Biology Reference
In-Depth Information
biotin. In the absence of normal biotinidase activity, affected individuals are
entirely dependent on their dietary intake of biotin and typically begin to
show symptoms of biotin deficiency in early infancy (Wolf et al. 1985).
Hearing loss, which is eventually seen in about 60% of untreated patients,
is a completely preventable complication of this disease. Subsequent to the
introduction of newborn screening for this treatable form of genetic deaf-
ness, large numbers of affected individuals have been identified throughout
the world. Table 4.1 shows the geotyping results for polymorphic markers
in the p21-22 region of chromosome 3 in twelve isolated consanguineous
probands with biotinidase deficiency, many of whom had been identified in
newborn screening programs. The shaded area indicates the chromosomal
regions in which the typed probands exhibited marker homozygosity. Initial
analyses of eleven markers localized the gene to a small region containing
D3S1286. Subsequent typing of probands P5 and P274 for six additional
markers flanking D3S1286 further refined the critical region. Notice that,
in contrast to inbred kindreds, the homozygosity involved different alleles
in each proband. Proband P5 was the offspring of third cousins once
removed and the conserved chromosomal region surrounding the bio-
tinidase locus had been narrowed by recombination during a total of eleven
meiotic divisions to a very small interval. By typing only twelve individuals,
it was ultimately possible to assign the probable location of the biotinidase
gene to the small segment of chromosome 3p between D3S3613 and
D3S1286 (Blanton et al. 2000).
4. Functional Genomics of the Ear
As new genes for deafness have been mapped and cloned, the delineation
of their base-pair sequences has frequently allowed their function to be
surmised by matching the amino acid sequences of their protein products
with data bases of genes whose function has already been established. This
knowledge is providing dazzling insights into the normal and pathophysi-
ology of hearing.
4.1 Organogenesis
Among genes that can cause deafness, some of the most exciting and poten-
tially significant are those that encode DNA binding transcription factors.
These genes produce proteins that bind to specific regulatory sequences
on their target genes and act in concert with other transcription factors to
promote or inhibit the activities of those genes (Avraham and Hasson,
Chapter 2). The miraculous process of organogenesis that leads to the for-
mation of a normal inner, middle and external ear results from a precise
cascade of differential gene expression that is controlled by a hierarchy of
DNA binding regulatory genes. The molecular defects in two forms of
