Connexins and Deafness: From Molecules to Disease

ABSTRACT

Gap junctions are important structures in cell communication. Mutations in connexins, the building blocks of gap junctions, are involved in several human disorders including skin disease, peripheral neuropathy, cataracts, and deafness, the most common of all sensory deficits. Mutations in five connexin-encoding genes-GJB1, GJB2, GJB3, GJB6, and GJA1-are linked to deafness. GJB2 is of particular importance since mutations in this gene are the most common cause of congenital autosomal recessive nonsyndromic deafness. The severity of deafness caused by mutations in GJB2 varies from mild to profound as a function of the type of mutation. Persons who segregate two mutations of GJB2 that result in no protein product (also known as truncating mutations) are more likely to have severe-to-profound hearing loss than are persons with one truncating mutation and one missense mutation (a mutation that results in the generation of an abnormal protein product). Persons carrying two missense mutations have the mildest degree of GJB2-related deafness. Understanding these phenotype-genotype relationships and the limitations of GJB2 mutation screening is of major importance for genetic counseling.

KEYWORDS

Connexins - deafness - DFNB1 - genotype-phenotype - clinical application

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