Genetics Midterm Part 1 Flashcards
Are the basic physical and functional unit of heredity. Made up of DNA, acts as instructions to make molecules called proteins.
Genes
alternate forms of a gene which occupy the same locus on homologous chromosomes. Indicated by uppercase (dominant A) and lowercase letters (recessive a)
Typically a gene will have two of these, but it is possible for three to be present
alleles
thread-like structures located inside the nucleus of cells. Made of protein and a single strand of DNA
chromosome
the specific location or position of a gene on a chromosome
locus
part of the genetic makeup of a cell, and therefore of an organism or individual, which determines a specific characteristic (phenotype) of that cell/organism/individual.
One of three factors that determine phenotype, the other two being inherited epigenetic factors, and non-inherited environmental factors
genotype
observable traits; result from interactions between your genes and the environment. Differences in some ___________, like height, are determined mostly by genes. If you have short parents and grandparents, you probably don’t tower over your peers, though environmental factors like a healthy diet might give you a little lift
phenotype
changing the function in a way that can be viewed, often a gain of function
An allele that overrules a recessive allele, and only one copy of this allele is needed to express the trait
dominant
often a loss of function
masked by a dominant allele, and both alleles must be present to express the trait.
recessive
A diploid organism is ____________ at a gene locus when its cells contain two different alleles of a gene. The cell or organism is called a ___________ specifically for the allele in question, therefore, this refers to a specific genotype
heterozygous; heterozygote
When an individual has two of the same allele, whether dominant or recessive
homozygous
containing two complete sets of chromosomes, one from each parent
diploid
term used when a cell has half the usual number of chromosomes. A normal eukaryotic organism is composed of diploid cells, one set of chromosomes from each parent. However, after meiosis, the number of chromosomes in gametes is halved contributing to this
haploid
(of a nucleus, cell, or organism) having an exact multiple of the haploid number of chromosomes
euploid
the presence of an abnormal number of chromosomes in a cell, such as having 45 or 47 chromosomes when 46 is expected. It does not include a difference of one or more complete sets of chromosomes, which is called euploidy
Aneuploid
An alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents or in the fertilized egg itself
de novo mutations
denotes the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg. Think calico cats and X inactivation. In each of our cells, one X is turned off, but it is not necessarily always the same X chromosome. Even though X chromosomes are homologous, they are different because we inherit one from each parent
may result from a mutation during development which is propagated to only a subset of the adult cells
Mosaicism
when several different genes result in one phenotype
Heterogeneity
an individual showing features characteristic of a genotype other than its own, but produced environmentally rather than genetically
Phenocopy
determined by one or more genes as well as the environment. Genes + environment = birth defects. Cleft lip/palate and spina bifida are examples, NIHL and ARHL can be too
Multifactorial Traits
One gene causes multiple phenotypic effects in the body
A mutation in this gene may have an effect on some or all traits simultaneously
ex: phenylketonuria: a human disease that affects multiple systems but is caused by one gene defect
Pleiotropy
● May be due to errors in meiosis or environmental factors
● A high contributor to miscarriages
● Occur in 2% of pregnancies in women over 35 years old
● Can be attributed to 50-70% of first-trimester miscarriages
● 7/1,000 Births
Chromosome Abnormalities
Chromosomes other than sex chromosomes. Humans have 22 pairs of this
autosomes
X and Y Chromosomes
Sex Chromosomes
part of a chromosome that links sister chromatids. During mitosis, spindle fibers attach to the __________ via the kinetochore. Note: It may not always be in the middle
Centromere
The chromosomal complement of an individual, including the number of chromosomes and any abnormalities. The term is also used to refer to a photograph of an individual’s chromosomes
Karyotype
region of repetitive nucleotide sequences at each end of a chromatid, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes
Telomere
complex of macromolecules found in cells, consisting of DNA, protein, and RNA. DNA is wrapped around a protein core (histones) and this together is __________
Chromatin
one copy of a newly replicated chromosome, which typically is joined to the other copy by a single centromere. Before replication, one chromosome is composed of one DNA (double-helix) molecule
Chromatid
highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation
histones
a tightly packed form of DNA, which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative. Both play a role in the expression of genes. Transcriptionally inactive and may have a repressive effect on nearby genes
Heterochromatin
a lightly packed form of chromatin (DNA, RNA and protein) that is rich in gene concentration, and is often (but not always) under active transcription. Comprises the most active portion of the genome within the cell nucleus
Euchromatin
Special form of cell division that reduces the number of chromosomes in half. Only occurs in gametes
Meiosis
crossing over during meiosis, exchanging material. Shuffles the genes between the two chromosomes in each pair (one received from each parent), producing chromosomes with new genetic combinations in every gamete generated
recombination
very precise, nothing lost or added
the exchange of DNA between paired homologous chromosomes (one from each parent) that occurs during the development of egg and sperm cells (meiosis
homologous crossing over
a rare process that occurs when genetic material is exchanged between non-homologous chromosomes
site-specific
nonhomologous crossing over
The farther genes are located from each other on a chromosome, the less likely it is that they will be on the piece that crosses over. The closer they are, the more likely they are linked. You can calculate this and derive a score. By calculating this you can establish the order of genes and identify hot spots and sex effects. It can be a measure of what actually happens. Greater than 3 is significant.
LOD or linkage scores
A chromosomal number that is a multiple of the normal haploid chromosome set
polyploidy (abnormal chromosome numbers in meiosis)
A chromosomal number that is not an exact multiple of the haploid set
aneuploidy (abnormal chromosome numbers in meiosis - monosomy and trisomy)
one extra chromosome of a pair; so instead of 2 chromosomes an individual has 3
trisomy
caused by an extra 21st chromosome
Trisomy 21 (Down Syndrome)
an organism has a whole extra set of chromosomes; an additional half set, so 3 of every chromosome.
Triploidy
Chromosomes don’t separate and end up in one gamete
non-disjunction
normal chromosome number
euploidy
missing a chromosome
monosomy
May have no ill effects. A chromosome rearrangement in which a segment of a chromosome is reversed end to end. Occurs when a single chromosome undergoes breakage and rearrangement within itself. Two types: paracentric and pericentric.
Inversions
- Ill effects or not viable. UV radiation is famous for creating this
- A mutation in which a part of a chromosome or a sequence of DNA is missing
- the loss of genetic material
deletions
may have no ill effect
duplications
a chromosome abnormality caused by the rearrangement of parts between nonhomologous chromosomes
translocations (reciprocal and Robertsonian)
DNA moves from one location to another
Transposons
Often associated with learning disabilities, speech-language delays, and a complex phenotype. These may not show up when looking at the karyotype
microdeletions
● Velocardiofacial, Shprintzen Sydnrome, DiGeorge Syndrome
● Rarely can be autosomal dominant but is usually de novo.
● This is the most common deletion.
● Extremely variable
● Karyotype is normal, but shows up with FISH
● Congenital heart disease in 74%
● Palatal abnormalities in 69%
● Reduced immune function
● Calcium metabolism abnormalities
● Learning difficulties in 70-90%
● Schizophrenia in 25%
● Microtia, SNHL (25%), CHL (45%), recurrent OM, possible ossicular abnormalities
22q11.2 deletion syndrome
7q11.23 deletion
Williams
A deletion syndrome. Clinical characteristics include: microcephaly, deep-set eyes, flat nose and nasal bridge, pointed chin, clefting abnormalities (17%), hypothyroidism (20%), developmental delay/MR (100%), hearing loss (82%)
Monosomy 1p36
a way to look more closely at karyotype
Can identify microdeletions/duplications and chromosome location through the use of a fluorescently labeled probe - time required to culture cells
FISH (Fluorescence in situ hybridization)
● XX and XY are both normal even though XX has twice the genes (dosage compensation)
● In XX both chromosomes can be active but one is deactivated by the epigenetic process
● Sometimes genes from a paternal or maternal source are inactivated preferentially (Imprinting)
X Chromosome Inactivation - Mosaicism
the epigenetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. If the allele inherited from the father is imprinted, it is thereby silenced, and only the allele from the mother is expressed
Imprinting
● DNA is packaged with proteins - packaging controls availability for transcription (methylation, histone modification, nucleosome positioning, small RNAs)
● Changes in packaging can be inheritable
● Can be environmentally meditated
● Sequence does not change
Epigenetics
genes are expressed differently based on the parent of origin
Epigenetics Imprinting
● Sporadic paternal chromosome deletion, maternal copy is turned off by imprinting. Signs and symptoms include: intense cravings for food, hypotonia, mild MR, and hypogonadism
● Results in obesity
● Paternal deletion
Prader-Willi Syndrome (15q11-q13 deletion)
● Deletion on the mother’s chromosome, non-functional paternally-inherited UBE3A gene in the brain. Signs and symptoms include: developmental delay, absent speech, ataxia, microcephaly, seizures, hypermotoric activity, drooling, sleep disturbance, happy demeanor with an excitable personality
● Very thin, frail body
● Maternal deletion
Angelman Syndrome (15q11-q13 deletion)
Complete set of information in an organism’s DNA. The total set of different DNA molecules in an organism. There are an estimated 21,000 genes in the human
genome
the study of genetic material recovered directly from environmental samples. The broad field may also be referred to as environmental genomics, ecogenomics or community genomics
Metagenome
DNA and RNA
nucleic acids
_________ direct development. You have your _________, and then environmental and genetic interactions can also shape your __________. The ________ contains all the genes and alleles present in an organism while the __________ is the outward expression of the genotype
Genes; genotype; phenotype; genotype; phenotype
● A project that sequenced the entire human genome.
● It took 13 years and they found about 3 billion base pairs and 21,000 genes
The Human Genome Project
Genetic information is stored in the ________ of DNA.
sequence
What are the 4 nucleotides (bases) in DNA?
Adenine, Guanine, Thymine, and Cytosine
What are the complimentary pairs of DNA bases?
A = T and C = G
Nucleotides contain a base, sugar, and phosphate. In ______, the sugar is always deoxyribose
DNA
● Made up of four types of nucleotide but the sugar is always ribose and the bases are adenine, guanine, cytosine, and uracil. Usually single-stranded
● intermediary in humans and plays many different roles
● the primary genetic material in some viruses
● in both the nucleus and cytoplasm (it can go between both and carry information). DNA is only in the nucleus
Ribonucleic Acid (RNA)
T replaced by U
RNA sequences
Two antiparallel chains. the helix is stabilized by hydrogen bonds between bases. The polar structure of DNA is directional: 5’ → 3’ (read: 5 prime)
Double helix
the relationship between 4 unit alphabet (bases) of DNA organized into triplet codons and 20 unit alphabet of proteins
genetic code
● Occurs before a cell divides and must be accurate. Existing strands are used as templates (semiconservative - meaning it doesn’t start from scratch every time).
● Requires enzymes to open up a helix (helicase is the enzyme)
DNA replication
A protein with an active job
Enzyme
● adds nucleotides that match. This process goes in a specific direction (adds 3’)
● Enzymes that create DNA molecules by assembling nucleotides, the building blocks of DNA. These enzymes are essential to this process and usually work in pairs to create two identical DNA strands from a single original DNA molecule
DNA Polymerase
Structures on chromosomes help govern replication: _________ is where spindle attaches, the ________ marks the end.
The new strand is complementary to the old strand.
centromere; telomere
Semi Conservative replication and DNA polymerase are forms of ……
Proofreading
DNA __________ moves along a single strand of DNA, building the complementary strand as it goes. The two-stranded molecule passes through the DNA polymerase molecule after _________ is complete. If the wrong base is inserted then the bond is unstable. Because the double strand is passing through the DNA polymerase the missing base can be detected and replaced. The replacement is done by a different part of the enzyme. If DNA polymerase did use single-stranded DNA as a template and the completed double strand did not continue to interact with the enzyme after synthesis then the number of errors in DNA _________ would be much higher
polymerase; synthesis; replication
● the process of combining two complementary single-stranded DNA or RNA molecules and allowing them to form a single double-stranded molecule through base pairing. In a reversal of this process, a double-stranded DNA (or RNA, or DNA/RNA) molecule can be heated to break the base pairing and separate the two strands.
● a part of many important laboratory techniques such as polymerase chain reaction and Southern blotting
Hybridization
this means you make a lot of copies
amplification (molecular or in bacteria)
● can occur in replication or meiosis
● can include chromosomal changes, changes in the number of copies of genes, or epigenetic changes
human variation
Can cause benign changes or mutations
Base changes
Single Base Changes
SNPs
○ There are about 12 million (polymorphisms, genetic variants) that occur at the level of about 1% or more in the population
○ May affect susceptibility
○ Some can be used as markers
○ Database of frequency, alleles
SNPs
● Most common genetic variation
● Change in a single base in at least 1% of the population
● Most are between genes and have no effect
Single Nucleotide Polymorphisms (SNPs)
A group of specific alleles at neighboring genes or markers that tend to be inherited together
haplotype
Genome wide database of patterns of common human genetic sequence variation among multiple ancestral population samples
HapMap
genome wide association studies
GWAS
● Diagnosis and prediction of disease and disease susceptibility, ancestry
● Prediction of risk of many conditions - no evidence based guidelines for use yet
● Intervention
● Identification of genes that cause HL
● Identification of genes that are involved in development of the auditory system
Why SNPs matter
may be conserved, unique, or transcribed - it has a function that has not been identified yet
Noncoding DNA
○ Usually not the primary genetic sequence
○ Made in the nucleus but can travel into the cytoplasm
○ Many functions (messenger, factory, regulation)
○ Managed by different enzymes
○ If something goes wrong in RNA you will see the results very clearly
Functional differences between DNA and RNA
translation, protein synthesis
Messenger RNA (mRNA), Ribosomal RNA (rRNA), Transfer RNA (tRNA)
regulatory
microRNA (miRNA) and small interfering (siRNA)
RNA that carries information
mRNA
control of gene expression and other processes
regulatory functions
Translation machinery
rRNA and tRNA
● how you get RNA
● Copying one strand of DNA into a complementary RNA sequence by RNA polymerase
● Copy just a short piece (single gene) when it is needed (rate, time)
● DNA is the library book, while RNA is the disposable and edited xerox copy
● very specific
Transcription
genes are usually turned off, control is multiple and combinatorial
Transcriptional control
______ ___________ tell RNA polymerase when to start and stop - promoter, enhancer. Not all __________ are equally effective. Sometimes the problem can be degree instead of presence
DNA sequences; promoters
● mRNA is processed as it is made
● 5’ capping (methylated G, 1st modification)
● 3’ polyadenylation
● Exons and Introns - RNA splicing
*All of this happens in the nucleus. RNA loses exons before it leaves the nucleus.
So, one genes may produce several related proteins
RNA Processing
the process by which cellular ribosomes create proteins. This may be turned up or down
Controls Protein folding, modification, associations and deployment
Translation
Sequence is read as codons
Details of transcription and translation
start and stop codons
Reading frame of the mRNA
a 3 nucleotide sequence corresponding to a tRNA attached to an amino acid
codons
● Can be a heritable change in genotype, change in DNA base sequence, affects phenotype, and may be conditional (may only show up under certain circumstance).
● Single base pair change: UV and mutagens or spontaneous changes
● may be due to multiple base pairs, repeats, or chromosomal.
● may be in the exons (translated or untranslated), splice site, or promoter or regulatory site.
● may affect the sequence and/or shape of a protein (protein shape very important), transcriptions
mutations
depend on where the mutation occurs and how big it is
outcomes of mutation
most damaging and can often lead to a nonsense mutation (it can introduce a premature stop codon in the DNA sequence, causing translation to end early and resulting in a truncated protein)
a genetic mutation that occurs when a DNA sequence’s nucleotide bases are inserted or deleted in a number that is not a multiple of three. This disrupts the reading frame of the DNA sequence, which can lead to a variety of problems
Frameshift mutation
a term used to describe a deletion mutation that doesn’t disrupt the reading frame of a gene. Protein still functional, even though it may be shorter than normal (could still lead to the production of dysfunctional or unstable proteins, even though the body can still express a normal amount of protein.)
in-frame (missense mutation)
a type of genetic variation that occurs when a single base pair in a DNA sequence is substituted, resulting in a different amino acid being incorporated into a protein
missense (addition or deletion of entire codon)
create a stop codon, which can prevent the protein from being produced entirely
a DNA sequence change that causes a protein to end its translation early, resulting in a shorter and potentially nonfunctional protein
truncating mutation
non-sense mutation
a genetic mutation that disrupts the reading frame of a gene, preventing it from being read in triplets
Will almost always lead to a nonsense mutation
out-of-frame mutation
a mutation that exchanges one base for another (i.e., a change in a single “chemical letter” such as switching an A to a G). Such a substitution could: change a codon to one that encodes a different amino acid and cause a small change in the protein produced
Substitution (missense)
happens when a section of DNA breaks away and reattaches to the chromosome in a reversed order
Inversion Mutation
a genetic variant that results in a shorter version of a protein being produced. This can happen when a DNA sequence change creates an early stop codon, which ends translation and produces a shortened protein
Truncating mutation
a mutation that doesn’t completely inactivate a protein, and is associated with milder kidney disease
Can include in-frame insertions or deletions (indels) and substitutions
Non-truncating mutations
● Changes in many genes (chromosomal level)
● Mutation in a transcription factor (one gene) or in genes along a developmental pathway
● Mutation in a gene responsible for a fundamental process/structure (WFS1)
Causes of syndromes
Genetic change in one component may affect long term function, but initially the function may be present. An example is muscular dystrophy (dystrophin essential not for initial function, but for repeated function
Complex structures
An example of a locus would be 3q25, which means the _________ is on the long arm of ___________ 3, 25 places out from the ___________
gene; chromosome; centromere
deafness gene
how nonsyndromic loci are labeled: DF
DFN, DFX
how nonsyndromic loci are labeled: X linked deafness gene
DFNA
how nonsyndromic loci are labeled: dominant deafness gene
DFNB
how nonsyndromic loci are labeled: recessive deafness gene
DFNM
how nonsyndromic loci are labeled: modifier
a nonsyndromic recessive deafness gene that was the first of its kind to be mapped
The gene name is “gap junction protein, beta 2, 26kDA” and the gene symbol is GJB2
Located on chromosome 13q11-q12
DFNB1 (Connexin 26)
● variable
● post-lingual
● progressive
Autosomal dominant
● more severe
● congenital
● stable
Autosomal recessive
● Most common nonsyndromic SNHL (40-50% of recessive nonsyndromic HL in US)
● ⅓ of ALL genetic HL; Over 10% of ALL congenital HL
● Typically congenital, severe to profound stable sloping SNHL
● However, there is variability in the phenotype (even in the same family) and it may not be recognized initially
● The inheritance is Autosomal Recessive
● Homozygous and biallelic frequent, also rare digenic inheritance
● Carrier frequency: 1/33 in some north american populations, in Belarus it is >1/20
● It is a small gene (Exon 1 ~ 3000 bp, Exon 2 ~ 681 bp)
● Over 100 mutations, polymorphisms (mostly exon 2 (expressed) but also splice site in Exon1 and also in intron)
Connexin 26/ Cn26/ GJB2/ DFNB1
GJB2 (98%) connexin 26, DFNB1a
GJB6 (2%) connexin 30, DFNB1b
DFNB1 includes both
○ Single large, translated exon, untranslated exon
○ coding sequence of GJB2 (exon 2): 681 base pairs (including the stop codon) and is translated into a 226 amino acid protein
○ GJB6 contains a promoter of GJB2 expression
The gene product of Connexin 26
○ Even though the deletion does not extend into GJB2, that GKB2 gene is not expressed
○ So, if heterozygous condition with a mutation like 35delG on one chromosome and a GJB6 deletion on the other, there is no useable connexin 26 protein
Effect of GJB6 Deletions
2 different genes
Digenic
2 different alleles, 1 gene. Many variations in Cx26
Biallelic
○ At least 20 in humans
○ Cochlea is involved mostly with 26, 30, and 31
○ Gap junction components -Passage of ions and small molecules; Regulated
○ Mutations responsible for disease in epithelia, eye, ear, and nervous system
The role of Connexins
Human connexins involved in syndromic hearing loss:
Cx26 → GJB2 → _______ (recessive), _______ (dominant)
DFNB1; DFNA3
Human connexins involved in syndromic hearing loss:
Cx30 → GJB6 → ________, ________
DFNA3; DFNB1
Human connexins involved in syndromic hearing loss:
Cx31 → GJB3 → ________ , an unnamed recessive form
DFNA2
Human connexins involved in syndromic HL
Cx26 → GJB2 →
Vohwinkel, KID, Bart-Pumphrey, PPK/DDFN (all dominant)
Human connexins involved in syndromic HL
Cx30 → GJB6 →
KID (mild-moderate HL)
Human connexins involved in syndromic HL
Cx31 → GJB3 →
Mild HL with mixed neuropathy
Human connexins involved in syndromic HL
Cx32 → GJB1 →
X-linked Charcot-Marie-Tooth disease
Human connexins involved in syndromic HL:
Cx43 → GJA1 →
occulo-dento-digital dysplasia (conductive HL)
the connection of cells
The function of connexin
○ Cx26 and Cx30 ________ channels differ in transfer of larger molecules
○ _________ channels show faster intercellular Ca2+ signaling (inositol) than __________ counterparts
homomeric; Heteromeric; homomeric
Made up of multiple units of the same protein
Ex: gap junction channels made up of a single type of connexin protein
Homomeric channels
Made up of two or more different types of proteins
Ex: gap junction channels made up of two or more different types of connexin proteins.
Heteromeric channels
○ Conduits for the circulation of potassium ions in the inner ear
○ Maintenance of the endothelial barrier (capillaries) in the stria vascularis
Function: Intercellular ionic coupling
○ Mutations reduce permeability
○ Cx26 mutation (V84L) represses an intercellular calcium wave
○ Messenger for apoptosis
Function: Biochemical coupling
○ Decreases K+ recycling
○ Impairs CCa+ signaling
○ Affects endocochlear potential
○ Affects developmental process
Postulated Pathophysiology
○ Not directed to the cell membrane
○ Gets to membrane but can’t form channels
○ Permeable to ions but not small molecules
○ Can’t form heterotypic channels, hemichannels, ot stable channels
○ But not the expected relationship for genotype: phenotype
Effects of mutation
● Severe to profound HL
● Congenital, prelingual
● Symmetric
Typical Phenotype of truncating frameshift mutation (35delG)
● Variable audiologically
● Vestibular dysfunction not prominent
● Associated disabilities not prominent
● mid frequency hearing loss is rare
● Fluctuation with improvement is rare
● Usually but not always symmetrical
● Good CI results
Phenotype of GJB2 and GBJ6
may have poorer hearing compared to controls
○ Differences in OAEs
○ high frequencies
○ extended high frequencies
Cx26 Heterozygotes
characterized by childhood-onset, progressive, moderate-to-severe high-frequency SNHL. Affected individuals have no other associated medical findings
DFNA3 (autosomal dominant non-syndromic hearing loss 3A)
X linked Charcot-Marie-Tooth (degeneration of peripheral nervous system, more than 40 other genes can cause this as well)
Connexin 32
cochlear schwann cells
Connexin 29 GJC3
○ GJB2 and GJB6
○ Early testing only looked for common allele
○ One pitfall is ethnicity
○ Now the standard is to sequence GJB2 completely
Molecular testing
confirm or establish diagnosis, estimate prognosis, plan habilitation, rehabilitation, answer questions, rule out syndromes
Why test: diagnostic
carrier, prenatal
Why test: predict risk
○ Does not necessarily find the answer
○ Severity of HL may not be predicted
○ A person may have mutations but not have HL
○ May have regulatory elements outside of the sequence
○ Negative results do not exclude a genetic basis
Limitations of genetic testing
used to look at copy number variants as small as a single exon by using two specific probes that flank the area of interest which is filled by a specific enzyme and the resulting linked piece of DNA is amplified and compared to controls (if exon is missing, the non linked probes are not amplified
Multiplex ligation-dependent probe amplification (MLPA)
● Congenital severe-to-profound SNHL
● Product is myosin XV
● Interacts with whirlin at tip of stereocilia, probably leading to elongation
MYO15A, DFNB3
● Myosin that moves things in cells
● Affects stereocilia in hair cells and retinal pigmented cells
MYO7A (DFNA11 DFNB2, Usher Syndrome I)
Gene: SLC26A4
21 exons
780 amino acid transmembrane anion transporter protein pendrin
Anion exchanger: CI lodide, HCO3
Role in maintaining the endocochlear potential
Found in thyroid, inner ear, and kidney
PDS (Pendred Syndrome) and DFNB4
● Over 160 mutations
● Mostly missense, but can be deletions and duplications
● SLC26A4 is about 50%, sometimes only 0 or 1 mutations, some deletions
● FOXI1 is about 1% (transcription factor that binds to the promoter region of SLC26A4)
● KCNJ10 is about 1%
● Can be digenic
● likely additional genetic heterogeneity
Genotype of DFNB4/PDS
● Huge spectrum
● For both it is often congenital, bilateral SNHL, often severe to profound, can be mild-moderate
● May be fluctuating or progressive
● May have vestibular dysfunction
● may have EVA ot other temporal bone abnormalities
● PDS Only: incompletely penetrant euthyroid goiter, usually developing teens - 20s and often mondini dysplasia
Phenotype DFNB4/PDS
● Two mutant alleles of SLC26A4 correlated with bilateral EVA and PDS
● One (M1) or zero (M0) mutant alleles of SLC26A4 correlated with unilateral EVA and NSEVA
● Goiter - correlated with two mutant alleles of SLC26A4 in pediatric patients, but not in older patients
More Genotype/Phenotype
● If bilateral EVA is present, then there is significantly higher likelihood of having SLC26A4 mutations and of having Pendred syndrome
● If unilateral EVA, PDS not likely
● Presence of mutations overall did not increase the likelihood of progressive hearing loss or the severity of hearing loss in either EVA group
● Audiometric phenotype overlapped in patients with unilateral and bilateral EVA
● Development of hearing loss or hearing loss progression is high in the ear without EVA in unilateral cases
Greinwald Study 2013
● Confusing, possible that DFNB4 will turn into PS with age
● Can have EVA without SLC264A or PDS
Genotype DFNB4, PDS, EVA
● Incompletely penetrant
● Highly variable in severity and frequency
● Abnormal testing frequent in patients without subjective dizziness
High incidence of increased amplitude and decreased thresholds on VEMPS w/EVA
Vestibular Results EVA
Product is Cadherin 23
Bilateral moderate-to-profound progressive SNHL, prelingual
SNHL, retinitis pigmentosa, and vestibular dysfunction in USher
CDH23, DFNB12, Usher ID
Product is stereocilin (hair cells)
15q15.3 (also infertility)
Severe to profound prelingual hearing loss
Some estimates of 1% carrier prevalence
Relatively common but hard to test for
STRC, DFNB16
the T (thymine) at position 167 of the connexin 26 sequence has been deleted
Jewish
Frameshift mutation
HL variable
167delT
the G (guanine) at position 35 of the connexin 26 sequence has been deleted
European
Severe to Profound deafness
Frameshift mutation
35delG
the C (cytosine) at position 235 of the connexin 26 sequence has been deleted
East Asian population
Congenital or postlingual HL
Asymmetrical HL
Severe to profound HL along with other HL ranges
Frameshift mutation
235delC
methionine-to-threonine substitution at amino acid 34 of the GJB2 gene
Missense mutation
French or Belgium?
Mild to moderate HL
VUS (variant of unknown significance)
M34T
valine-to-isoleucine substitution at amino acid 37 of the GJB2 gene
East and Southeast Asians
Associated with mild to moderate hearing loss
a missense mutation in the connexin 26 (GJB2) gene
V37I
missense substitution at position 143, where R (Arginine) is replaced by W (Tryptophan)
Ghana (Africa)
Profound HL
R143W
