Biology Reference
In-Depth Information
unaffected family members, or 100 non-related individuals. In all cases, the
conserved zona pellucida domain of the a-tectorin protein is compromised
by the replacement of alternate amino acids, suggesting this region has a
crucial function for this protein (Verhoeven et al. 1998).
Connexin 26 is a transmembrane protein that forms cylindrical channels
in gap junctions used to transfer small molecules between cells. This gap
junction protein is highly expressed between supporting cells of the inner
ear, and in the spiral lamina facing the endolymphatic duct and may play a
role in K
+
recycling in the inner ear (Spicer and Schulte 1996). All connexin
26 mutations characterized to date are either nucleotide substitutions
(missense/nonsense/splicing mutations), or insertions and deletions ranging
from small (1 bp) to large (38 bp) in the coding region (mutations updated
regularly in the Connexin 26 (
GJB2
) Deafness Homepage (World Wide
Web URL: http://www.iro.es/cx26deaf.html). The common 35delG mutation
is a one-base-pair deletion in a stretch of six G nucleotides in codon 10 that
results in a frameshift; a glycine is converted to a valine at codon 12 and a
stop codon is formed at codon 13 (Zelante et al. 1997). In other families,
an insertion has been detected at the same site, 35insG, leading to a
frameshift and stop codon at codon 47 (Estivill et al. 1998). In both cases,
it is highly unlikely that any protein is translated. A mutation involving both
an insertion and deletion has been identified in a family with recessive
NSHL (Sobe et al. 2000). A deletion of 12 bp occurred, with the insertion
of one nucleotide, to form a 51del12insA mutation. This mutation occurs
in the first intracellular amino terminus domain, leading to a stop codon at
the beginning of the first extracellular domain. A frameshift is formed in
the amino-terminal portion of the protein, resulting in 26 additional novel
amino acids followed by a premature termination.
Additional examples of mutations in the DNA sequence affecting the
translation of RNA into protein and causing NSHL are shown in Table 2.3.
4.1.2 Mutations in Components of the Translation Machinery
Cause Hearing Loss
The RNA components of the ribosome are essential for translation of
mRNA into protein. Hearing loss has been correlated with mutations in
both tRNA genes and the 12S rRNA gene, genes found on the mitochon-
drial genome (Fischel-Ghodsian, Chapter 7). Unlike the deafness genes
described elsewhere in this chapter, this mitochondrial-dependent hearing
loss is transmitted directly from mother to child. Presumably, these muta-
tions alter the translational machinery in the inner ear, and compromise the
production of essential protein components of the mitochondria.
