18 - Genetics in Relation to the Skin Flashcards
The genetic basis of more than 2000 inherited single gene disorders has now been determined, of which _____% have a skin phenotype
25
The human genome:
_____ chromosomes
_____ pairs of autosomes
_____ sex chromosomes
46
22
2
Autosomes are numbered in (ascending/descending) order of size
Largest: chromosome _____
Smallest: chromosome _____
Descending
1
22
_____% of the genome corresponds to protein-encoding exons
1.5
As much as _____% of the genome is of unknown function, often referred to as “junk” DNA
97
Number of human genes
20,000-25,000
Y/N: The human genome is comparable in size and complexity to that of primitive organisms such as the fruit fly
Yes
Two chromosomal arms
“p” or short arm
“q” arm
The bands are numbered from the centromere (outward/inward)
Outward
Ends of the chromosomal arms
Consist of multiple tandem repeats of short DNA sequences
Telomeres
Additional repeats are added to telomeres by a protein-RNA enzyme complex known as
Telomerase
By measuring the _____, the “age” of somatic cells, in terms of the number of times they have divided during the lifetime of the organism, can be determined
Length of telomeres
The chromosome arms are separated by the ______, which is a large stretch of highly repetitious DNA sequence
Centromere
Where the double chromosomes align and attach during the prophase and anaphase stages of mitosis (and meiosis)
Site of kinetochore formation
Centromeres of sister chromatids
Multiprotein complex to which microtubules attach, allowing mitotic spindle formation, which ultimately results in pulling apart of the chromatids during anaphase of the cell division cycle
Kinetochore
Collectively code for the amino acid sequence of the protein (or open reading frame)
Exons
Exons are separated by noncoding
Introns
Y/N: Although all genes are present in all human cells that contain a nucleus, not every gene is expressed in all cells of tissues
Yes
The _____ enzyme transcribes the coding strand of the gene, starting from the cap site and continuing to the end of the final exon
RNA polymerase II
Initial RNA transcript
Contains intronic as well as exonic sequences
Heteronuclear RNA
The primary transcript undergoes splicing to remove the introns, resulting in the _____ molecule
Messenger RNA
The bases at the 5’ end (start) of the mRNA are chemically modified
Capping
A large number of adenosine bases are added at the 3’ end known as the
Poly-A tail
If the mRNA contains a nonsense mutation, otherwise known as a ______, the test round of translation fails
Premature termination codon mutation
The genes of prokaryoted, such as bacteria, do not contain ______, so ______ is a process that is specific to higher organisms
Introns
mRNA splicing
In some more primitive eukaryotes, RNA molecules contain catalytic sequences known as _____, which mediate the self-splicing out of introns
Ribozymes
Y/N: A single gene can encode several functionally distinct variants of a protein
Yes
Base pairs at the beginning of an intron
5’ splice site or splice donor site
Base pairs at the end of an intron
3’ splice site or splice acceptor site
The mRNA contains two untranslated regions (UTR)
- 5’ UTR upstream of the initiating ATG codon
2. 3’ UTR downstream of the terminator
Stop codon
TGA
TAA
TAG
Whereas the _____ UTR can and often does possess introns, the _____ UTR of more than 99% of mammalian genes does not contain introns
5’
3’
The natural stop codon is always followed immediately by the
3’ UTR
Gene expression is largely determined by the _____ elements of the gene
Promoter
In general, the most important region of the promoter is the stretch of sequence immediately upstream of the
Cap site
Proteins that either bind to DNA directly or indirectly by associating with other DNA-binding proteins
Binding of these factors to the promoter region of a gene leads to activation of the transcription machinery
Transcription factors
Involves studying pedigrees of affected and unaffected individuals and isolating which bits of the genome are specifically associated with the disease phenotype
Genetic linkage
Involves first looking for a clue to the likely gene by finding a specific disease abnormality
Candidate gene approach
Genetic code of two healthy individuals may show a number of sequence dissimilarities that have no relevance to disease or phenotypic traits
Polymorphisms
Single nucleotide polymorphisms do not change the amino acid composition
Silent mutation
Some single nucleotide polymorphisms do change the nature of the amino acid
Missense change
Mutations which lead to premature termination of translation
Nonsense mutations
Deletion of _____ nucleotides (or multiples thereof) will not significantly perturb the overall reading frame
Three
Half the normal amount of protein is insufficient for function
Haploinsufficiency
Alterations in the gene sequence close to the boundaries between the introns and exons
Splice site mutations
Y/N: Mutations within one gene do not always lead to a single inherited disorder
Yes
Other transacting factors may further modulate phenotypic expression
Allelic heterogeneity
Some inherited diseases can be caused by mutations in more than one gene
Genetic (or locus) heterogeneity
The same mutation in one particular gene may lead to a range of clinical severity in different individuals
Variability in phenotype produced by a given genotype
Expressivity
If an individual with such a genotype has no phenotypic manifestations
Nonpenetrant
Four main patterns of inheritance
Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive
One parent is affected unless there has been a de novo mutation in a parental gamete
Males and females are affected in approximately equal numbers
Can be transmitted from generation to generation
Autosomal dominant
In affected individuals with autosomal dominant disorders, the risk of transmitting the disorder is _____% for each of their individual
50
Any offspring that are affected by an autosomal dominant disorder will have a _____% risk of transmitting the mutated gene to the next generation, but for any unaffected offspring, the risk of the next generation being affected is _____
50
Negligible
Distinguish autosomal dominant from X-linked dominant disorders
Best hallmark of autosomal dominant inheritance
Male-to-male transmission
Phenotype in heterozygous individuals is less than that observed for homozygous subjects
Semidominant
Both parents are carriers of one normal and one mutated allele for the same gene, and typically, they are phenotypically unaffected
Autosomal recessive
If both mutated alleles from both parents are transmitted to the offspring, this will give rise to an autosomal recessive, the risk of which is _____%
25
Mutations from both parents are the same
Homozygote
Different parental mutations within a gene have been inherited
Compound heterozygote
More common in consanguineous families
Autosomal recessive
If the partner of an individual with an autosomal recessive disorder is also a carrier of the same mutation, albeit clinically unaffected, then there is a 50% chance of the offspring inheriting two mutant alleles and therefore also inheriting the same autosomal recessive disorder
Pseudominant
Examples of autosomal recessive disorders
Lamellar ichthyosis
Xeroderma pigmentosum
Junctional epidermolysis bullosa
Kindler syndrome
Examples of X-linked dominant disorders
Conradi-Hunermann-Happle syndrome
Incontentia pigmenti
Focal dermal hypoplasia
X-linked dominant protoporphyria
Occur almost exclusively in males, but the gene is transmitted by carrier females, who have the mutated gene only on one X chromosome (heterozygous state)
X-linked recessive
Normally random process that inactivates either the wild-type or mutated X chromosome in each cell during the first weeks of gestation and all progeny cells
In X-linked recessive disorders, females can show some features because of this
Lyonization
Examples of X-linked recessive disorders
Hypohidrotic ectodermal dysplasia X-linked ichthyosis Wiskott-Aldrich syndrome Fabry disease Menkes syndrome
Abberations in chromosome number or structure occur in about _____% of all conceptions, although most of these lead to miscarriage, and the frequency of chromosomal abnormalities in live births is about _____%
6
0.6
Number and arrangement of the chromosomes
Karyotype
Most common chromosomal numerical abnormality
Trisomy
Presence of an extra chromosome
Trisomy
Loss of a complete chromosome
Monosomy
Loss of part of a chromosome
Deletion
If two chromosomes break, the detached fragments may be exchanged
Reciprocal translocation
If translocation involves no loss of DNA
Balanced translocation
Inheritance of both copies of a chromosome pair from just one parent
Uniparental disomy
Presence of a pair of chromosome homologs from just one parent
Uniparental heterodisomy
Two identical copies of a single homolog from just one parent
Uniparental isodisomy
Mixture uniparental heterodisomy and uniparental isodisomy
Meroisodisomy
Uniparental disomy can result in distinct phenotypes depending on the parental origin of the chromosomes
Means that, during development, the parental genomes function unequally in the offspring
Genomic imprinting
Most common examples of genomic imprinting
Prader-Willi and Angelman syndromes
Can result from maternal uniparental disomy for chromosome 15
Prader-Willi syndrome
Can result from paternal uniparental disomy for chromosome 15
Angelman syndrome
Three phenotypic abnormalities commonly associated with uniparental disomy for chromosomes with imprinting
- Intrauterine growth retardation
- Developmental delay
- Short stature
Small head with flat face Short and squat nose Ears small and misshape Slanting palpebral fissures Thickened eyelids Eyelashes short and sparse Shortened limbs, lax joints Fingers short, sometimes webbed Hypoplastic iris, lightee outer zone (Brushfield spots)
Trisomy 21
Down syndrome
Severe mental deficiency Abnormal skull shape Small chin, prominent occiput Low-set, malformed ears “Rocker bottom” feet Short sternum Malformations of internal organs Only 10% survive beyond first year
Trisomy 18
Edwards syndrome
Mental retardation Sloping forehead because of forebrain maldevelopment (holoprosencephaly) Microphthalmia or anophthalmia Cleft palate or cleft lip Low-set ears “Rocker bottom” feet Malformations of internal organs Survival beyond 6 months is rare
Trisomy 13
Patau syndrome
Microcephaly Mental retardation Hypospadias Cleft lip or cleft palate Low-set ears, preauricular pits
Chromosome 4, short arm deletion
Mental retardation
Microcephaly
Cat-like cry
Low-set eats, preauricular skin tag
Chromosome 5, short arm deletion
Hypoplasia of midface
Sunken eyes
Prominent ear antihelix
Multiple skeletal and ocular abnormalities
Chromosome 18, long arm deletion
Early embryonic loss; prenatal ultrasound findings of cystic hygroma, chylothorax, ascites and hydrops
Short stature, amenorrhea
Broad chest, widely spaced nipples
Wide carrying angle of arms
Low misshapen ears, high arched palate
Short fourth and fifth fingers and toes
Skeletal abnormalities, coarctation of aorta
45 XO
Turner syndrome
No manifestations before puberty
Small testes, poorly developed secondary sexual characteristics
Infertility
Tall, obese, osteoporosis
47 XXY
Klinefelter syndrome
Similar to Klinefelter syndrome
48 XXYY
Phenotypic males (tall)
Mental retardation
Aggressive behavior
47 XYY
Low birth weight
Slow mental and physical development
Large, low-set, malformed ears
Small genitalia
49 XXXXY
Mental retardation
Mild dysmorphism
Hyperextensible joints, flat feet
Fragile X syndrome
An affected male transmits the disorders to all his daughters and to none of his sons
Almost always limited to females; affected males may be aborted spontaneously or die before implantation
X-linked dominant
Examples of autosomal dominant disorders
Icthyosis vulgaris Neurofibromatosis Tuberous sclerosis Darier disease Hailey-Hailey disease
Segmental mosaicism for autosomal dominant disorders is thought to occur in one of two ways:
- Type 1 - postzygotic mutation with the skin outside the segment and genomic DNA being normal
- Type 2 - heterozygous genomic mutation in all cells that is then exacerbated by loss of heterozygosity within a segment or along the lines of Blaschko
Lines of migration and proliferation of epidermal cells during embryogenesis
Lines of Blaschko
Refers to genetic correction of an abnormality be various different phenomena
Revertant mosaicism
Natural gene therapy
Mosaicism can also be influenced by environmental factors
Epigenetic mosaicism
The human leukocyte antigen is located on the short arm of chromosome 6, at 6p21, referred to as
Major histocompatibility
Three classic loci at HLA class I
HLA-A
HLA-B
HLA-Cw
Five loci at HLA class II
HLA-DR HLA-DQ HLA-DP HLA-DM HLA-DO
Contributes to defining a unique “fingerprint” for each person’s cells, which allows an individual’s immune system to define what is foreign and what is self
HLA molecules
HLA haplotype: psoriasis
HLA cw6
HLA haplotype: alopecia areata
HLA DWB1*03
HLA DR4
HLA DQ7
HLA haplotype: psoriatic arthropathy
HLA B27 HLA B7 HLA B13 HLA B16 HLA B38 HLA B39 HLA B17 HLA cw6
HLA haplotype: dermatitis herpetiformis
HLA DQw2
HLA haplotype: pemphigus
HLA DR4
HLA DQ1
HLA haplotype: reactive arthritis syndrome
HLA B27
HLA haplotype: Behcet disease
HLA B51
HLA haplotype: increased risk for carbamazepine-induced SJS and TEN
HLA-B*1502
Additional influences at the biochemical, cellular, tissue, and organism levels occur
Epigenetic phenomena
Mammalian DNA methylation machinery is made up of two components
- DNA methyltransferases
2. Methyl-CpG-binding proteins
Establish and maintain genome-wide DNA methylation patterns
DNA methyltransferases
Involved in scanning and interpreting the methylation patterns
Methyl-CpG-binding proteins
Analysis of any changes in DNA methylation
Epigenomics
DNA (hyper-/de-)methylation contributes to gene silencing by preventing the binding of activating transcription factors and by attracting repressor complexes that induce the formation of inactive chromatin structurez
Hyper
Fetal DNA from amniotic cells taken at
16 weeks AOG
Fetal DNA from samples of chorionic villi taken at
10-12 weeks AOG
Treatment of (dominant/recessive) genetic diseases with gene therapy are generally technically more feasible than treatment (dominant/recessive) genetic conditions
Recessive
Dominant
Treatment of dominant-negative genetic disorders
Patients already carry one normal copy of the gene as well as one mutated copy - where one normal allele is sufficient for skin function, suppression of expression of the dominant negative mutant allele should be therapeutically beneficial
Gene inhibition therapy
Using an (in vivo/ex vivo) approach, the gene therapy agent would be delivered directly to the patient’s skin or another tissue
In vivo
In an (in vivo/ex vivo) approach, a skin biopsy would be taken. Keratinocytes or fibroblasts would be expanded in culture, treated with the gene therapy agent, and then grafted onto or injected back into the patient
Ex vivo
Expressing the normal complementary DNA encoding the gene of interest from some form of gene therapy vector adapted from viruses that can integrate their genomes stably into the human genome
Gene replacement therapy
Small synthetic double-stranded RNA molecules of 19 to 21 bp that can efficiently inhibit expression of human genes in a sequence-specific, user-defined manner
Short inhibitory RNA
Main obstacles in developing topical short inhibitory RNA therapied
Rapid degradation
Poor cellular uptake
Mitochondrial disorders are inherited solely from the
Mother
Mitochondrial DNA has the capacity to form a mixture of both wild-type and mutant DNA within a cell, leading to cellular dysfunction only when the ratio of mutated to wild-type DNA reaches a certain threshold
Heteroplasmy
Predominant technology for mapping complex diseases
Genome-wide association studies
Involves collecting DNA from a well-phenotyped case series of the condition of a choice, preferably from an ethnically homogenous population
Genome-wide association studies
Currently the method of choice in mapping complex disease genetics
Single nucleotide polymorphisms-based genome-wide association studies
Presence of a mixed population of cells bearing different genetic or chromosomal characteristics leading to phenotypic diversity
Mosaicism
Mosaicism for a single gene
Indicates a mutationsl event occurring after fertilization
Somatic mosaicism
The (earlier/later) mosaicism occurs, the more likely it is that there will be clinical expression of a disease phenotype as well as involvement of gonadal
Earlier
Mosaicism with involvement of both gonads and somatic tissue
Gonosomal mosaicism
Mosaicism the occurs eclusively in gonadal tissue
Gonadal mosaicism
