The congenital multiple organ malformation syndrome, Ritscher-Schinzel syndrome is an endosomal recyclinopathy

Abstract

Ritscher-Schinzel syndrome (RSS) is a congenital malformation syndrome characterized by cerebellar, cardiac, and craniofacial malformations and phenotypes associated with liver, skeletal and kidney dysfunction. The genetic cause of RSS remains to be fully defined, and limited information is available regarding the root cause of the multiple tissue phenotypes. Here, we combine genetic and clinical analysis in patient cohorts with in-cellulo analysis and in vivo phenotypic analysis of a mouse model of RSS, to identify novel causative genes for RSS within the Commander endosomal recycling pathway. We reveal how perturbed endosomal recycling reduces tissue-specific presentation of cell surface integral membrane proteins essential for kidney, bone and brain development and how this leads to major RSS-associated clinical phenotypes including proteinuria, skeletal malformation, and neurological impairment. Our data establishes RSS as a recyclinopathy that arises from a dysfunction in the Commander endosomal recycling pathway.