Biology Reference
In-Depth Information
that generalized neuronal dysfunction is also expressed in the auditory
system.
In 1992 several families with diabetes mellitus and sensorineural hearing
loss were described, and surprisingly were found to have inherited the het-
eroplasmic A3243G mutation in the gene for
tRNAleu(UUR)
the very same
mutation as is associated with the systemic MELAS syndrome (Reardon et
al. 1992; van den Ouweland et al. 1992). In none of these cases were other
neurological symptoms present. One family had, instead of the A3243G
mutation, a heteroplasmic large deletion/insertion event (Ballinger et al.
1992), and more recently the heteroplasmic point mutations T14709C in the
tRNAglu
gene and A8296G in the
tRNAlys
gene were also found to be asso-
ciated with maternally inherited diabetes and deafness (Vialettes et al.
1997; Kameoka et al. 1998). This association between diabetes mellitus,
hearing loss, and mtDNA mutations has been confirmed in population
studies of diabetic patients (Oka et al. 1993; Alcolado et al. 1994; Kadowaki
et al. 1994; Katagiri et al. 1994; Sepehrnia et al. 1995; Newkirk et al. 1997;
Rigoli et al. 1997). For example, Kadowaki et al. (1994) found the A3243G
mutation in 2 to 6% of diabetic patients in Japan, and in 3 out of 5 patients
with diabetes and deafness. Of their 44 patients with diabetes and the
A3243G mutation, 27 had hearing loss. The hearing loss is sensorineural
and usually develops only after the onset of diabetes. In the non-Japanese
populations that have been examined, the A3243G mutation accounts for
less than 1% of the diabetic patients (Sepehrnia et al. 1995; Newkirk et al.
1997; Rigoli et al. 1997). More recently, several patients have been described
with maternally inherited diabetes and deafness and also either macular
dystrophy or adrenal insufficiency (Harrison et al. 1997; Nicolino et al. 1997;
Souied et al. 1998). In one of these cases, the heteroplasmic A3243G muta-
tion was found (Harrison et al. 1997), while in the other cases a hetero-
plasmic large deletion was identified (Nicolino et al. 1997; Souied et al.
1998).
The A7445G mutation was initially described as a nonsyndromic deaf-
ness mutation, but was subsequently found to be also associated with the
skin condition palmoplantar keratoderma (PPK) in at least some of the
cases (Reid et al. 1994a; Fischel-Ghodsian et al. 1995; Sevior et al. 1998). It
is discussed more fully in the next section.
3.2 Mitochondrial DNA Mutations and Nonsyndromic
Hearing Loss
The first mutation associated with nonsyndromic deafness was identified in
an Arab-Israeli pedigree, when the striking pattern of transmission only
through mothers was noted (Jaber et al. 1992; Prezant et al. 1993). Most of
the deaf family members had onset of severe to profound sensorineural
hearing loss during infancy, but a minority of family members had onset
during childhood, or even adulthood (Braverman et al. 1996). The homo-
