Transcript Mitochondrial hearing loss

International Conference
Diagnosis & Treatment of Inner Ear Disorders
Genetics of deafness
Lech Korniszewski
The Medical University of Warsaw
Institute of Physiology and Pathology of
Hearing
Hearing loss – incidence:
6-8% of population – when all
causes are combined hearing loss –
most common birth defect
1 in 1000 newborns are deaf
1 in 300 children are affected with
congenital hearing loss of a lesser
degree additional 1 in 1000 become
profoundly hearing impaired before
adulthood
Genetic hearing loss
approximately 1% of all human genes are involved in
the hearing process
inheritance: autosomal recessive
autosomal dominant
X-linked
mitochondrial
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allelic mutatione in some genes can cause recessive and
dominant hearing loss
mutations in the same gene may cause syndromic or
nonsyndromic hearing loss
recessive hearing loss may be caused by a combination of two
mutations in differrent genes from the same functional group
Syndromic hearing loss
Over 400 syndromes have been described
in which hearing loss is a component part.
There are many factors that make specific
syndrome diagnosis difficult:
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The rarity of most of these syndromes (lack
personal experience)
Variability of clinical expression
Genetic heterogeneity (a single phenotype may
be result of different genes mutations)
Pleiotropy (single gene may cause many
different phenotypic effects)
Waardenburg syndromes
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Bilateral or unilateral sensorineural
hearing loss in association with defects in
tissues derived from neural crest cells
pigmentary abnormalities hair, skin and eyes
hearing loss is due to defective migration of
melanocytes info the intermediate layer of
the stria vascularis
genetically heterogeneous; inheritance AD
four clinical subtypes
Waardenburg syndromes
Type Gene
Protein/funct
ion
Clinical features
WS1
PAX3
transcription factor
Abnormal pigmentation of hair, eyes
and skin. Dystopia canthorum, short
philtrum, synophrys. Deafness in
20% (unilateral or bilateral)
WS2
MITF
transcription factor
Abnormal pigmentation of hair, eyes
and skin. Deafness in 40%
(unilateral or bilateral). No
dysmorphic features
WS3
PAX3
transcription factor
Features of WS1 with limb
anomalies
WS4
EDN3
EDNRB
SOX10
endothelin ligand
endothelin receptor
transcription factor
Abnormal pigmentation of hair, eyes
and skin with Hirschprung disease
Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF
expression by SOX10 and PAX3
EDN3 EDNRB3
WS 1
WS 3
PAX 3
SOX 10
transactivation
WS 2
MITF
transactivation
melanocyte tyrosinase
WS 4
Branchio-oto-renal syndrome
Hearing loss conductive, sensorineural or
mixed;
Branchial cysts and fistulae, external ear
malformations, renal dysplasia or hypoplasia.
Some patients also eye anomalies
Gene EYA1 on 8q13.3; encoded molecule –
transcription factor.
Inheritance autosomal dominant. Genetically
heterogenous (second BOR locus on 1p31)
Treacher-Collins syndrome
Hearing loss conductive, sensorineural or mixed;
Clinical features: down-slanting palpebral
fissures, malformation of external and middle
ears, sparse lower eyelashes and colobomata of
lower eyelids, malar hypoplasia.
Gene TCOF; encoded nuclear cytoplasmic
transport protein
Inheritance autosomal dominant
Usher syndromes
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Syndromic association of hearing loss with retinitis
pigmentosa
Accounts 2-4% of all cases of profound deafness and 50%
of the deaf-blind population
Inheritance autosomal recessive.
Genetic heterogeneity high – more than 12 loci
Clinically three main types:
TYPE
HEARING LOSS
VESTIBULAR
RESPONSE
ONSET OF REINITIS
PIGM.
I
Profound from birth
Absent
1st decade
II
Moderate from birth
Normal
1st or 2nd decade
III
Progressive
Variable
Variable
Usher syndrome
Type
Locus
Gene
Protein
USH1A
14q32
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USH1B
11q13.5
MYO7A
myozyn VIIA
USH1C
11p15.1
USH1C
harmonin
USH1D
10q21
CDH23
cadherina 23
USH1E
21q21
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USH1F
10q21-22
PCDH15
protocadherin15
USH1G
17q24-25
USH1G
SANS
USH2A
1q41
USH2A
usherin
USH2B
3p23-24.2
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USH2C
5q14.3-21.3
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USH3A
3q21-25
USH3A
clarin 1
Usher syndromes
Usher
syndrome
type
Gene
Molecule
encoded/function
clinical features
1B
MYO7A
myosin 7A (motor
molecule)
profound congenital deafness, retinitis
pigmentosa, vestibular areflexia
1C
USH1C
harmonin
1D
CDH23
cadherin 23
progfound congenital deafness, variable
retinitis pogmentosa and variable
vestibular function
1F
PCDH15
protocadherin 15
profound congenital deafness, retinitis
pigmentosa, vestibular dysfunction
2A
USH2A
usherin (extracellular
matrix protein)
congenital moderate to severe
sensorineural hearing loss (normal
vestibular function) retinitis pigmentosa
3A
USH3A
clarin 1 (transmembrane protein)
Progressive sensorineural hearing loss,
normal or absent vestibular function,
retinitis pigmentosa
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Nonsyndromic deafness: DFNA11 (dominant) and DFNB2 (recessive) results from other
alleles of MYO7A; DFNB18 results from different harmonin mutation.
Pendred syndrome
Sensorineural deafness, goiter and malformation of the inner
ear
 Hearing loss is most frequently profound, variable in its
onset, rapidly progressive
 Goiter results from a specific defect in the organification of
iodine (abnormal release of iodine trapped by thyroid after
administration of perchlorate)
 Malformation of the inner ear in 86% of cases:
dilatation of the vestibular aqueduct and endolymphatic
sacs, Mondini malformation
Inheritance autosomal recessive
Mutation of SLC26A4 gene encoding pendrin – protein
primarily involved in transport of chloride and iodide
ions.
Nonsyndromic deafness DFNB4 also result from
mutation in the SLC26A4 gene.
Jervell and Lange-Nielsen
syndrome
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Congenital sensorineural hearing loss and
prolongation of the QT interval on electrocardiogram
Hearing loss initially involves the high frequencies
and progress to become a profound
Prolongation of QT reflect a defect in cardiac
repolarization. This can lead to recurrent attacks of
syncope, ventricular arrhythmia and possible sudden
death.
Mutation in genes KCNQ4, KCNE1 coding potassium
chanels (K+ active transport in outer hair cells)
Inheritance autosomal recessive
Alport syndrome
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Association of sensorineural high frequency hearing
loss with progressive nephritis. Anterior lenticonus,
macular flecks, cataracts
Gene mutation: COL4A5, COL4A3, COL4A4 coding
tissue specific polypeptide subunits of collagen
The subunits are expressed in the basilar membrane,
spiral ligament and basement membranes of the stria
vascularis
Genetically heterogeneous. Inheritance X-linked
dominant and autosomal recessive
Stickler syndrome
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sensorineural hearing loss, high
frequency, progressive
Myopia, retinal detachment
Arthropathy
Mid-face hypoplasia, cleft palate,
micrognathia
Gene defect: COL2A1, COL11A1,
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Inheritance autosomal dominant
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COL11A2
Most important genes involved in non-syndromic hearing loss
Chromosomal
location
Locus
/mutation
Gene
symbol
Inheritance
Protein
Function
13q11-12
DFNB1/DFNA
3
GJB2
AR/AD
Conexin 26
Gap junction
GJB6
AR/AD
Conexin 30
Gap junction
7q31
DFNB4
SLC26A4
AR
pendrin
Anion transporter
14q12-13
DFNA9
COCH
AD
cochlin
Extracellular matrix
protein
mitochondriu
m
1555A>G
MTRNR1
Mitoch.
7445A>G
MTTs1
12SrRNA
tRNA serine
7472insC
7511T>C
Xq21.1
DFN3
POU3F4
XL
domain
class 3 Pou
Transcription factor
4p16.1
DFNA6/14/38
WFS1
AD
wolframin
ER transmembrane
protein
Hearing loss caused by mutation in
GJB2 (connexin deafness)
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most common cause of hearing loss in many populations
deafness usually stable, onset is nearly always prelingual (but not
necessarily congenital); hearing may be normal at birth and hearing
loss progress rapidly during first few month of life (some babies may
pass neonatal hearing screening but become deaf during infancy)
GJB2 encodes a gap junction protein – connexin 26
most common mutation is a deletion of single guanine – 35delG
(70% mutant alleles, carrier frequency 2-3%)
mutation 35delG in thought rather a founder effect not hot-spot
deletion
GJB2 mutations may also be a rare cause of autosomal dominant
deafness – syndromic and nonsyndromic (DFNA3).
Specific mutation:
- hyperkeratosis palmoplantaris
- mutilating keratoderma – (Vohwinkel sy.)
- keratoderma – ichthyosis – deafness (KID sy.)
Screening GJB2 should be offering as part of
the routine work-up in the diagnosis of all cases
of non-syndromic deafness of unknown cause.
Rationale:
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common cause of hearing impairment
phenotype unremarkable and variable
small coding region
common mutations in some populations
enables accurate genetic information to
be given to families
disadvantages: counselling difficult with missense and
heterozygous mutation
Mitochondrial hearing loss
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Sensorineural hearing loss is present in 40-70% patients with
mitochondrial disorders and can be syndromic or non-syndromic.
Mitochondrial mutations are transmitted exclusively through the
maternal line and demonstrate complete (or nearly complete)
homoplasmy.
Up to 20% patients receiving aminoglycosides experience hearing
impairment. 50% of those carry the 12S ribosomal RNA mutation
1555A>G.
Mitochondrial hearing loss may be syndromic: Kearns-Sayre sy.,
MELAS, maternally inherited diabetes and deafness, and others
Pathogenesis of mitochondrial hearing loss is based on high ATP
requirement in the cochlear hair cells. A reduction of available ATP
caused by dysfunction of the mitochondrial oxidative
phosphorylation results in disturbances of the ionic gradient in the
inner ear.