ArticleBrain : a journal of neurology2017
ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss.
Article in Brain : a journal of neurology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 31 citations in OpenAlex.
- Znhit3 regulates p53/p21 signaling and governs cerebellar granule cell development.Cell death and differentiation · 2026Article
- A homozygous synonymous NOP58 variant causes a neurodevelopmental disorder by impairing maturation of pre-ribosomal RNAs.HGG advances · 2026Article
- 17q12 deletion syndrome presenting with chronic pancreatitis: a case report.Frontiers in medicine · 2026Article
- Infantile Spasms (West Syndrome): Integrating Genetic, Neurotrophic, and Hormonal Mechanisms Toward Precision Therapy.Medicina (Kaunas, Lithuania) · 2025Review
- Genome sequencing reveals CCDC88A variants in malformations of cortical development and immune dysfunction.Human molecular genetics · 2025Article
- ZNHIT3 Regulates Translation to Ensure Cell Lineage Differentiation in Mouse Preimplantation Development.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Prenatal diagnosis, ultrasound findings, and pregnancy outcome of 17q12 deletion and duplication syndromes: a retrospective case series.Archives of gynecology and obstetrics · 2024Article
- NewmedRxiv : the preprint server for health sciences · 2024Article
- Genetic etiology of progressive pediatric neurological disorders.Pediatric research · 2024Article
- 17q12 deletion syndrome mouse model shows defects in craniofacial, brain and kidney development, and glucose homeostasis.Disease models & mechanisms · 2022Article
- Overlapping Genetic Architecture Between Schizophrenia and Neurodegenerative Disorders.Frontiers in cell and developmental biology · 2021Article
- West syndrome: a comprehensive review.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2020Review
- PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene.European journal of medical genetics · 2020Article
- A novel homozygous nonsense mutation in CCDC88A gene cause PEHO-like syndrome in consanguineous Saudi family.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2019Article
- Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.American journal of human genetics · 2018Article
- Insulin-Like Growth Factors in the Pathogenesis of Neurological Diseases in Children.International journal of molecular sciences · 2017Review
- The phenotypic and molecular spectrum of PEHO syndrome and PEHO-like disorders.Brain : a journal of neurology · 2017Article
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22 authors at 11 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
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.
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