Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive pediatric neurodevelopmental/neurodegenerative disorders, characterized clinically by severe age-dependent neurological impairment, and notable radiographic volume loss of the pons and cerebellum. Currently there are 10 partially overlapping subtypes and 13 genes known mutated in PCH, but most cases remain without genetic diagnosis, suggesting new causes remain to be identified. Several of the genes are implicated in protein synthesis including key steps of tRNA maturation, mRNA splicing, protein translation and apoptosis, but fundamental questions remain: 1] How many genetic subtypes remain to be discovered? 2] Why do these mutations predispose to neuropathology? 3] Can we effect new treatments for these disorders? Through an international recruitment effort, we have ascertained a cohort of 190 families with recessive PCH and have begun sequencing to identify new causes and mechanisms. Our preliminary data suggests new treatments may emerge from these studies. In our preliminary data we have: 1] Recruited a cohort of 190 PCH probands, including 124 still without cause identified. 2] Identified mutations in AMPD2 associated with a syndromic form of PCH, leading to GTP depletion and subsequent collapse of protein synthesis. 3] Identified a common founder mutation in CLP1 leading to defective assembly of the tRNA splicing machinery. 4] Identified mutations in TOE1 as the long-sought snRNA 3'-exonuclease, leading to defective mRNA splicing. 5] Identified mutations in several other genes encoding tRNA processing factors. 6] Identified mutations in PPIL1 predicted to lead to defective mRNA splicing. 7] Uncovered a total of 13 new genetic causes of PCH, more than doubling the number of known causes. These novel PCH candidate genes are mutated in patients with unique presenting features, highlighting new genotype-phenotype correlations, emphasizing the protein synthetic defect model and pointing to new mechanisms of disease. The goal of this application is to identify the remaining `discoverable' genes that when mutated lead to PCH, functionally validate mutations within a pathogenic framework, and test the hypothesis that mutations in PCH genes lead to collapse of protein synthesis and vulnerability to apoptosis.
Pontocerebellar hypoplasia syndrome is a polygenic neurodevelopmental disorder showing loss of subclasses of neurons within the hindbrain. We propose to identify the remaining disease genes and to test mechanisms of defective protein synthesis as an underlying cause.
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