RT Journal Article SR Electronic T1 A homozygous missense mutation in ERAL1, encoding a mitochondrial rRNA chaperone, causes Perrault syndrome JF bioRxiv FD Cold Spring Harbor Laboratory SP 115790 DO 10.1101/115790 A1 Iliana A. Chatzispyrou A1 Marielle Alders A1 Sergio Guerrero-Castillo A1 Ruben Zapata Perez A1 Martin A. Haagmans A1 Laurent Mouchiroud A1 Janet Koster A1 Rob Ofman A1 Frank Baas A1 Hans R. Waterham A1 Johannes N. Spelbrink A1 Johan Auwerx A1 Marcel M. Mannens A1 Riekelt H. Houtkooper A1 Astrid S. Plomp YR 2017 UL http://biorxiv.org/content/early/2017/03/10/115790.abstract AB Perrault syndrome (PS) is a rare recessive disorder characterized by ovarian dysgenesis and sensorineural deafness. It is clinically and genetically heterogeneous, and previously mutations have been described in different genes, mostly related to mitochondrial proteostasis. We diagnosed three unrelated females with PS and set out to identify the underlying genetic cause using exome sequencing. We excluded mutations in the known PS genes, but identified a single homozygous mutation in the ERAL1 gene (c.707A>T; p.Asn236Ile). Since ERAL1 protein binds to the mitochondrial 12S rRNA and is involved in the assembly of the small mitochondrial ribosomal subunit, the identified variant represented a likely candidate. In silico analysis of a 3D model for ERAL1 suggested that the mutated residue hinders protein-substrate interactions, potentially affecting its function. On a molecular basis, PS skin fibroblasts had reduced ERAL1 protein levels. Complexome profiling of the cells showed an overall decrease in the levels of assembled small ribosomal subunit, indicating that the ERAL1 variant affects mitochondrial ribosome assembly. Moreover, levels of the 12S rRNA were reduced in the patients, and were fully rescued by lentiviral expression of wild type ERAL1. At the physiological level, mitochondrial respiration was markedly decreased in PS fibroblasts, confirming disturbed mitochondrial function. Finally, knockdown of the C. elegans ERAL1 homologue E02H1.2 almost completely blocked egg production in worms, mimicking the compromised fertility in PS-affected women. Our cross-species data in patient cells and worms support the hypothesis that mutations in ERAL1 can cause PS and are associated with changes in mitochondrial metabolism.