Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation

Area of Science:

• Genetics
• Neurology
• Otolaryngology

Background:

• Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited disorder caused by mutations in mitochondrial DNA, notably the 3243A>G mutation.
• Hearing loss is a common symptom in various genetic disorders, and its genetic underpinnings are complex.
• The P2RX2 gene encodes a purinergic receptor involved in neurotransmission, and its role in hearing loss is an emerging area of research.

Observation:

• A family presented with MELAS, and some members exhibited hearing loss.
• Genetic analysis identified a novel mutation (c.601G>A, p.Asp201Tyr) in the P2RX2 gene in two individuals with severe sensorineural hearing loss.
• Family members with MELAS but without the P2RX2 mutation had normal hearing, suggesting a distinct genetic cause for hearing loss in this subset.

Findings:

• This study reports the first instance of hearing loss attributed to a P2RX2 gene mutation in patients diagnosed with MELAS.
• The identified P2RX2 mutation (p.Asp201Tyr) is directly associated with severe sensorineural hearing loss.
• Individuals with MELAS and the mitochondrial 3243A>G mutation but lacking the P2RX2 mutation did not present with hearing loss.

Implications:

• The findings suggest that P2RX2 mutations can cause hearing loss independently or in conjunction with MELAS.
• A potential mechanism involves the reduced adenosine triphosphate (ATP) production in MELAS suppressing P2X2 receptor activation, thereby influencing hearing.
• This research highlights the importance of considering P2RX2 gene mutations in the differential diagnosis of hearing loss, particularly in patients with mitochondrial disorders.