2. Academic Validation
  3. Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

  • Hum Mutat. 2019 Mar;40(3):267-280. doi: 10.1002/humu.23694.
Atteeq U Rehman 1,  Maryam Najafi 2,  Marios Kambouris 3,  Lihadh Al-Gazali 4,  Periklis Makrythanasis 5 6,  Abolfazl Rad 2 7,  Reza Maroofian 8,  Anna Rajab 9,  Zornitza Stark 10 11 12,  Jill V Hunter 13,  Zeineb Bakey 2 14,  Mari J Tokita 1,  Weimin He 15,  Francesco Vetrini 15,  Andrea Petersen 1,  Federico A Santoni 5 16,  Hanan Hamamy 5,  Kaman Wu 2,  Fatma Al-Jasmi 4 17,  Martin Helmstädter 18,  Sebastian J Arnold 19,  Fan Xia 1 15,  Christopher Richmond 10,  Pengfei Liu 1 15,  Ehsan Ghayoor Karimiani 20 21,  GholamReza Karami Madani 22,  Sebastian Lunke 10 11 12,  Hatem El-Shanti 23 24,  Christine M Eng 1 15,  Stylianos E Antonarakis 5,  Jozef Hertecant 4 17,  Magdalena Walkiewicz 1 15 25,  Yaping Yang 1 15,  Miriam Schmidts 2 14
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 2 Genome Research Division, Human Genetics Department, Radboud University Medical Center Nijmegen and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
  • 3 Division of Genetics, Department of Pathology and Laboratory Medicine, Sidra Medicine, Doha, Qatar.
  • 4 Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
  • 5 Department of Genetic, Medicine and Development, University of Geneva Medical Faculty, Geneva, Switzerland.
  • 6 Biomedical Research Institute of the Academy of Athens, Athens, Greece.
  • 7 Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran.
  • 8 Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, London, UK.
  • 9 VPS Healthcare, Muscat, Sultanate of Oman.
  • 10 Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.
  • 11 University of Melbourne, Melbourne, Australia.
  • 12 Australian Genomics Health Alliance, Melbourne, Australia.
  • 13 Texas Children's Hospital, Houston, TX, USA.
  • 14 Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Freiburg, Germany.
  • 15 Baylor Genetics Laboratories, Baylor College of Medicine, Houston, TX, USA.
  • 16 Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland.
  • 17 Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates.
  • 18 Renal Division, Department of Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Freiburg, Germany.
  • 19 Institute of Experimental and Clinical Pharmacology and Toxicology II, Faculty of Medicine, University of Freiburg and, BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany.
  • 20 Molecular and Clinical Sciences Institute, St. George's, University of London, London, UK.
  • 21 Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
  • 22 Department of Biology, Damghan Branch, Islamic Azad University, Cheshmeh-Ali Boulevard, Sa'dei Square, Damghan, Iran.
  • 23 Department of Pediatrics, School of Medicine University of Jordan, Amman, Jordan.
  • 24 Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
  • 25 The National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
PMID: 30520571 DOI: 10.1002/humu.23694
Abstract

Next-generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co-immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin-488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.

Keywords

PPP1R21; early endosome; endo-lysosome; neurodevelopmental syndrome; storage disease.

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