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

Détails

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Etat: Public
Version: Final published version
Licence: CC BY-NC 4.0
ID Serval
serval:BIB_02BDC16E8839
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function.
Périodique
Human mutation
Auteur(s)
Rehman A.U., Najafi M., Kambouris M., Al-Gazali L., Makrythanasis P., Rad A., Maroofian R., Rajab A., Stark Z., Hunter J.V., Bakey Z., Tokita M.J., He W., Vetrini F., Petersen A., Santoni F.A., Hamamy H., Wu K., Al-Jasmi F., Helmstädter M., Arnold S.J., Xia F., Richmond C., Liu P., Karimiani E.G., Karami Madani G., Lunke S., El-Shanti H., Eng C.M., Antonarakis S.E., Hertecant J., Walkiewicz M., Yang Y., Schmidts M.
ISSN
1098-1004 (Electronic)
ISSN-L
1059-7794
Statut éditorial
Publié
Date de publication
03/2019
Peer-reviewed
Oui
Volume
40
Numéro
3
Pages
267-280
Langue
anglais
Notes
Publication types: Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
Adult, Alleles, Child, Child, Preschool, Endocytosis, Endosomes/metabolism, Endosomes/ultrastructure, Female, Fibroblasts/metabolism, Fibroblasts/ultrastructure, Homozygote, Humans, Infant, Infant, Newborn, Loss of Function Mutation/genetics, Male, Myelin Sheath/metabolism, Myelin Sheath/ultrastructure, Neurodevelopmental Disorders/genetics, Neurodevelopmental Disorders/pathology, Pedigree, Phosphoprotein Phosphatases/chemistry, Phosphoprotein Phosphatases/genetics, Syndrome, Transferrin/metabolism, PPP1R21, early endosome, endo-lysosome, neurodevelopmental syndrome, storage disease
Pubmed
Web of science
Open Access
Oui
Création de la notice
05/01/2019 17:48
Dernière modification de la notice
15/01/2021 8:08
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