PNPT1 – Hearing Loss Disorder

Autosomal-recessive hearing loss encompasses a genetically heterogeneous group of disorders in which the PNPT1 gene (HGNC:23166) has emerged as a causative locus for nonsyndromic sensorineural hearing impairment. PNPT1 encodes the mitochondrial polynucleotide phosphorylase (PNPase) required for mitochondrial RNA import and homeostasis. Biallelic loss-of-function or hypomorphic variants in PNPT1 disrupt mitochondrial function specifically in auditory hair cells and neurons, leading to prelingual severe-to-profound sensorineural hearing loss (SNHL).

Genetic evidence for PNPT1-associated hearing loss includes three unrelated probands with biallelic variants in PNPT1: a homozygous missense variant c.1424A>G (p.Glu475Gly) (PMID:23084290), compound heterozygous missense variants c.137C>G (p.Ala46Gly) and c.1620G>A (p.Asn540Ser) in a South Indian family (PMID:34374074), and identification of the recurrent p.Glu475Gly variant in a Tunisian family (PMID:34194829). Segregation of these variants with hearing loss was demonstrated in all families, confirming autosomal recessive inheritance.

The variant spectrum in PNPT1-associated hearing loss is predominantly missense changes affecting the RNA-binding and RNase-PH domains of PNPase. The recurrent p.Glu475Gly variant has been reported in at least two independent populations, suggesting a mutational hotspot or founder effect. No large deletions or deep-intronic variants have been described to date in the context of hearing loss, and variants have been confined to the gene’s coding exons.

Functional assays further substantiate the pathogenicity of PNPT1 variants. The p.Glu475Gly substitution impairs PNPase trimerization and abrogates mitochondrial RNA import in bacterial, yeast, and mammalian cell models, leading to reduced mitochondrial translation and respiratory chain defects (PMID:23084290). Immunohistochemical analysis demonstrated robust PNPase expression in murine cochlear hair cells and auditory neurons, aligning with the tissue-specific phenotype.

Concordance between genetic findings and functional disruption supports a mechanism of loss of PNPase function leading to cochlear dysfunction. No conflicting evidence has been reported to date, and all available data demonstrate a consistent autosomal recessive inheritance pattern, early-onset SNHL, and mitochondrial impairment reproducible in multiple model systems.

Key Take-home: Biallelic PNPT1 variants cause autosomal-recessive prelingual sensorineural hearing loss via impaired mitochondrial RNA import, warranting inclusion of PNPT1 in diagnostic panels for early-onset hearing impairment.

References

• American journal of human genetics • 2012 • A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss. PMID:23084290
• Annals of human genetics • 2022 • PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India. PMID:34374074
• Journal of advanced research • 2021 • Novel pathogenic mutations and further evidence for clinical relevance of genes and variants causing hearing impairment in Tunisian population. PMID:34194829

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