Otoacoustic emissions and brainstem evoked potentials in compound carriers of connexin 26 mutations.

This study compares the effects of mutations in the gap junction protein connexin 26 (Cx26), on outer hair cells (OHCs), inner hair cells (IHCs) and auditory nerve/brainstem among carriers of these mutations. One hundred and twenty eight individuals, from a village with widespread consanguinity and congenital deafness, due to three Cx26 mutations, were selected among relatives of deaf persons, and divided into non-carriers, carriers of one mutation, homozygous to one mutation, or compound heterozygous carriers of two different mutations. Distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABRs) and audiometric evaluation were compared in these genetic groups. Hearing loss among homozygotes and compound heterozygotes was comparable and ranged from mild to profound. Most ABRs from these groups showed no responses or partial responses (peaks III, V) with prolonged latencies, but some individuals had all peaks at normal latencies. DPOAEs were absent, except sporadic responses. Carriers of one mutation had significantly smaller DPOAEs compared to non-carriers, although normal pure tone audiograms and ABRs were found in these groups. In conclusion, based on DPOAEs, Cx26 mutations may impact OHC function among carriers of one or two Cx26 mutations. IHC/nerve impairment among homozygotes and compound heterozygotes is variable. OHCs may be more susceptible to Cx26 mutations compared to IHCs and the auditory nerve and brainstem pathway activated by them.

The effects of a connexin 26 mutation--35delG--on oto-acoustic emissions and brainstem evoked potentials: homozygotes and carriers.

The purpose of this study was to examine whether outer hair cells (OHCs), inner hair cells and the brainstem auditory pathway are impaired due to a mutation in a gap junction protein, connexin 26 (Cx26), 35delG. Fifty-six individuals, from a village with widespread consanguinity and profound, non-syndromic congenital deafness, due to 35delG mutation, were selected among relatives of deaf people. The individuals were either non-carriers (n=20), heterozygous (n=20) or homozygous (n=16) for the mutation. Distortion product oto-acoustic emissions (DPOAEs) and auditory brainstem evoked potentials (ABEPs) in mutation non-carriers, in heterozygotes (carriers) and in subjects homozygous for the mutation were compared in addition to audiometric evaluation. Most deaf homozygotes had no DPOAEs, except some sporadic responses at 1000, 8000 and 10000 Hz. This was also observed in audiometry which showed profound hearing loss in most cases. Two cases were unique: one had moderate to severe hearing loss and the other had severe to profound hearing loss. A significant difference was found between non-carriers and carriers of 35delG: non-carriers had larger DPOAE responses than heterozygotes at all frequencies. The prevalence of responses got lower with higher frequencies in both groups, but between 6000 and 10000 Hz 50-70% of the carriers had no DPOAE responses, compared to 30-60% of non-carriers. In both groups responses diminished with age, but no significant interaction was found between age and the genetic group. ABEPs among homozygotes were variable: in most homozygotes ABEPs were absent or partial (waves III, V) with prolonged latencies, but two subjects had ABEPs within normal limits, in one ear. ABEPs were normal with no differences between carriers and non-carriers. We suggest that OHC function is affected by the 35delG mutation in Cx26. In addition, the hearing of carriers of this mutation may be impaired at very high frequencies (8000-10000 Hz), which are not assessed in routine audiometry or ABEP testing.

Mutations and alternative splicing of the BRCA1 gene in UK breast/ovarian cancer families.

BRCA1 is a tumour suppressor gene located on chromosome band 17q21. It is estimated that mutations in the BRCA1 gene account for approximately 45% of the breast cancer families and almost all of the breast/ovarian cancer families. We have used single strand conformation polymorphism analysis, direct sequencing, allele specific oligonucleotide hybridisation, and reverse transcription polymerase chain reaction (RT-PCR) to look for mutations in the BRCA1 gene in 49 breast or breast/ovarian cancer families. Five distinct mutations, three novel and two previously observed, were detected in seven families. Each novel mutation was identified in one family: 3896delT in exon 11, a splicing mutation in the intron 9-exon 10 junction, and an inferred regulatory mutation. The 185delAG in exon 2 was found in three families sharing the same haplotype, but this haplotype is different from that shared by the Ashkenazi Jewish families, suggesting that the 185delAG in our families may have arisen independently. Another previously reported mutation, the 3875del4 in exon 11, was identified in one family. Of the 49 families examined, linkage analyses for both the BRCA1 and the BRCA2 regions were performed on 33 families, and mutations in the BRCA1 gene were identified in all but one family that have a lod score above 0.8 for BRCA1. All of the mutations cause either a truncated BRCA1, or loss of a BRCA1 transcript, thus are likely to be functionally disruptive. In addition, we found that alternative splicing is a common phenomenon in the processing of the BRCA1 gene. Seven variant BRCA1 transcripts were identified by RT-PCR; all but one maintained the BRCA1 open reading frame. We believe that alternative splicing may play a significant role in modulating the physiological function of BRCA1.