Novel mutations affecting the secondary structure of MT-RNR1 gene: a causal relationship with profound nonsyndromic...

Mutations in mitochondrial DNA (mtDNA) are one of the most important causes of sensorineural hearing loss, especially in the MT-RNR1 gene. In the present study we have performed mutational screening for m.1555A>G and a region of the MT-RNR1 gene in 303 unrelated patients (including family members of 25 probands) with nonsyndromic hearing loss and 200 controls. Three homoplasmic variants, namely, m.1453A>G, 1462G>A, and 1508C>T, were identified in addition to the known deafness-associated m.1555A>G mutation in the MT-RNR1 gene. All the variants were detected only in the patients and not in the controls. m.1555A>G was detected in three probands amounting to 1.0%. Prediction of RNA secondary structure showed changes in all the three variants, the most severe being in m.1453A>G that was inherited in a typical maternal pattern in two families. Screening of GJB2 and GJB6 genes in all these probands revealed cosegregation of the p.W24X mutation (GJB2) in one family with m.1453A>G. Only the proband carrying the p.W24X mutation in a homozygous state expressed the condition while heterozygous and normal homozygous relatives had normal hearing in spite of having the mutation in MT-RNR1. The conservation index (CI) of m.1453A>G was found to be 82%, suggesting it to be a possibly deleterious mutation. Functional studies using cell lines derived from muscle tissue of these patients may reveal the pathogenic mechanism of deafness in them.