CIB2 Human
Description
Genetic Associations and Disease Links
Mutations in CIB2 are linked to multiple pathologies:
Hearing Loss
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DFNB48: Recessive mutations cause nonsyndromic deafness by disrupting TMC1/2 interactions critical for mechanoelectrical transduction (MET) in cochlear hair cells .
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Mechanism: Loss of CIB2 abolishes MET currents and causes stereocilia elongation defects, leading to hair cell degeneration .
Retinal and Cardiac Disorders
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Age-related macular degeneration (AMD): Cib2 mutants show reduced autophagy and lysosomal dysfunction in retinal pigment epithelium .
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Atrial fibrillation (AF): CIB2 depletion promotes calcineurin-NFAT signaling, driving atrial remodeling .
Mechanotransduction in Auditory Hair Cells
CIB2 is a core component of the MET complex:
In Cib2 knockout mice, MET currents are absent, leading to profound deafness without vestibular dysfunction .
Autophagy Regulation
CIB2 inhibits mTORC1 by binding inactive Rheb-GDP, enhancing autophagic clearance. Cib2 mutants exhibit:
Cardiac Protection
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Atrial specificity: CIB2 is enriched in atrial myocytes and suppresses calcineurin-NFAT signaling under stress (e.g., angiotensin II) .
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Therapeutic potential: Overexpression ameliorates atrial remodeling in AF models .
Pathogenic Mutations and Functional Impact
Notable CIB2 variants include:
| Mutation | Phenotype | Functional Defect |
|---|---|---|
| p.R186W | DFNB48 deafness | Disrupted TMC1/2 binding, abolished MET currents |
| p.K64N | Usher syndrome-like phenotype | Impaired Ca²⁺-dependent conformational changes |
Research Gaps and Therapeutic Directions
Product Specs
Product Science Overview
CIB2 was first isolated from a cDNA library of human fetal brains by Seki et al. over two decades ago . The protein consists of 187 amino acids and has a broad distribution in various human tissues, including the brain, heart, kidney, lung, thymus, spleen, placenta, ovary, and testis . This widespread expression suggests that CIB2 plays a fundamental role in basic cellular functions.
CIB2 is a calcium-binding regulatory protein that interacts with DNA-dependent protein kinase catalytic subunits (DNA-PKcs). It plays a crucial role in intracellular calcium homeostasis and acts as an auxiliary subunit of the sensory mechanoelectrical transduction (MET) channel in hair cells . This function is essential for mechanoelectrical transduction currents in auditory hair cells, which are necessary for hearing .
CIB2 regulates the function of hair cell mechanotransduction by controlling the distribution of transmembrane channel-like proteins TMC1 and TMC2. It is also required for the maintenance of auditory hair cell stereocilia bundle morphology and function, as well as for hair-cell survival in the cochlea .
Mutations in the CIB2 gene have been associated with several disorders, including:
- Deafness, Autosomal Recessive 48 (DFNB48): This condition is characterized by non-syndromic hearing loss .
- Usher Syndrome Type 1J (USH1J): Usher syndrome is a genetic disorder that causes deafness and progressive vision loss .
In addition to its role in hearing, CIB2 has been implicated in various other processes, such as integrin signaling in platelets and skeletal muscle, and autophagy . This extensive functional plasticity highlights the importance of CIB2 in multiple physiological contexts.
Despite the significant progress in understanding the role of CIB2, many molecular aspects remain unclear and warrant further investigation. Future research aims to elucidate the detailed mechanisms by which CIB2 regulates calcium homeostasis and integrin signaling, as well as its potential involvement in other cellular processes.
