Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of neurodevelopmental disorders with poor prognosis. Recent discoveries have greatly expanded the repertoire of genes that are mutated in epileptic encephalopathies and DEE, often in a de novo fashion, but in many patients, the disease remains molecularly uncharacterized. Here, we describe a new form of DEE in patients with likely deleterious biallelic variants in PTPN23. The phenotype is characterized by early onset drug-resistant epilepsy, severe and global developmental delay, microcephaly, and sometimes premature death. PTPN23 encodes a tyrosine phosphatase with strong brain expression, and its knockout in mouse is embryonically lethal. Structural modeling supports a deleterious effect of the identified alleles. Our data suggest that PTPN23 mutations cause a rare severe form of autosomal-recessive DEE in humans, a finding that requires confirmation.
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We thank the families for their participation in this research project. The research by STA reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST). The exome analysis was performed on CHEOPS, a high performance computer cluster of the regional data center of the University of Cologne (RRZK), funded by the Deutsche Forschungsgemeinschaft (DFG). We acknowledge the support of the Saudi Human Genome Program.
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Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Alazami AM, Patel N, Shamseldin HE et al (2015) Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep 10:148–161CrossRefPubMedGoogle Scholar
Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinform Oxf Engl 22:195–201CrossRefGoogle Scholar
Doyotte A, Mironov A, McKenzie E, Woodman P (2008) The Bro1-related protein HD-PTP/PTPN23 is required for endosomal cargo sorting and multivesicular body morphogenesis. Proc Natl Acad Sci USA 105:6308–6313CrossRefPubMedPubMedCentralGoogle Scholar
Gahloth D, Levy C, Heaven G et al (1993) Structural basis for selective interaction between the ESCRT regulator HD-PTP and UBAP1. Struct Lond Engl 2016(24):2115–2126Google Scholar
Gingras M-C, Zhang YL, Kharitidi D et al (2009a) HD-PTP is a catalytically inactive tyrosine phosphatase due to a conserved divergence in its phosphatase domain. PLoS One 4:e5105CrossRefPubMedPubMedCentralGoogle Scholar
Gingras M-C, Kharitidi D, Chénard V et al (2009b) Expression analysis and essential role of the putative tyrosine phosphatase His-domain-containing protein tyrosine phosphatase (HD-PTP). Int J Dev Biol 53:1069–1074CrossRefPubMedGoogle Scholar
Gürsoy S, Erçal D (2016) Diagnostic approach to genetic causes of early-onset epileptic encephalopathy. J Child Neurol 31:523–532CrossRefPubMedGoogle Scholar
Husedzinovic A, Neumann B, Reymann J et al (2015) The catalytically inactive tyrosine phosphatase HD-PTP/PTPN23 is a novel regulator of SMN complex localization. Mol Biol Cell 26:161–171CrossRefPubMedPubMedCentralGoogle Scholar
Manteghi S, Gingras M-C, Kharitidi D et al (2016) Haploinsufficiency of the ESCRT component HD-PTP predisposes to cancer. Cell Rep 15:1893–1900CrossRefPubMedGoogle Scholar
McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE (2016) The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol 15:304–316CrossRefPubMedGoogle Scholar
Miura GI, Roignant J-Y, Wassef M, Treisman JE (2008) Myopic acts in the endocytic pathway to enhance signaling by the Drosophila EGF receptor. Dev Camb Engl 135:1913–1922Google Scholar
Scheffer IE, Berkovic S, Capovilla G et al (2017) ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:512–521CrossRefPubMedGoogle Scholar
Spielmann M, Kakar N, Tayebi N et al (2016) Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice. Genome Res 26:183–191CrossRefPubMedPubMedCentralGoogle Scholar
Stefani F, Zhang L, Taylor S et al (2011) UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting. Curr Biol 21:1245–1250CrossRefPubMedGoogle Scholar
Tavyev Asher YJ, Scaglia F (2012) Molecular bases and clinical spectrum of early infantile epileptic encephalopathies. Eur J Med Genet 55:299–306CrossRefPubMedGoogle Scholar
The UniProt Consortium (2017) UniProt: the universal protein knowledgebase. Nucleic Acids Res 45:D158–D169CrossRefGoogle Scholar
Trujillano D, Bertoli-Avella AM, Kumar Kandaswamy K et al (2017) Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Eur J Hum Genet 25:176–182CrossRefPubMedGoogle Scholar
Vogt J, Kohlhase J, Morlot S et al (2011) Monozygotic twins discordant for neurofibromatosis type 1 due to a postzygotic NF1 gene mutation. Hum Mutat 32:E2134–E2147CrossRefPubMedGoogle Scholar