Journal article
Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function
Human mutation, Vol.40(3), pp.267-280
03/2019
DOI: 10.1002/humu.23694
PMCID: PMC6370506
PMID: 30520571
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.
Details
- Title: Subtitle
- Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function
- Creators
- Atteeq U Rehman - Baylor College of MedicineMaryam Najafi - Radboud University NijmegenMarios KambourisLihadh Al-Gazali - United Arab Emirates UniversityPeriklis Makrythanasis - Biomedical Research Foundation of the Academy of AthensAbolfazl Rad - Radboud University NijmegenReza Maroofian - St George's, University of LondonAnna Rajab - VPS Healthcare Muscat Sultanate of OmanZornitza Stark - University of MelbourneJill V Hunter - Texas Children's HospitalZeineb Bakey - University Medical Center FreiburgMari J Tokita - Baylor College of MedicineWeimin He - Baylor GeneticsFrancesco Vetrini - Baylor GeneticsAndrea Petersen - Baylor College of MedicineFederico A Santoni - University of GenevaHanan Hamamy - University of GenevaKaman Wu - Radboud University NijmegenFatma Al-Jasmi - United Arab Emirates UniversityMartin Helmstädter - University Medical Center FreiburgSebastian J Arnold - University of FreiburgFan Xia - Baylor College of MedicineChristopher Richmond - Victorian Clinical Genetics ServicesPengfei Liu - Baylor College of MedicineEhsan Ghayoor Karimiani - Islamic Azad University, MashhadGholamReza Karami Madani - Department of Biology, Damghan Branch, Islamic Azad University, Cheshmeh-Ali Boulevard, Sa'dei Square, Damghan, IranSebastian Lunke - University of MelbourneHatem El-Shanti - University of JordanChristine M Eng - Baylor College of MedicineStylianos E Antonarakis - University of GenevaJozef Hertecant - United Arab Emirates UniversityMagdalena Walkiewicz - Baylor College of MedicineYaping Yang - Baylor College of MedicineMiriam Schmidts - University Medical Center Freiburg
- Resource Type
- Journal article
- Publication Details
- Human mutation, Vol.40(3), pp.267-280
- DOI
- 10.1002/humu.23694
- PMID
- 30520571
- PMCID
- PMC6370506
- ISSN
- 1059-7794
- eISSN
- 1098-1004
- Grant note
- 716344 / European Research Council GNT1113531 / National Health and Medical Research Council CRC1140 KIDGEM / Deutsche Forschungsgemeinschaft 2017-906 / RCH Foundation 249968 / Swiss National Science Foundation Z99 AI999999 / Intramural NIH HHS RIMLS Nijmegen Radboudumc
- Language
- English
- Date published
- 03/2019
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984353848102771
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