Premium
Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function
Author(s) -
Rehman Atteeq U.,
Najafi Maryam,
Kambouris Marios,
AlGazali Lihadh,
Makrythanasis Periklis,
Rad Abolfazl,
Maroofian Reza,
Rajab Anna,
Stark Zornitza,
Hunter Jill V.,
Bakey Zeineb,
Tokita Mari J.,
He Weimin,
Vetrini Francesco,
Petersen Andrea,
Santoni Federico A.,
Hamamy Hanan,
Wu Kaman,
AlJasmi Fatma,
Helmstädter Martin,
Arnold Sebastian J.,
Xia Fan,
Richmond Christopher,
Liu Pengfei,
Karimiani Ehsan Ghayoor,
Karami Madani GholamReza,
Lunke Sebastian,
ElShanti Hatem,
Eng Christine M.,
Antonarakis Stylianos E.,
Hertecant Jozef,
Walkiewicz Magdalena,
Yang Yaping,
Schmidts Miriam
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23694
Subject(s) - biology , loss function , phenotype , neurodevelopmental disorder , exome sequencing , joubert syndrome , allele , hypotonia , genetics , exome , compound heterozygosity , endosome , gene , intracellular
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.