Biology Reference
In-Depth Information
that gives rise to a codon that does not correspond to an amino acid
(e.g., a stop codon), are very likely to be causal (Avraham and Hasson,
Chapter 2).
3.2 Heterogeneity
The underlying cause of most forms of hereditary hearing loss is a muta-
tion in a single gene. Results from linkage studies of several families are
often pooled to increase the probability that the correct location has been
found for the gene. However, the gene in one family may be different from
that in another (e.g., at least nine different genes cause Usher syndrome).
This is known as locus heterogeneity. In this situation, pooling families will
hinder rather than help the analysis. Studying endogamous populations or
large pedigrees minimizes the chance of locus heterogeneity, but does not
necessarily eliminate it.
A phenotype such as nonsyndromic hearing impairment is caused by
many different genes, and the etiology may not be the same even for
affected members of the same family. In some cases, auditory testing (par-
ticularly if it covers more than pure tone air conduction audiometry) may
detect phenotype differences among members of the same kindred. Such
findings may be critical for linkage studies. For example, in the family
studied by Vahava et al. (1998) auditory testing showed that the hearing
impairment in one member was different from that in the other members.
Knowing that this individual was a phenocopy (same clinical phenotype,
but different etiology) facilitated the linkage analysis.
Unlike locus heterogeneity, allelic heterogeneity does not confound
linkage studies. In this case, different alleles (that is, different mutations in
the same gene) are responsible for the phenotypes, which are generally
similar. However, different alleles do not necessarily result in the same phe-
notype, and the mode of inheritance may even be different. For example,
most mutations in the human myosin VIIa gene (
MYO7A
) cause Usher syn-
drome type IB, but a few result in recessive nonsyndromic hearing loss, and
others in dominant nonsyndromic hearing loss.
4. Mouse Models
Finding a mutation that probably makes a gene deleterious is a critical step,
but it does not prove that the defect actually causes the hearing impair-
ment. However, if a transgenic or knockout mouse is hearing impaired, then
the argument that the defect causes the abnormal phenotype is convincing.
To obtain a transgenic mouse, copies of the gene are injected into mouse
