Biology Reference
In-Depth Information
drome is caused by the deletion of multiple genes. Miller-Dieker patients
have lissencephaly, severe mental retardation, and a characteristic facial
appearance. They may also have growth retardation, heart defects, and
seizures (Dobyns et al. 1991). Ninety percent of Miller-Dieker patients have
deletions in chromosome 17p13. More than one gene must be involved in
the syndrome because mutations in the
LIS1
gene at this locus cause
isolated lissencephaly, without the other features characteristic of Miller-
Dieker syndrome (Chong et al. 1997). Presumably, deletion of genes in
addition to
LIS1
at 17p13 contribute to the full spectrum of anomalies.
Miller-Dieker syndrome illustrates how analysis of individual genes
within a critical deletion region can help establish which gene is responsible
for a specific feature of a syndrome. Collections of overlapping deletions are
used to narrow the critical region, allowing identification and analysis of
individual genes and the role they play in the pathobiology of the disease.
Alternatively, chromosomal deletions may cause disease by unmasking
recessive alleles on the sister chromosome. This mechanism may be the
etiology for the hearing loss associated with Smith-Magenis syndrome
(Greenberg et al. 1996).
2.2 Cytogenetics and Hearing Loss
Hearing loss is a component of a number of chromosomal syndromes.
Aneuploidies, translocations, inversions, duplications, and deletions have
each been found that cause hearing loss. However, cytogenetics has not
been a traditional technique used in investigations of genetic deafness. No
large scale cytogenetic studies of patients with isolated hearing loss have
been reported.
In the next sections, some of the syndromes and isolated cases of chro-
mosomal rearrangement in which hearing loss has been found are reviewed.
Cytogenetic studies may complement molecular investigations, allowing a
better understanding of a syndrome and the gene(s) that cause it. Three
specific examples in which cytogenetic findings facilitated gene discovery
are discussed below.
2.2.1 Aneuploidy and Hearing Loss
Depending on the missing or additional chromosome, individuals with chro-
mosome aneuploidies can have a wide spectrum of physical and mental
handicaps, reflecting developmental disorders at various stages of fetal life.
Generally, the more complex organ systems or structures appear to be
affected most profoundly. Thus, among autosomal aneuploidies, the brain
is uniformly abnormal, and physical anomalies, especially craniofacial, are
typical. Heart, genitourinary system, eyes, hands and feet are also often
involved (Therman and Susman 1993). It is of no surprise that hearing loss
or deafness is found in several of the human aneuploidies.
