Developmental epileptic encephalopathy with hypomyelination and brain atrophy associated with PTPN23 variants affecting the assembly of UsnRNPs

  • Eur J Hum Genet. 2018 Oct;26(10):1502-1511. doi: 10.1038/s41431-018-0179-2.
Robert Smigiel  1 ,  Gerd Landsberg  2 ,  Maximilian Schilling  2 ,  Małgorzata Rydzanicz  3 ,  Agnieszka Pollak  4 ,  Anna Walczak  3 ,  Anna Stodolak  1 ,  Piotr Stawinski  3  4 ,  Hanna Mierzewska  5 ,  Maria M Sasiadek  6 ,  Oliver J Gruss  7 ,  Rafal Ploski  8
Affiliations
  • 1. Department of Paediatrics and Rare Disorders, Wroclaw Medical University, Wroclaw, Poland.
  • 2. Institute of Genetics, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
  • 3. Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland.
  • 4. Department of Genetics, Institute of Physiology and Pathology of Hearing, Warsaw, Poland.
  • 5. Department of Child and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland.
  • 6. Department of Genetics, Wroclaw Medical University, Wroclaw, Poland.
  • 7. Institute of Genetics, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany. [email protected].
  • 8. Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland. [email protected].
PMID: 29899372 DOI: 10.1038/s41431-018-0179-2
Abstract

PTPN23 encodes a ubiquitously expressed non-receptor type, catalytically inactive protein-tyrosine Phosphatase found in all cells including neurons. Recently, we have identified PTPN23 in a cellular screen for the systematic identification of novel regulators of survival motor neuron (SMN) function in the assembly of splicing factors (Uridine-rich small nuclear ribonucleoproteins, UsnRNPs). Based on three families, recessive PTPN23 variants have been associated with human disease tentatively, without functional studies. Here, we describe a pediatric proband with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy on MRI. Whole exome Sequencing and family study showed two novel PTPN23 variants, c.1902C>G (p.(Asn634Lys)) and c.2974delC (p.(Leu992Tyrfs*168)), in compound heterozygous state, which are predicted in silico to be damaging. When studying patient's fibroblasts we found similar expression of SMN but a dramatic reduction of cells displaying SMN accumulation in Cajal bodies (CB). SMN strongly accumulated in CB in more than 50% of unrelated control cell fibroblasts as well as in fibroblasts from the parent carrying only the c.2974delC (p.(Leu992Tyrfs*168)) variant (predicted to cause loss-of-function). In contrast, only 22% of cells showed respective SMN accumulations in patient fibroblasts (p = 1.9-2.5 × 10-7) while showing a higher level of nucleoplasmic SMN. Furthermore, the remaining accumulations in patient cells displayed weaker SMN signals than control or heterozygous wt/c.2974delC (p.(Leu992Tyrfs*168)) fibroblasts. Our report provides the first description of the clinical phenotype of recessive PTPN23 variants with pathogenicity substantiated by a functional study.