2. Academic Validation
  3. Loss of PCLO function underlies pontocerebellar hypoplasia type III

Loss of PCLO function underlies pontocerebellar hypoplasia type III

  • Neurology. 2015 Apr 28;84(17):1745-50. doi: 10.1212/WNL.0000000000001523.
Mustafa Y Ahmed 1,  Barry A Chioza 1,  Anna Rajab 1,  Klaus Schmitz-Abe 1,  Aisha Al-Khayat 1,  Saeed Al-Turki 1,  Emma L Baple 1,  Michael A Patton 1,  Ali Y Al-Memar 1,  Matthew E Hurles 1,  Jennifer N Partlow 1,  R Sean Hill 1,  Gilad D Evrony 1,  Sarah Servattalab 1,  Kyriacos Markianos 1,  Christopher A Walsh 1,  Andrew H Crosby 1,  Ganeshwaran H Mochida 2
Affiliations

Affiliations

  • 1 From Monogenic Molecular Genetics (M.Y.A., B.A.C., E.L.B., A.H.C.), University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Exeter; Centre for Human Genetics (M.Y.A., B.A.C., E.L.B., M.A.P., A.H.C.), St. George's, University of London, UK; National Genetic Center (A.R.), Ministry of Health, Muscat, Sultanate of Oman; Division of Genetics and Genomics, Department of Medicine (K.S.-A., J.N.P., R.S.H., G.D.E., S.S., K.M., C.A.W., G.H.M.), Manton Center for Orphan Disease Research (K.S.-A., J.N.P., R.S.H., G.D.E., S.S., K.M., C.A.W., G.H.M.), and Howard Hughes Medical Institute (J.N.P., R.S.H., G.D.E., S.S., C.A.W.), Boston Children's Hospital; Departments of Pediatrics (K.S.-A., K.M., C.A.W., G.H.M.) and Neurology (C.A.W.), and Program in Biological and Biomedical Sciences (G.D.E.), Harvard Medical School, Boston; Program in Medical and Population Genetics (K.S.-A., K.M., C.A.W.), Broad Institute of MIT and Harvard University, Cambridge, MA; Department of Biology (A.A.-K.), College of Science, Sultan Qaboos University, Sultanate of Oman; Wellcome Trust Sanger Institute (S.A.-T., M.E.H.), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Department of Neurology (A.Y.A.-M.), Atkinson Morley Wing, St. George's Hospital, London, UK; and Pediatric Neurology Unit (G.H.M.), Department of Neurology, Massachusetts General Hospital, Boston, MA.
  • 2 From Monogenic Molecular Genetics (M.Y.A., B.A.C., E.L.B., A.H.C.), University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Exeter; Centre for Human Genetics (M.Y.A., B.A.C., E.L.B., M.A.P., A.H.C.), St. George's, University of London, UK; National Genetic Center (A.R.), Ministry of Health, Muscat, Sultanate of Oman; Division of Genetics and Genomics, Department of Medicine (K.S.-A., J.N.P., R.S.H., G.D.E., S.S., K.M., C.A.W., G.H.M.), Manton Center for Orphan Disease Research (K.S.-A., J.N.P., R.S.H., G.D.E., S.S., K.M., C.A.W., G.H.M.), and Howard Hughes Medical Institute (J.N.P., R.S.H., G.D.E., S.S., C.A.W.), Boston Children's Hospital; Departments of Pediatrics (K.S.-A., K.M., C.A.W., G.H.M.) and Neurology (C.A.W.), and Program in Biological and Biomedical Sciences (G.D.E.), Harvard Medical School, Boston; Program in Medical and Population Genetics (K.S.-A., K.M., C.A.W.), Broad Institute of MIT and Harvard University, Cambridge, MA; Department of Biology (A.A.-K.), College of Science, Sultan Qaboos University, Sultanate of Oman; Wellcome Trust Sanger Institute (S.A.-T., M.E.H.), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Department of Neurology (A.Y.A.-M.), Atkinson Morley Wing, St. George's Hospital, London, UK; and Pediatric Neurology Unit (G.H.M.), Department of Neurology, Massachusetts General Hospital, Boston, MA. ganesh.mochida@childrens.harvard.edu.
PMID: 25832664 DOI: 10.1212/WNL.0000000000001523
Abstract

Objective: To identify the genetic cause of pontocerebellar hypoplasia type III (PCH3).

Methods: We studied the original reported pedigree of PCH3 and performed genetic analysis including genome-wide single nucleotide polymorphism genotyping, linkage analysis, whole-exome Sequencing, and Sanger Sequencing. Human fetal brain RNA Sequencing data were then analyzed for the identified candidate gene.

Results: The affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. Genome-wide single nucleotide polymorphism analysis confirmed the linkage to chromosome 7q we previously reported, and showed no other genomic areas of linkage. Whole-exome Sequencing of 2 affected individuals identified a shared homozygous, nonsense variant in the PCLO (piccolo) gene. This variant segregated with the disease phenotype in the pedigree was rare in the population and was predicted to eliminate the PDZ and C2 domains in the C-terminus of the protein. RNA Sequencing data of human fetal brain showed that PCLO was moderately expressed in the developing cerebral cortex.

Conclusions: Here, we show that a homozygous, nonsense PCLO mutation underlies the autosomal recessive neurodegenerative disorder, PCH3. PCLO is a component of the presynaptic cytoskeletal matrix, and is thought to be involved in regulation of presynaptic proteins and synaptic vesicles. Our findings suggest that PCLO is crucial for the development and survival of a wide range of neuronal types in the human brain.

Figures