TY - JOUR
T1 - RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder
AU - Paul, Franziska
AU - Ng, Calista
AU - Mohamad Sahari, Umar Bin
AU - Nafissi, Shahriar
AU - Nilipoor, Yalda
AU - Tavasoli, Ali Reza
AU - Bonnard, Carine
AU - Wong, Pui-Mun
AU - Nabavizadeh, Nasrinsadat
AU - Altunoğlu, Umut
AU - Estiar, Mehrdad A.
AU - Majoie, Charles B.
AU - Lee, Hane
AU - Nelson, Stanley F.
AU - Gan-Or, Ziv
AU - Rouleau, Guy A.
AU - van Veldhoven, Paul P.
AU - Massie, Rami
AU - Hennekam, Raoul C.
AU - Kariminejad, Ariana
AU - Reversade, Bruno
N1 - Publisher Copyright: © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
PY - 2022/10/28
Y1 - 2022/10/28
N2 - Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts show accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.
AB - Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts show accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.
UR - http://www.scopus.com/inward/record.url?scp=85141005252&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/hmg/ddac120
DO - https://doi.org/10.1093/hmg/ddac120
M3 - Article
C2 - 35652444
SN - 0964-6906
VL - 31
SP - 3729
EP - 3740
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 21
ER -