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

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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

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Notes: issn: 1098-1004

Keyword: Endosom
Speicherkrankheit

Event: Veröffentlichung

(where): Freiburg

(who): Universität

(when): 2019

Creator: Rehman, Atteeq U.
Najafi, Maryam
Kambouris, Marios
Al-Gazali, 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
Jasmi, Fatma Al
Helmstädter, Martin
Arnold, Sebastian Johannes
Xia, Fan
Richmond, Christopher
Liu, Pengfei
Karimiani, Ehsan Ghayoor
Madani, GholamReza Karami
Lunke, Sebastian
El‐Shanti, Hatem
Eng, Christine M.
Antonarakis, Stylianos E.
Hertecant, Jozef
Walkiewicz, Magdalena
Yang, Yaping
Schmidts, Miriam

DOI: 10.1002/humu.23694

URN: urn:nbn:de:bsz:25-freidok-1494483

Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 25.03.2025, 1:51 PM CET

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Associated

Rehman, Atteeq U.
Najafi, Maryam
Kambouris, Marios
Al-Gazali, 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
Jasmi, Fatma Al
Helmstädter, Martin
Arnold, Sebastian Johannes
Xia, Fan
Richmond, Christopher
Liu, Pengfei
Karimiani, Ehsan Ghayoor
Madani, GholamReza Karami
Lunke, Sebastian
El‐Shanti, Hatem
Eng, Christine M.
Antonarakis, Stylianos E.
Hertecant, Jozef
Walkiewicz, Magdalena
Yang, Yaping
Schmidts, Miriam
Universität

Time of origin

2019

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

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