international conference diagnosis & treatment of inner ear disorders genetics of deafness lech...
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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 deaf1 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 lossapproximately 1% of all human genes are involved in the hearing process
inheritance: autosomal recessive autosomal dominant X-linked mitochondrial
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:
* 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– 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/function
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 EDN3EDNRBSOX10
endothelin ligandendothelin receptortranscription factor
Abnormal pigmentation of hair, eyes and skin with Hirschprung disease
EDN3 EDNRB3
WS 1WS 3
PAX 3 SOX 10 WS 4
transactivation
WS 2 MITF
melanocyte tyrosinase
transactivation
Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3
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 anomaliesGene EYA1 on 8q13.3; encoded molecule – transcription factor. Inheritance autosomal dominant. Genetically heterogenous (second BOR locus on 1p31)
Treacher-Collins syndromeHearing loss conductive, sensorineural or
mixed;Clinical features: down-slanting palpebralfissures, malformation of external and middleears, sparse lower eyelashes and colobomata
oflower eyelids, malar hypoplasia.Gene TCOF; encoded nuclear cytoplasmic transport proteinInheritance autosomal dominant
Usher syndromes* 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 lociClinically 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 - -
USH1B 11q13.5 MYO7A myozyn VIIA
USH1C 11p15.1 USH1C harmonin
USH1D 10q21 CDH23 cadherina 23
USH1E 21q21 - -
USH1F 10q21-22 PCDH15 protocadherin15
USH1G 17q24-25 USH1G SANS
USH2A 1q41 USH2A usherin
USH2B 3p23-24.2 - -
USH2C 5q14.3-21.3 - -
USH3A 3q21-25 USH3A clarin 1
Usher syndromesUsher 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 (trans-membrane protein)
Progressive sensorineural hearing loss, normal or absent vestibular function, retinitis pigmentosa
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 malformationInheritance autosomal recessiveMutation of SLC26A4 gene encoding pendrin – proteinprimarily involved in transport of chloride and iodideions. Nonsyndromic deafness DFNB4 also result from mutation in the SLC26A4 gene.
Jervell and Lange-Nielsen syndrome
* 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 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– sensorineural hearing loss, high
frequency, progressive– Myopia, retinal detachment– Arthropathy– Mid-face hypoplasia, cleft palate,
micrognathia– Gene defect: COL2A1, COL11A1,
COL11A2 – Inheritance autosomal dominant
Most important genes involved in non-syndromic hearing loss
Chromosomal location
Locus/mutation
Gene symbol
Inheritance Protein Function
13q11-12 DFNB1/DFNA3
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
mitochondrium
1555A>G MTRNR1 Mitoch. 12SrRNA
7445A>G MTTs1 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)
– 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: - 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– 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.