disease affecting the brain, with patients experiencing progressive features including seizures, motor difficulties, cognitive decline and early death. Although LCC most often presents in childhood, the disease can first manifest at any age from infancy to late adulthood, with no genetic correlation yet known to explain the variation in age of onset. Until recently there was no diagnostic blood test for the disease, and there are currently no effective treatments for those affected.
The name LCC refers to the changes observed on brain imaging of patients; these include white matter damage (‘leukodystrophy’), a particular pattern of cerebral calcification, and the presence of ‘holes’ (cysts) in the brain tissue. Examination of brain samples taken from patients shows that the disease affects the small blood vessels in the brain, a so-called microangiopathy.
Following their identification, in 2016, of the LCC disease-associated gene (SNORD118), Prof Crow’s group have recently published a zebrafish model of LCC, and reported on the largest series of LCC patients yet described. SNORD118 encodes a small nucleolar RNA (snoRNA) called U8, which plays a key role in the biology of ribosomes, an integral component of the cellular translation machinery. How dysfunction of U8 leads to the problems seen in the brain blood vessels is yet to be established.
In the MRC awarded project, Yanick Crow and his group, together with Ray O’Keefe from the University of Manchester, Denis Lafontaine from the IMBM in Brussels, and HGU colleagues Greg Kudla and Javier Caceres, will combine their access to patient material and clinical data with experimental cellular systems and their zebrafish model to try to better understand the pathology of LCC. These studies will help to explain how the snoRNA U8 functions to maintain healthy brain blood vessels, and how disruption of U8 function leads to the development of disease. Such insights should take us nearer to a treatment for the devastating disorder LCC, and perhaps shed light on other diseases of the cerebral vasculature including stroke.
We are delighted to receive such generous funding from the MRC to study the orphan disease LCC. This award will allow us to shed new light on the function of the understudied snoRNA U8, and represents a real source of hope for affected parents and their families.