Loss of PCLO function underlies pontocerebellar hypoplasia type III

2.50
Hdl Handle:
http://hdl.handle.net/11287/593900
Title:
Loss of PCLO function underlies pontocerebellar hypoplasia type III
Authors:
Ahmed, Mustafa Y.; Chioza, Barry A.; Rajab, A.; Schmitz-Abe, K.; Al-Khayat, A.; Al-Turki, S.; Baple, E. L.; Patton, M. A.; Al-Memar, A. Y.; Hurles, M. E.; Partlow, J. N.; Hill, R. S.; Evrony, G. D.; Servattalab, S.; Markianos, K.; Walsh, C. A.; Crosby, Andrew H.; Mochida, G. H.
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.
Citation:
Neurology. 2015 Apr 28;84(17):1745-50.
Publisher:
Neurology
Journal:
Neurology
Issue Date:
28-Apr-2015
URI:
http://hdl.handle.net/11287/593900
DOI:
10.1212/WNL.0000000000001523
PubMed ID:
25832664
Additional Links:
http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25832664/
Note:
This article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.
Type:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Language:
eng
ISSN:
1526-632X
Appears in Collections:
2015 RD&E publications; Honorary contracts publications

Full metadata record

DC FieldValue Language
dc.contributor.authorAhmed, Mustafa Y.en
dc.contributor.authorChioza, Barry A.en
dc.contributor.authorRajab, A.en
dc.contributor.authorSchmitz-Abe, K.en
dc.contributor.authorAl-Khayat, A.en
dc.contributor.authorAl-Turki, S.en
dc.contributor.authorBaple, E. L.en
dc.contributor.authorPatton, M. A.en
dc.contributor.authorAl-Memar, A. Y.en
dc.contributor.authorHurles, M. E.en
dc.contributor.authorPartlow, J. N.en
dc.contributor.authorHill, R. S.en
dc.contributor.authorEvrony, G. D.en
dc.contributor.authorServattalab, S.en
dc.contributor.authorMarkianos, K.en
dc.contributor.authorWalsh, C. A.en
dc.contributor.authorCrosby, Andrew H.en
dc.contributor.authorMochida, G. H.en
dc.date.accessioned2016-01-19T12:37:08Zen
dc.date.available2016-01-19T12:37:08Zen
dc.date.issued2015-04-28en
dc.identifier.citationNeurology. 2015 Apr 28;84(17):1745-50.en
dc.identifier.issn1526-632Xen
dc.identifier.pmid25832664en
dc.identifier.doi10.1212/WNL.0000000000001523en
dc.identifier.urihttp://hdl.handle.net/11287/593900en
dc.description.abstractOBJECTIVE: 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.en
dc.language.isoengen
dc.publisherNeurologyen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25832664/en
dc.titleLoss of PCLO function underlies pontocerebellar hypoplasia type IIIen
dc.typeJournal Articleen
dc.typeResearch Support, N.I.H., Extramuralen
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalNeurologyen
dc.description.noteThis article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.en

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