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

被引:61
作者
Chatzispyrou, Iliana A. [1 ]
Alders, Marielle [2 ]
Guerrero-Castillo, Sergio [3 ]
Perez, Ruben Zapata [1 ]
Haagmans, Martin A. [2 ]
Mouchiroud, Laurent [4 ]
Koster, Janet [1 ]
Ofman, Rob [1 ]
Baas, Frank [2 ]
Waterham, Hans R. [1 ]
Spelbrink, Johannes N. [3 ]
Auwerx, Johan [4 ]
Mannens, Marcel M. [2 ]
Houtkooper, Riekelt H. [1 ]
Plomp, Astrid S. [2 ]
机构
[1] Acad Med Ctr, Lab Genet Metab Dis, NL-1105 AZ Amsterdam, Netherlands
[2] Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands
[3] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Mitochondrial Med, Dept Pediat, NL-6525 GA Nijmegen, Netherlands
[4] Ecole Polytech Fed Lausanne, Lab Integrat & Syst Physiol, CH-1015 Lausanne, Switzerland
关键词
CAUSE OVARIAN DYSGENESIS; HEARING-LOSS; CAENORHABDITIS-ELEGANS; RESPIRATORY-CHAIN; DEAFNESS; COMPLEX; GENE; CLPP; DYSFUNCTION; SYNTHETASE;
D O I
10.1093/hmg/ddx152
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:2541 / 2550
页数:10
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