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

Atteeq U. Rehman, Maryam Najafi, Marios Kambouris, Lihadh Al-Gazali, Periklis Makrythanasis, Abolfazl Rad, Reza Maroofian, Anna Rajab, Zornitza Stark, Jill V. Hunter, Zeineb Bakey, Mari J. Tokita, Weimin He, Francesco Vetrini, Andrea Petersen, Federico A. Santoni, Hanan Hamamy, Kaman Wu, Fatma Al-Jasmi, Martin HelmstädterSebastian J. Arnold, Fan Xia, Christopher Richmond, Pengfei Liu, Ehsan Ghayoor Karimiani, Gholam Reza Karami Madani, Sebastian Lunke, Hatem El-Shanti, Christine M. Eng, Stylianos E. Antonarakis, Jozef Hertecant, Magdalena Walkiewicz, Yaping Yang, Miriam Schmidts

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)267-280
Number of pages14
JournalHuman Mutation
Issue number3
Publication statusPublished - Mar 2019


  • PPP1R21
  • early endosome
  • endo-lysosome
  • neurodevelopmental syndrome
  • storage disease

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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