ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss

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Anttonen , A-K , Laari , A , Kousi , M , Yang , Y J , Jääskeläinen , T , Somer , M , Siintola , E , Jakkula , E , Muona , M , Tegelberg , S , Lönnqvist , T , Pihko , H , Valanne , L , Paetau , A , Lun , M P , Hästbacka , J , Kopra , O , Joensuu , T , Katsanis , N , Lehtinen , M K , Palvimo , J J & Lehesjoki , A-E 2017 , ' ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss ' , Brain : a journal of neurology , vol. 140 , pp. 1267-1279 . https://doi.org/10.1093/brain/awx040

Title: ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss
Author: Anttonen, Anna-Kaisa; Laari, Anni; Kousi, Maria; Yang, Yawei J.; Jääskeläinen, Tiina; Somer, Mirja; Siintola, Eija; Jakkula, Eveliina; Muona, Mikko; Tegelberg, Saara; Lönnqvist, Tuula; Pihko, Helena; Valanne, Leena; Paetau, Anders; Lun, Melody P.; Hästbacka, Johanna; Kopra, Outi; Joensuu, Tarja; Katsanis, Nicholas; Lehtinen, Maria K.; Palvimo, Jorma J.; Lehesjoki, Anna-Elina
Contributor organization: Department of Medical and Clinical Genetics
Neuroscience Center
Anna-Elina Lehesjoki / Principal Investigator
University of Helsinki
Research Programme for Molecular Neurology
Research Programs Unit
Doctoral Programme in Biomedicine
Institute for Molecular Medicine Finland
HUS Children and Adolescents
Children's Hospital
Lastenneurologian yksikkö
Department of Diagnostics and Therapeutics
HUS Medical Imaging Center
Department of Pathology
Date: 2017-05
Language: eng
Number of pages: 13
Belongs to series: Brain : a journal of neurology
ISSN: 0006-8950
DOI: https://doi.org/10.1093/brain/awx040
URI: http://hdl.handle.net/10138/304497
Abstract: Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.
Subject: PEHO syndrome
progressive encephalopathy
3124 Neurology and psychiatry
3112 Neurosciences
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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