What proteins are responsible for sound signal transmission in the inner ear and hearing loss?

Proteins Responsible for Sound Signal Transmission and Hearing Loss

Connexin 26 (encoded by GJB2) and connexin 30 (encoded by GJB6) are the most clinically important proteins, accounting for 50% of all autosomal recessive nonsyndromic hearing loss and 15-40% of all deaf individuals across diverse populations. 1

Primary Proteins in Genetic Hearing Loss

Gap Junction Proteins (Most Common)

• Connexin 26 (GJB2 gene) is the single most important protein, with over 150 deafness-causing variants identified 1
• The hearing loss is typically sensorineural, bilateral, present at birth, and can range from mild to profound severity 1
• Connexin 30 (GJB6 gene) works in conjunction with connexin 26, with deletions affecting GJB6 causing hearing loss through regulatory effects on GJB2 expression 1
• These gap junction proteins are critical for ion homeostasis in the cochlea 1

Synaptic Transmission Proteins

• Otoferlin (encoded by OTOF gene) is essential for neurotransmitter release at the synapse between inner hair cells and auditory nerve fibers 2, 3, 4
• Otoferlin mutations cause DFNB9, representing 1-8% of congenital nonsyndromic hearing loss and are the leading cause of auditory neuropathy spectrum disorders 2, 5
• The protein directly interacts with syntaxin 1A, SNAP-25, and the L-type voltage-gated calcium channel Cav1.3 in a calcium-dependent manner 6
• Otoferlin deficiency results in impaired synaptic vesicle release, causing signal transmission failure despite preserved otoacoustic emissions 2, 4
• Most patients present with severe-to-profound prelingual deafness, though 10-15% display atypical phenotypes including mild-to-moderate, progressive, or temperature-sensitive hearing loss 5

Ion Channel Proteins

• KCNQ4 (potassium channel) is implicated in both early-onset dominant hearing loss and age-related hearing loss 1
• Cav1.3 calcium channels are critical for hair cell synaptic function and interact directly with otoferlin 6

Mitochondrial Proteins

• MT-RNR1 gene (encoding mitochondrial 12S ribosomal RNA) causes aminoglycoside-induced hearing loss, particularly with the A1555G mutation 1
• MT-TS1 gene (encoding mitochondrial transfer RNA) is associated with nonsyndromic mitochondrial hearing loss 1
• Mitochondrial hearing loss accounts for approximately 1% in Western populations but 10-20% in some Asian populations 1

Cytoskeletal Proteins

• ACTG1 (actin gamma 1) is involved in both early-onset and age-related hearing loss 1

Oxidative Stress-Related Proteins

• GRM7, GRHL2, and N-acetyltransferase are implicated in age-related hearing loss through oxidative stress pathways 1

Clinical Implications by Protein Type

Connexin-Related Hearing Loss

• Testing for GJB2 mutations should be performed first in nonsyndromic cases, whether simplex or multiplex 1
• A negative GJB2 test does NOT exclude genetic etiology—this is a critical counseling point 1
• The mutation spectrum varies significantly by ethnicity, affecting testing interpretation 1

Otoferlin-Related Hearing Loss (Critical Pitfall)

• Standard newborn hearing screening using otoacoustic emissions (OAE) will MISS otoferlin-related deafness because OAEs remain preserved despite profound hearing loss 2, 5
• Auditory brainstem responses are absent despite preserved cochlear function 4
• Cochlear potentials show low-amplitude prolonged negative waveforms consistent with decreased neurotransmitter release 4
• These patients are candidates for upcoming gene therapy trials projected to begin in 2021 2

Mitochondrial Protein-Related Hearing Loss

• Patients with MT-RNR1 mutations must avoid aminoglycoside antibiotics to prevent hearing loss 1
• This represents a mutation-specific preventive therapy opportunity 1

Genetic Architecture Summary

• Autosomal recessive inheritance: 77-80% of nonsyndromic hearing loss, predominantly connexin-related 1
• Autosomal dominant inheritance: 15-22% of nonsyndromic hearing loss, more variable phenotypes 1
• X-linked inheritance: ~1% of cases 1
• Mitochondrial inheritance: 1% in Western populations, higher in specific Asian populations 1

Testing Algorithm Based on Protein Involvement

1. For simplex nonsyndromic cases: Test GJB2 first, then consider CMV testing 1
2. For multiplex nonsyndromic cases: Proceed directly to connexin 26 testing 1
3. For auditory neuropathy with preserved OAEs: Test OTOF gene 2, 3
4. For family history of aminoglycoside sensitivity: Test MT-RNR1 for A1555G mutation 1
5. For dominant inheritance patterns: Consider KCNQ4, ACTG1, and other dominant loci 1