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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Shashi, Vandana; Magiera, Maria M; Klein, Dennis et al. (2018) Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration. EMBO J 37:
Breuss, Martin W; Nguyen, Thai; Srivatsan, Anjana et al. (2017) Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability. Hum Mol Genet 26:258-269
Nguyen, Thi Tuyet Mai; Murakami, Yoshiko; Sheridan, Eamonn et al. (2017) Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia. Am J Hum Genet 101:856-865
Marin-Valencia, Isaac; Gerondopoulos, Andreas; Zaki, Maha S et al. (2017) Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia. Am J Hum Genet 101:441-450
Friedman, Jennifer; Feigenbaum, Annette; Chuang, Nathaniel et al. (2017) Pyruvate dehydrogenase complex-E2 deficiency causes paroxysmal exercise-induced dyskinesia. Neurology 89:2297-2298
Lardelli, Rea M; Schaffer, Ashleigh E; Eggens, Veerle R C et al. (2017) Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet 49:457-464
Breuss, Martin W; Sultan, Tipu; James, Kiely N et al. (2016) Autosomal-Recessive Mutations in the tRNA Splicing Endonuclease Subunit TSEN15 Cause Pontocerebellar Hypoplasia and Progressive Microcephaly. Am J Hum Genet 99:228-35
Johansen, Anide; Rosti, Rasim O; Musaev, Damir et al. (2016) Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features. Am J Hum Genet 99:912-916
Rosti, Rasim O; Dikoglu, Esra; Zaki, Maha S et al. (2016) Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene. Am J Med Genet A 170A:992-8
Zaki, Maha S; Bhat, Gifty; Sultan, Tipu et al. (2016) PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive. Ann Neurol 80:59-70

Showing the most recent 10 out of 11 publications