Genes for photoreceptor proteins in cones

The gene for the blue receptor is autosomal; the
genes for the red and green receptors are X
chromosomal. The absorption spectra of the
three receptors show maxima of 426 nm for
blue, about 530 for green, and about 550 for red.
The red receptorwas discovered to be polymorphic,
with two somewhat different absorption
maxima at 552 and 557 nm.

Hearing and Deafness

Acoustic signals are essential for an animal’s
ability to respond appropriately to its environment.
Hearing is orchestrated by a large ensemble
of proteins acting in concert. Specialized
sensory cells in the cochlea of the inner ear
process the incoming sound waves, converting
them into cellular information that is relayed to
the brain via the acoustic nerve. A missing or
defective protein involved in the hearing
process results in hearing loss. Hearing loss is
common in humans. One out of 1000 newborns
lacks the ability to hear or has severely impaired
hearing. Two categories of genetic hearing loss
can be distinguished: nonsyndromic and syndromic.
In the former category the genetic defect
is limited to the ear; in the latter the ear is
one of several organ systems affected.
The types of genes implicated when defective as
the cause of nonsyndromic hearing loss include
those encoding proteins involved in cytoskeletal
structure, transcription factors, ion
channels (potassium channel), and intercellular
gap channels composed of junction connexins.

The main components of the ear

The auditory system consists of the outer ear,
the middle ear, and the inner ear. Sound waves
are funneled through the outer ear (auricle) and
transmitted through the external ear canal to
the tympanic membrane, which they cause to
vibrate. These vibrations are transmitted
through the tympanic cavity of the middle ear
by a chain of three movable bones, the malleus,
the incus, and the stapes. Three major cavities
form the inner ear: the vestibule, the cochlea,
and the semicircular canals. The chochlea is the
site where auditory signals are processed. The
cochlea contains amembranous labyrinth filled
with a fluid, the endolymph. The vestibular apparatus
includes three semicircular canals
oriented at 90! degree angles to each other.
They respond to rotatory and linear acceleration.
Signals received here are transmitted via
the vestibular nerve, which fuses with the
cochlear nerve to form the acoustic nerve. The
latter transmits the information to the brain.

The cochlea

The cochlea contains the cochlear duct, which
forms the organ of Corti. The organ of Corti converts
sound waves in the endolymph of the
cochlea into intracellular signals. These are
transmitted to auditory regions of the brain.
The organ of Corti contains two types of sensory
cells: one row of inner hair cells and three rows
of outer hair cells. The inner hair cells are pure
receptor cells. Vibrations induced by sound lead
to slight deflections of the stereocilia and open
potassium channels at the tips of the stereocilia.
The influx of potassium ions at the tips of the
cilia of the hair cells (see C) causes a change in
membrane potential that results in a nerve impulse,
which is transmitted as an auditory signal
to the auditory cortex of the brain.
Potassium ions are recycled to the supporting
cells and the spiral ligament into the endolymph
of the scala media. The tectorial membrane
amplifies the sound waves as a resonator.

The outer hair cell

The outer hair cells combine sensory function
with the ability to elongate and contract when
acoustically stimulated. The apical pole of a hair
cell carries an array of about 100 cylindrical
stereocilia in a V-shaped arrangement. Each
stereocilium contains an actin molecule, which
enables it to elongate or to contract. The tips of
the stereocilia are connected by tip links. The
potassium channels are formed by the KCNQ4
protein (yellow) and by connexins (red). Important
for the structural integrity and dynamics of
the hair cells is a cytoskeleton involving actin,
myosin 7A, myosin 15, and the protein diaphanous.

Chromosomal locations of human deafness genes

Almost every human chromosome harbors at
least one gene involved in nonsyndromic
monogenic hearing loss. The diagrammatic
presentation shown here is limited to nonsyndromic
hearing loss.

Odorant Receptor Gene Family

Vertebrates can differentiate thousands of individual
odors. Although their ability to distinguish
differences in color is based on only three
classes of photoreceptors, their sense of smell is
regulated by a large multigene family of receptors
that are highly specific for individual
odorants. In fish, about 100 and in mammals
about 1000 genes code for specific olfactory receptors.
These genes are expressed exclusively
in the olfactory epithelium of the nasal mucous
membrane.

Olfactory nerve cells in the nasal mucous membrane

The peripheral olfactory neuroepithelium of
the nasal mucous membrane consists of three
cell types: olfactory sensory neurons, whose
axons lead to the olfactory bulb, supporting
cells, and basal cells, which serve as stem cells
for the formation of olfactory neurons during
the individual’s entire lifespan. Each olfactory
neuron is bopolar, with olfactory cilia in the
lumen of the nasal mucous membrane and a
projection to the olfactory bulb, the first relay
station of the olfactory systemon theway to the
brain.

Odor-specific transmembrane receptors and GTP-binding protein (Gs[olf])

Each receptor in the cilia of the olfactory neurons
binds specifically to one odorant. Binding
of the receptor activates adenylate cyclase via a
specific GTP-binding protein (stimulatory G
protein of the olfactory system, Gs[olf]). This
opens a sodium ion channel and initiates a cascade
of intracellular signals that result in a
nerve signal, which is transmitted to the brain.

Olfactory receptor protein

The cloning of a large gene family from the olfactory
epithelium of the rat (Buck and Axel,
1991), demonstrated that a receptor protein
contains seven transmembrane regions and
shows marked structural homology with
rhodopsin and !-adrenergic receptors. Unlike
rhodopsin, the olfactory receptor proteins contain
variable amino acids, especially in the
fourth and fifth transmembrane domains. The
third intracellular loop between transmembrane
domains V and VI is relatively short (17
Genetics and Medicine
amino acids), in contrast to other receptor proteins.
It is assumed that contact with the
various G proteins takes place here

Assignment of olfactory receptor RNA to neurons

A gene for the receptor of a given odorant is expressed
in an individual in only a few neurons.
Ngai et al. 1993 classified individual olfactory
neurons in the olfactory epithelium of the catfish
(Ictalurus punctatus). Only 0.5–2% of all olfactory
neurons recognize a given receptor
probe such as probe 202 (1) or 32 (2). Odors are
distinguished in the brain according to which
neurons are stimulated. The topographical
position of each neuron is specific for each
odorant.

Subfamilies within the multigene family

Amino acid sequences derived from partial nucleotide
sequences of cDNA clones (F2–F24) (1)
investigated by Buck and Axel (1991) were very
variable, especially in transmembrane domains
III and IV. Within subfamilies, there was homology
due to conserved sequences (2). For example,
F12 and F13 differ in only 4 of 44 positions
(91% identical).

Mammalian Taste Receptor Gene Family

Aside from the main olfactory system, mammals
have evolved two other chemosensory
systems, the taste receptor gene family (for bitter
taste) and the mammalian pheromone receptor
gene family. Five different types of taste
can be perceived: salty, sour, bitter, sweet, and
umani (the taste of monosodium glutamate,
present in Asian food). Salty and sour tastes involve
direct effects due to the entry of H+ and
Na+ ions through specialized membrane channels.
In contrast, bitter, sweet, and umani tastes
are mediated via a G protein-coupled receptor
(GPCR) signaling pathway system. A sweet taste
may herald a desirable carbohydrate content,
whereas a bitter taste is associated with potentially
toxic substances such as alkaloids, cyanides,
or other detrimental aromatic compounds.

Mammalian chemosensory epithelia

The oral and nasal cavities of mammals contain
three distinct chemosensory epithelia: (i) the
main olfactory epithelium (MOE) containing
sensory cells with odorant receptors in the nose
(see previous page), (ii) the taste sensory
epithelium of the taste buds of the tongue, soft
palate, and epiglottis, and (iii) the vomeronasal
organ (VOM, also called Jacobson’s organ), a
tubular structure in the nasal septum containing
sensory cells with pheromone receptors.
The main olfactory bulb (MOB) relays signals
from the MOE to the olfactory cortex of the
brain. The accessory olfactory bulb (AOB) relays
signals from the VOM to areas of the amygdala
and hypothalamus.

Mammalian chemosensory system

The receptor cells are organized in three corresponding
molecular and cellular chemosensory
systems. Each neuron of the main olfactory
sensory system (1) expresses one of the different
olfactory receptor genes and sends axons to
specific glomeruli of the main olfactory bulb
(mitral cells). The odorant receptor (OR) gene
family comprises about 1000 members, each
encoding a seven-transmembrane cyclic nucleotide-
gated channel with distinct odorant
specificity (G-olfactory proteins, Golf). The bitter
taste sensory system (2) connects axonal projections
of receptor cells in the taste sensory
epithelium of the taste buds to gustatory nuclei
of the brain stem. Two families of taste receptors,
the TIRs (two genes) and T2Rs (50–80
genes of the gustducin class) have been described.
Two families of mammalian putative
pheromone receptors (V1Rs and V2Rs) are encoded
by 30–50 and over 100 genes, respectively
(3).

Taste receptor gene family

The two novel taste receptor gene families,
T1R1 and T1R2, are expressed in distinct subsets
of taste receptor cells. The figure shows an
alignment of the predicted amino acid
sequences of 23 different T2 receptors (T2Rs) of
human (h), rat (r), and mouse (m) origin between
the first (TM1) and the third (TM3) transmembrane
domain. Dark blue indicates identity
in at least half of the aligned sequences;
light blue represents conserved substitutions;
and the remainder are divergent regions. They
reflect the ability to bind many structurally
different ligands. The T2R genes cluster on a few
chromosomes, human chromosomes 5, 7, and
12 and mouse chromosomes 6 and 15.

Expression of many taste receptor genes in the same cell

Unlike olfactory system receptor cells, individual
taste receptor cells express multiple
T2R receptors. Up to ten T2R probes hybridize to
only a few cells, shown darkened (1). Doublelabel
fluorescent in-situ hybridization shows
that different receptor genes (2, T2R-3 in green
and T2R-7 in red, 3) are expressed in the same
taste receptor cell. The T2Rs confer high sensitivity
for bitter substances at low concentrations
but do not distinguish between them.

Genes in Embryonic Development

Developmental Mutants in
Drosophila
The embryonic development of an organism is
determined by genes that may be active only
during specific phases. Analysis of
developmental mutants of embryos of the fruit
fly Drosophila melanogaster has provided insight
into the genetic regulation of
developmental processes. Early developmental
phases in embryos of very different organisms
are regulated by similar genes.

The segmental organization of the fruit fly (Drosophila melanogaster)

The development of a fruit fly from the fertilized
egg cell to the segmented body of the adult
organism takes nine days. The larvae hatch after
one day and pass through defined stages of
embryonic development. The embryo forms a
cocoon at five days and, after metamorphosis,
emerges as a 2 mm-long adult fly. The head of
the adult has three segments (C1–3), the thorax
three (T1–3), and the abdomen eight segments
(A1–8). A fruit fly has altogether 14 parasegments
(P1–14), each corresponding to the last
half of one and the first half of the next segment.
The segmental organization is discernible in the
larva.

Embryonic lethal mutations

Embryonic lethal mutations can be identified
by appropriate crosses. One-fourth of the progeny
of heterozygous flies (A/a) for an embryonic
mutant gene (a) are homozygotes (aa) for the
mutant allele (1). If a mutation involves maternal
genes only (maternal effect), progeny of
female homozygotes (bb) are lethally affected
(2). Maternal effect genes code for early gene
products that determine the polarity of the embryo;
see below (C).

Examples of developmental mutants

Many developmental mutations are known in
Drosophila melanogaster. They can be classified
into different hierarchical gene classes. The normal
larva (wild type) consists of three head segments,
three thorax segments, eight abdominal
segments, and the tail end (1). A mutation for
anterior maternal effect, bicoid, leads to the
development of a larva without head or thorax
(2). Amutation of a gene called nanos affects the
posterior end of the early larva. Gap genes establish
the basic pattern of segmental organization.
Mutations of the gap genes lead to omissions
(gaps) in the segmental construction of
the larva. In the Krüppel mutant (3), all thoracic
and the abdominal segements 1–5 aremissing;
in the Knirps mutant (4), abdominal segments
1–6 are absent. The genes for pair-rule determine
the orientation and developmental fate of
the 14 parasegments. Some mutations affect
every second segment. With even-skipped (5),
all even-numbered parasegments are missing.
Mutation of the gene fushi tarazu leads to fewer
than normal segments being formed (fushi
tarazu is Japanese for too few segments). Segment
polarity genes determine the polarity of
each segment (7). There are more than ten segment
polarity genes. Homeotic selector genes (8)
determine the ultimate fate of each segment.
With the mutant antennapedia (Ant), the
antenna normally attached immediately under
the eye is replaced by a leg (homeotic leg).