ERAL1 – Perrault syndrome

Perrault syndrome (PS) is a rare autosomal recessive disorder characterized by ovarian dysgenesis in 46,XX females and bilateral sensorineural hearing impairment in both sexes. The syndrome displays clinical heterogeneity with pathogenic variants reported in eight genes involved in mitochondrial proteostasis. ERAL1 encodes a mitochondrial 12S rRNA chaperone essential for assembly of the small ribosomal subunit. Although PS had been linked to proteases and aminoacyl-tRNA synthetases, ERAL1 was only recently implicated. Here, we summarise the evidence establishing ERAL1 as a PS gene.

Exome sequencing in three unrelated females with classic PS phenotypes identified a homozygous ERAL1 NM_005702.4:c.707A>T (p.Asn236Ile) variant not seen in population databases (3 probands) (PMID:28449065). Each proband exhibited sensorineural deafness and ovarian insufficiency consistent with PS, and no additional candidate variants in known PS genes were detected. The variant affects a residue conserved across metazoans and is predicted deleterious by multiple algorithms. Autosomal recessive inheritance is supported by homozygosity in affected individuals and heterozygosity without phenotype in parents. These genetic data fulfil moderate ClinGen criteria for AR disease gene assignment.

Segregation data are limited; all cases were isolated with no affected siblings reported. Parental testing confirmed carrier status without clinical signs. Consequently, LOD score calculation was not possible, and human segregation evidence remains minimal. Nonetheless, the AR inheritance model is consistent across reported cases.

Functional assays in patient fibroblasts revealed markedly reduced ERAL1 protein levels and decreased assembly of the mitochondrial small ribosomal subunit (PMID:28449065). Levels of mitochondrial 12S rRNA were diminished and fully restored by lentiviral expression of wild-type ERAL1 (PMID:28449065). Mitochondrial respiration assays demonstrated significantly impaired oxidative phosphorylation, confirming disturbed mitochondrial function in mutant cells. Rescue of ribosomal and respiratory defects by wild-type ERAL1 underscores a direct loss-of-function mechanism. This experimental concordance provides strong functional support.

In vivo knockdown of the C. elegans ERAL1 orthologue E02H1.2 nearly abolished egg production, phenocopying the ovarian insufficiency seen in PS patients (PMID:28449065). No off-target phenotypes were observed, indicating specificity. This model recapitulates key reproductive defects and further supports a critical role for ERAL1 in fertility.

Collectively, three unrelated probands with homozygous ERAL1 c.707A>T (p.Asn236Ile) variants alongside robust cellular and animal model data establish a strong gene–disease association under ClinGen criteria. Key take-home: ERAL1 should be included in genetic testing panels for Perrault syndrome to enable accurate diagnosis and guide reproductive counseling.

References

• Human molecular genetics • 2017 • A homozygous missense mutation in ERAL1, encoding a mitochondrial rRNA chaperone, causes Perrault syndrome. PMID:28449065

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