Biology Reference
In-Depth Information
3.10.2
Shaker 1
Encodes Unconventional Myosin VIIa
Shaker 1
was identified by a physical map-based strategy (positional
cloning) and shown to encode an unconventional myosin designated
Myo7a
. Myosin genes are subdivided into conventional myosins (e.g.,
myosin class II of muscle and nonmuscle cells) and unconventional myosins
(classes I, III-XV) (Mermall et al. 1998; Wang et al. 1998). Myosins are
motor-proteins that bind cytoskeletal actin and hydrolyze ATP to produce
force and movement (Mermall et al. 1998). Myosin genes have an evolu-
tionarily conserved motor domain that is usually located at the amino ter-
minus, and a C-terminal tail domain that is divergent between different
myosin classes (Fig. 6.4). The functions of some unconventional myosins are
just now becoming known, and the existing data indicate a role for these
molecular motors in intracellular transport along actin filaments. Uncon-
ventional myosins are involved in the processes of endocytosis, regulation
of ion channels, localization of calmodulin, movement of vesicles and
particles in the cytoplasm, determinant localization and anchoring inner ear
cell stereocilia (Baker and Titus 1998; Mermall et al. 1998; Titus 1998).
MYO7A
mutations were found in two small Chinese families (Liu et al.
1997b) and in the original
DFNB2
family from Tunisia segregating non-
syndromic recessive deafness (Weil et al. 1997) (Fig. 6.4). An A-to-G tran-
sition in the last nucleotide of exon 15, encoding part of the
MYO7A
motor
domain, was found in the Tunisian family. This mutation is predicted to
result in substitution of isoleucine for methionine (M599I) (Weil et al.
1997). However, based on its position as the last nucleotide of exon 15, this
mutation could exert a deleterious effect by affecting the splicing efficiency
of
MYO15
mRNA. Compound heterozygosity or homozygosity for three
additional
MYO7A
mutations, R244P, a splice-acceptor-site mutation, and
a frameshift mutation (Val1199insT[FS]), co-segregated with NSRD in the
two small families from China (Liu et al. 1998; Liu et al. 1997b). Establish-
ing a convincing argument for a causal connection between the missense
mutation R244P and hearing loss is difficult in a small family. However, the
causality of this mutation is supported by the observation that
sh-1
6J
is also
a substitution of proline for arginine at the equivalent position in the
myosin motor (Mburu et al. 1997).
3.10.3
DFNA11
is the Same Locus as
DFNB2
Dominant, progressive, nonsyndromic hearing loss was mapped to 11q12.3-
q21 in a Japanese family and designated
DFNA11
(Tamagawa et al. 1996).
This is the same region to which
DFNB2
and Usher's syndrome type 1B
were mapped. Hearing loss in the
DFNA11
family is postlingual and pro-
gresses to a moderate loss by 60 years of age. All eight affected members
of the
DFNA11
family have a 9-bp deletion of exon 22 of
MYO7A
, which
removes three amino acids, but otherwise maintains the correct reading
frame. Exon 22 encodes a coiled-coil domain that allows myosin VIIA to
