Neurodevelopmental phenotype caused by a de novo PTPN4 single nucleotide variant disrupting protein localization in neuronal dendritic spines.

Autor: Szczałuba K; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Chmielewska JJ; Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland.; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland., Sokolowska O; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.; Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland.; Laboratory of Experimental Medicine, Center of New Technologies, University of Warsaw, Warsaw, Poland., Rydzanicz M; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Szymańska K; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland., Feleszko W; Department of Pediatric Respiratory Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland., Włodarski P; Department of Methodology, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland., Biernacka A; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland., Murcia Pienkowski V; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland., Walczak A; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Bargeł E; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Królewczyk K; Department of Methodology, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland.; Department of Histology and Embryology, Laboratory for Cell Research and Application, Medical University of Warsaw, Warsaw, Poland., Nowacka A; Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland., Stawiński P; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Nowis D; Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland.; Laboratory of Experimental Medicine, Center of New Technologies, University of Warsaw, Warsaw, Poland.; Genomic Medicine, Medical University of Warsaw, Warsaw, Poland., Dziembowska M; Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland., Płoski R; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2018 Dec; Vol. 94 (6), pp. 581-585. Date of Electronic Publication: 2018 Oct 11.
DOI: 10.1111/cge.13450
Abstrakt: Protein tyrosine phosphatase non-receptor type 4 (PTPN4) encodes non-receptor protein tyrosine phosphatase implicated in synaptic plasticity and innate immune response. The only report of PTPN4-associated disease described a neurodevelopmental disorder associated with a whole gene deletion. We describe a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems with a novel mosaic de novo variant in PTPN4 (hg19 chr2:g.120620188 T > C, NM_002830.3:p.[Leu72Ser]/c.215T>C) located in domain that controls protein subcellular distribution. Studies in mouse hippocampal neurons transfected with non-mutated or mutated human PTPN4 showed that despite their similar expression in neurons the mutated protein was absent from dendritic spines. Next, we studied patient's primary blood mononuclear cells' response to lipopolysaccharide stimulation and found no difference from control in phosphorylation of TBK1 and IRF3 (involved in Toll-like receptor 4 signaling) and induction of cytokines' messenger RNA. We conclude that the PTPN4 p.(Leu72Ser) variant is a likely cause of neurodevelopmental symptoms of our proband whereas its role in immune dysfunction requires further studies.
(© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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