A homozygous missense mutation in ERAL1, encoding a mitochondrial rRNA chaperone, causes Perrault syndrome

Abstract

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 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.

Perrault syndrome type 3 caused by diverse molecular defects in CLPP

“…Significantly, although this mutation is located within the Hp of CLPP (required for interaction with CLPX), a defect in CLPX-interaction or CLPX-mediated degradation of either a folded or unfolded substrate was not observed. One possible explanation for this surprising result is that CLPP C147S may exhibit a specific defect in the recognition and/or translocation (into CLPX) of a unique substrate such as ERAL1 that was recently linked to the PRLTS 9 , 47 , or a currently unknown substrate that may be associated with PRLTS. An alternate explanation is that the mutant protein is unstable in vivo , and hence the levels of CLPP drop below a minimum threshold concentration required for normal cellular function.…”

“…To date, mutations in six different genes have been linked to the disease: PRLTS1 is caused by compound heterozygous mutations in HSD17B4 (17-beta hydroxysteroid dehydrogenase); PRLTS2 results from compound heterozygous mutations in HARS2 (mitochondrial histidyl-tRNA synthetase); PRLTS3 is caused by homozygous or compound heterozygous mutations in CLPP (mitochondrial protease); PRLTS4 results from homozygous or compound heterozygous mutations in LARS2 (mitochondrial leucyl-tRNA synthetase); PRLTS5 is caused by homozygous or compound heterozygous C10orf2 (mitochondrial DNA helicase Twinkle) and PRLTS6 has been recently linked to a missense mutation in ERAL1 (mitochondrial chaperone required for mitochondrial ribosome assembly). Most of the causative genes for PRLTS (including CLPP ) are implicated in the maintenance of proteostasis in mitochondria, in particular mitochondrial protein translation 1 – 9 . Consistent with an important role for CLPP in Perrault syndrome, CLPP null mice ( CLPP −/− ) also display infertility, deafness and growth retardation 10 .…”

Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency

“…Very recently, mutations of ERAL1 and KIAA0391 were involved in PS. ERAL1 protein binds to the mitochondrial 12S rRNA and is involved in assembly of the small mitochondrial ribosomal subunit affecting mitochondrial respiration and function [64]. KIAA0391 encodes RNase P (PRORP) the metallonuclease subunit of the mitochondrial RNase P complex responsible for the 5 0 -end processing of mitochondrial precursor tRNAs [65].…”

Middle-age-onset cerebellar ataxia caused by a homozygous TWNK variant: a case report

“…However, cerebellar ataxia associated with hearing loss and sensory neuropathy in our patient was consistent with the neurological symptoms of PRLTS. PRLTS is classified as PRLTS1 to PRLTS6, caused by genes HSD17B4, HARS2, CLPP, LARS2, TWNK, and ERAL1 [1,7]. We first reported that TWNK was a causative gene for PRLTS5 in two families of Japanese and European ancestry [1].…”