Topic = Genetic Disorder
Presented By= M.Z.Arifeen
Department Of Biotechnology
University Of Malakand
Deafness, hearing impairment, or hearing
loss is a partial or total inability to hear.
Deafness affects 1 per 1000 children
About 50% of childhood HL attributed to genetic
factors, 20-25% environmental factors, and 25-
Hearing impairment is the world’s third leading
Recessive inherited deafness in Pakistan in high
due to high rate of consanguineous marriages.
Causes of Hearing Loss:
Hearing is a complex process, so it should be no
surprise that the causes of hearing loss are also complex.
Hearing loss can occur because of damage to the ear,
especially the inner ear. For example, infants may be
born with hearing loss caused by a viral infection that
was acquired during pregnancy.
At other times the cause is genetic and therefore due to
changes in the genes involved in the hearing process.
Sometimes, hearing loss is due to a combination of
genetic and environmen-tal factors.
There is, for example, a genetic change that makes some
people more likely to develop hearing loss after taking
certain antibiotic medications
How the ear works:
• The ear has three main
parts: the outer, middle
and inner ear.
• The outer ear (the part you
can see) opens into the ear
• The eardrum separates the ear
canal from the middle ear.
• Small bones in the middle ear help transfer sound to the inner
ear. (incus, malleus and stapes)
• The inner ear contains the Cochlea, auditory (hearing) nerve,
which leads to the brain.
Process of hearing
• Any source of sound sends vibrations or sound waves into the air.
• The funnel through the ear opening, down the ear, canal, and strike
your eardrum, causing it to vibrate.
• The vibrations are passed to the
small bones of the middle ear,
which transmit them to the hearing
nerve in the inner ear. Here, the
vibrations become nerve impulses
and go directly to the brain, which
interprets the impulses as sound
(music, voice, etc.).
The vibrations are changed into electrical
impulses that are sent to the brain to create what we understand as “hearing.”
The different types of hearing loss are classified according to
what part of the hearing system is affected. Sound is picked up by
the outer ear and then passes through the ear canal to the middle
ear. Problems in these places cause conductive hearing loss.
After passing through the middle ear, the sound then travels to a
part of the inner ear called the cochlea, where it is changed to a
signal that can be sent down the hearing nerve to the brain.
Problems here cause sensorineural hearing loss.
Types Of Hearing Loss
Hereditary hearing loss is divided into syndromic
and non-syndromic cases
syndromic = a condition with various symptoms
affecting multiple organ systems i.e deafness
that is accompanied by other clinical features.
Accounts for 30% of all cases of deafness
non-syndromic = no other phenotypic
abnormalities accompanying this type of deafness.
Accounts for 70% is non-syndromic
Types of Hearing Loss
congenital = Congenital means that a person was
born with the hearing loss.
acquired = Acquired hearing loss means that a
person could hear when he or she was born, but
developed hearing loss later in life.
o prelingual = If hearing loss starts before the age
when children usually begin talking, it is called
“prelingual”, which means “before speaking”.
o Postlingual = If hearing loss starts after the age
when children begin talking, it is called
“postlingual”, which means “after speaking”.
progressive= If the hearing loss gets worse over
time, it is called “progressive”.
nonprogressive= If the hearing loss does not
change over time, it is “nonprogressive” or stable.
familial = If more than one person in a family
has hearing loss, it is said to be “familial”. That
is, it runs in the family.
sporadic = If only one person in the family
has hearing loss, it is called “sporadic”. That is,
it does not run in the family.
Conductive =“Conductive” hearing loss is
caused by problems in the outer or middle ear.
Sensorineural= “Sensorineural” hearing loss
is caused by problems in the inner ear.
Classification of HHL
Also divided into groups by mode of
Autosomal Dominant Disorders
75-80% of genetic deafness attributed to
AR inheritance, 18-20% to AD, with the
remainder classified as X-linked or
X-linked inheritance is rare
Accounts for only 1% to 2% of cases of hereditary
May constitute about 6% of nonsyndromic
profound losses in males
X-linked congenital SNHL has been mapped to Xq
X-linked dominant SNHL has been mapped to Xp
Hearing Loss Hearing LossHearing Loss Hearing Loss
• Two genes are important for non-syndromic
1.MTRNR1: MTRNR1 gene encoding the 12S rRNA of Mt.
Mutations in MT-RNR1 can be associated with predisposition to
aminoglycoside ototoxicity and/or late-onset sensorineural
•The MTRNR1 mutations probably alter the secondary structure
of the 12S rRNA molecule, so that it resembles its bacterial
counterpart, the 16S rRNA, more closely. As the bacterial 16S
rRNA molecule is the target of aminoglycoside action, this might
explain the cumulating effect of these MTRNR1 mutations and
the use of aminoglycosides .
2. MTTS1: MTTS1 gene encodes transfer RNA for serine
both of which are important in mitochondrial protein
• Individuals with an MTTS1 mutation generally have an
onset of sensorineural hearing loss during childhood.
Accounts for 3% of childhood hearing impairment
Most common form of inheritable congenital deafness
Incidence is 1 in 4000 live births
sensorineural hearing loss
iris pigmentary abnormality (two eyes different color or iris
bicolor or characteristic brilliant blue iris)
hair hypopigmentation (white forelock or white hairs at other sites
on the body)
skin hypopigmentation(congenital leukoderma/white skin patches)
medial eyebrow flare (unibrow synophrys)
broad nasal root
premature graying of the hair (before age 30).
All features are variable in appearance
Types 1 and 3 caused by mutation of PAX3 gene on
chromosome 2q; Type 2 is caused by mutation of MITF
gene on chromosome 3q (The 'q' refers to the long arm of
Also linked to other genes -EDN3, EDNRB, and SOX10
Characterized by cleft palate, micrognathia, severe
myopia and retinal detachments
Severe HL in 15%; less severe HL in 80%
Most cases attributed to mutations in COL2A1
gene on chromosome 12
Estimated to occur in 2% of children with
congenital hearing loss
Involves ear pits/tags or cup ear and renal
involvement ranging from agenesis and renal
failure to minor dysplasia
75% of affected patients have significant hearing
Gene felt to be responsible is located on
chromosome 8q in humans
Nonsyndromic Hearing Loss
Nonsyndromic deafness is hearing loss that is not
associated with other signs and symptoms.
Most forms of nonsyndromic deafness are associated with
permanent hearing loss caused by damage to structures in
the inner ear.
The inner ear consists of three parts: a snail-shaped
structure called the cochlea that helps process sound,
nerves that send information from the cochlea to the brain,
and structures involved with balance.
Loss of hearing caused by changes in the inner ear is
called sensorineural deafness.
Hearing loss that results from changes in the middle ear is called
conductive hearing loss.
Some forms of nonsyndromic deafness, particularly a type of
deafness called DFN3, involve changes in both the inner ear and
the middle ear. This combination is called mixed hearing loss.
The causes of nonsyndromic deafness are complex. Researchers
have identified more than 30 genes that, when mutated, may cause
nonsyndromic deafness; however, some of these genes have not
been fully characterized
Many genes related to deafness are involved in the development
and function of the inner ear.
Mutations in these genes result in hearing loss by interfering with
critical steps in processing sound
What are GJB2 and Connexin 26?
Autosomal Recessive Non-syndromic Hearing loss:
–Connexin 26 mutations are the most common cause of
autosomal recessive, non-syndromic hearing loss
Mutations in the GJB2 gene causes prelingual nonsyndromic
This gene provides instructions for making a protein called
These proteins form parts (subunits) of channels called gap
junctions, which allow communication between neighboring cells.
Mutations in connexin proteins that make up gap junctions may
affect the function or survival of cells that are needed for hearing.
Gap junction are present inside cochlea.
The cochlea is a very complex and specialized part of the body
that needs many instructions to guide its development and
The GJB2gene contains the instructions for a protein called
Connexin 26; this protein plays an important role in the
functioning of a part of the ear called the cochlea.
Deafness Type 3 (DFN3)
DFN3 deafness is caused by mutations in the POU3F4 gene,
which is located on the X chromosome. (Xq21)
In people with this condition, one of the small bones in the
middle ear (the stapes) cannot move normally, which interferes
This characteristic sign of DFN3 is called stapes fixation
At least four other regions of the X chromosome are involved in
hearing loss, but the responsible genes have not been discovered
The middle ear contains small bones that help send sound from the air to the inner ear. The inner ear changes these sounds into nerve signals that go to the brain
Etiology=The study of causes or origins
Children receive one sex chromosome from their mother (shown in green) and one sex chromosome from their father (shown in blue). Because women have two X chromosomes, all children inherit an X chromosome from their mother. On the other hand, males have one X chromosome and one Y chromosome. Therefore, children may receive an X chromosome from their father and become a girl, or receive a Y chromosome and become a boy. In this example, a red band is used to represent a recessive mutation of one of the mother’s X chromosomes. As shown in the figure, even if the girls inherit an altered copy from their mother, they will still be unaffected because they will get an unaltered copy from their father. On the other hand, the boys receive a Y chromosome from their father so they do not have an unaltered copy of the X chromosome to block the effect of the mutation. Therefore, because sons have a 1 out of 2, or 50%, chance of inheriting the altered X chromosome from their mother, they have a 50% chance of being deaf.
Mammalian cells have 2 mitochondrial (12S and 16S) rRNA molecules and 4 types of cytoplasmic rRNA (the 28S, 5.8S, 18S, and 5S subunits). In prokaryotes a small 30S ribosomal subunit contains the 16S rRNA. The large 50S ribosomal subunit contains two rRNA species (the 5S and 23S rRNAs). The antibacterial properties of aminoglycosides were believed to result from inhibition of bacterial protein synthesis through irreversible binding to the 30S bacterial ribosome. (aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin) Ototoxicity is damage to the hearing functions of the ear by drugs or chemicals.
PAX3 is a gene that belongs to the paired box (PAX) family of transcription factors. PAX3 has been identified with ear, eye and facial development Microphthalmia-associated transcription factor (MITF) transcription factor involved in melanocyte and osteoclastdevelopment. Melanocytes are melanin-producing cells located in the bottom layer of the skin&apos;s epidermis, the middle layer of the eye the inner ear, meninges, bones, and heart. Melanin is the pigment primarily responsible for skin color. An osteoclast is a type of bone cell
Myopia=is a condition of the eye where the light that comes in does not directly focus on the retina but in front of it. This causes the image that one sees when looking at a distant object to be out of focus, but in focus when looking at a close object. cleft palate= Micrognathism (or Micrognathia) =is a condition where the jaw is undersized. Retinal detachment =is a disorder of the eye in which the retina peels away from its underlying layer of support tissue COL2A1= The gene responsible for the production of the alpha1(II) chain of type II collagen. Type II collagen, which adds structure and strength to connective tissues, is found primarily in cartilage, the gel that fills the eyeball (vitreous body),inner ear, and the center portion of the discs between the vertebrae in the spine (nucleus pulposus). `
agenesis refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue Dysplasia: is a term used in pathology to refer to an abnormality of development renal = kidney
POU domain, class 3, transcription factor 4 is a protein that in humans is encoded by the POU3F4 gene
5q31: 5= chromosome number, q = long arm (the lower arm) of the chromosome, 31= the band along the chromosome where the gene is found