Single Gene Disorders: Sex Linked Dominant and Recessive Inheritance Flashcards
how many genes on the X chromosome?
900-1400
how many genes on Y chromosome and why is it important?
70-200, includes SRY gene that makes males, father determines the sex of the child!
what does sex linked inheritance refer to?
inheritance pattern of a disease that is caused by mutation of a gene present on the X chromosome
what would you look for to determine X-linked dominant inheritance?
- seen in successive generations (at least 1 individual)
- seen twice as often in females
- ALL daughters of affected males are affected
- NO male to male transmission
- both sons and daughters of affected heterozygous female may be affected
examples of X-linked dominant diseases
- Rett syndrome
- hypophosphatemic rickets/vitamin D resistant rickets
- Fragile X syndrome
what causes Rett syndrome??
mutations in MECP2 gene
what does the MECP2 gene do?
binds methylated DNA sequence (CpG-rich regions) and recruits proteins to help repress transcription in the brain specifically
what occurs if MECP2 is not present/deficient
genes inappropriately expressed during brain development
who is commonly affected by Rett syndrome?
mostly females, because mutation is lethal if a normal allele is not present (males generally don’t survive to term)
why are males unlikely to survive with Rett Syndrome?
not viable unless 1 unaffected X allele, and males only have the 1 X.
symptoms of Rett syndrome
- spastic and ataxic
- development of autistic behavior
- wringing or flapping movements of hands
- microcephaly
- seizures
- mental deterioration
what is vitamin D resistent rickets?
hereditary hypophosphatemic rickets, mutations in PHEX gene
what does PHEX encode?
phosphate regulating neutral endopeptidase
what does mutation of PHEX indicate?
cannot regulate phosphate, so low serum phosphate
symptoms of vitamin D resistent rickets
- slow growth
- short stature
- bone abnormalities
- hypophosphatemia with low phosphate reabsorption
how to determine X-linked recessive?
- more affected males than females
- heterozygous females usually unaffected, but may show symptoms due to X-inactivation
- affected father will pass mutation to ALL daughters, who will be carriers
- NEVER transmitted from father to son
- affected males inherit disease through females who are carriers
most common bleeding disorder
hemophilia A
what is hemophilia A?
mutation in gene encoding clotting factor VIII
who was the first known carrier of hemophilia A?
Queen Victoria
characteristic of hemophilia A?
all affected individuals are MALE
symptoms of hemophilia A
- severe bleeding
- bruising
- hemarthroses
- intracranial hemorrhages
most prevalent forms of muscular dystrophy?
- duchenne muscular dystrophy
2. becker muscular dystrophy
inheritability of muscular dystrophy?
X linked recessive, predominantly affects males, but heterozygous females displace a small degree of muscle weakness
what causes duchenne and becker muscular dysrophies?
mutations in DMD gene, which encodes protein dystrophin
what does dystrophin do?
connects actin skeleton inside the cell to the extracellular matrix and plays a key role in maintaining the structural integrity of muscle cells
describe the mutation of DMD in Duchenne ?
deletions or duplications in DMD gene that PRODUCES FRAMESHIFT MUTATIONS.
a truncated non-functional dystrophin protein is produced, which is degraded by the cell
therefore, no protein is present, resulting in severe phenotype
is DMD produced in Duchenne?
no protein is present, resulting in severe phenotype
describe the mutation of DMD in Becker?
deletions or duplications in DMD but they do NOT cause frameshift mutations.
therefore, dystrophin protein is made, but has reduced function
less severe phenotype
is DMD produced in Becker?
yes, but reduced function, therefore less severe phenotype
most striking symptom of Duchenne MD?
- elevated (20x) creatine kinase levels in plasma due to death of muscle cells, can be detected presymptomatically and can be officially diagnosed by genetic testing
when do symptoms appear for Duchenne MD and what are they?
before 5yo
- delayed motor skill development
- unstable gait
- use of the Gower maneuver to stand (using hands and arms to walk up their body from a squatting to standing due to lack of hip and thigh strength)
- wheelchair bound by 12yo
- progressive heart and respiratory impairment
- death by 25yo due to respiratory or cardiac failure
which MD is more common?
Duchenne
describe symptoms of Becker MD
less severe than Duchenne, and slower progression (ataxia pretty much)
why do Duchenne patients usually die?
respiratory or cardiac failure
describe colorblindness
there are several genes that are responsible for red and green cones that are clustered on X chromosome. since genes have similar sequence, errors occur during homologous recombination (crossing over) and lead to deletions of part of “cluster region”. leads to red or green perception defects
what causes Christianson syndrome?
mutation in SLC9A6 gene
what does SLC9A6 gene encode?
sodium/hydrogen exchanger 6 (NHE6)
symptoms of Christianson syndrome?
- affects nervous system
- developmental delay
- intellectual disability
- inability to speak
- ataxia
- seizures
which are the X linked recessive diseases?
- Hunter’s disease
- Lesch-Nyhan syndrome
- Fabry Disease
- Menke’s disease
- Wiskoff Aldrich Syndrome
- glucose 6-PD deficiency
- bruton’s agammaglobulinemia
- Duchenne’s MD
- Hemophilia A and B
- Diabetes Insipidus
- colorblindness
- ornithine transcarbamoylase deficiency (OTC)
- SCID (IL receptor gamma chain deficiency)
what is manifesting (female) heterozygotes?
when a female expresses an X linked recessive mutation because her X chromosome inactivation is skewed toward the mutant chromosome (more normal X’s are inactivated than mutant X’s). however, the expression is milder because come cells still have the normal X chromosome expressing the unaffected allele
what does X inactivation create in females?
mosaicism
describe X inactivation in females
it is a normal mechanism to equalize the amount of protein encoded by X chromosome in males and females. is a random inactivation, so some cells inactivate X chromosome from the father and some cells inactivate X chromosomes from the mother. once the decision is made for which X chromosome is inactivated, that is fixed (the same X chromosome is inactivated in all descendants of the cell)
what is the inactivated X chromosome referred to as?
barr body
what does it mean that an inactivated X chromosome is fixed?
once the body decides which X chromosome to inactivate, that same X chromosome is inactivated in all the descendants of that cell
why does inactivating X related with manifesting heterozygotes?
because if a lot of active (not inactivated) mutated X chromosomes, may have a mild case of the disease.
what contribute to the inactivation of X chromosomes?
- XIST gene
- heterochromatin condensation
- METHYLATION OF GENES ON X CHROMOSOMES
what does the XIST gene do
a gene present on the X chromosome itself that produces RNA product that coats the chromosome, helping produce its inactivation
what is inheritance pattern deviates from mendelian inheritance pattern?
mitochondrial inheritance
what is mendelian inheritance?
genes expressed from both alleles in diploids, one from mother and one from father (dominant and recessive alleles)
what is unique about mitochondria?
they self replicate by fission, so all mitochrondria in organism originate from the mother – via nonmendelian inheritance
descrive mtDNA
mitochondria contain small amount of DNA, that encode for some but not all of the proteins required for its function. the rest is in the nuclear DNA. is circular.
why is no genetic diversity in terms of mitochondria?
DNA from only one parent is contained WITHIN the mitochondria, there is no homologous recombination. therefore, no contribution of genetic diversity from the father.
how many copies of mtDNA does mitochondria have?
2-10 copies of mitochondrial DNA
what does mtDNA code for?
37 genes, some of which are ETC enzymes and components
why do mitochondrial inherited diseases have large phenotypic variability?
because the mitochondria has 2-10 copies of mitochondrial DNA, aka heteroplasmy
what do pedigrees of mitochondrial inheritance look like?
- mitochondrial disorders can only be passed from mother to child and NOT from father to child
- if female has pathogenic mtDNA, SHE WILL PASS HER MTDNA TO ALL HER CHILDREN REGARDLESS OF GENDER
what is heteroplasmy?
uneven distribution of a specific mutation in mitochondrial DNA between daughter cells during cell division – meaning, some cells may inherit more normal mtDNA, while others inherit mostly mutated mtDNA
why do mitochondrial diseases have such variability?
since heteroplasmy is a thing, children may inherit more or less mutated vs normal mtDNA
can specific recurrence risk be generated for children?
specific recurrence risk to each child is unknown, because the number of mtDNA with the pathogenic variant can vary from child to child
what determines severity of mitochondrial disease expression?
the higher percentage of mutant mtDNA, the more severe the expression of the disease (relative proportions of normal vs mutant mtDNA – NOT BASED ON NUMBER OF MITOCHONDRIA)
inheritability characteristics of mitochondrial disorders
- reduced penetrance
- variable expressivity
- pleiotropy
examples of mitochondrial diseases
- Leber Hereditary optic neuropathy (LHON)
- myoclonic epilepsy with ragged red fiber syndrome (MERRF)
- mitochondrial encephalopathy, lactic acidosis, and stroke like episodes (MELAS)
- leigh syndrome
what are the common symptoms of mitochondrial diseases?
- encephalopathy
- myopathy
- ataxia
- retinal degeneration
which mitochondrial disease is NOT variable?
LHON (leber hereditary optic neuropathy)
what mutations cause LHON?
- MT-ND1
- MT-ND4
- MT-ND4L
- MT-ND6
expressivity of LHON?
heteroplasmy is minimal, so expression is uniform – clear pattern of mitochondrial inheritance in pedigree
when do symptoms arise in LHON and what are they?
teens and 20’s
- blurring vision and vision loss
- movement disorders
- cardiac conduction defects
what mutations cause myoclonic epilepsy with ragged red fiber disease? (MERRF)
single base mutations in MT-TK (gene encodes tRNA for lysine)
what is MERRF characterized by?
heteroplasmic mtDNA, so it is HIGHLY VARIABLE IN EXPRESSION
symptoms of MERRF?
- twitching muscle spasms
- seizures
- ataxia
- histological finding of ragged red fibers in muscle tissue
what are the ragged red fibers of MERRF?
an accumulation of damaged mitochondria in the muscle tissue — ONLY SEEN IN MITOCHONDRIAL DISORDERS
what causes mitochondrial encephalopathy, lactic acidosis, and stroke like episodes? (MELAS)
mutations in 1. MT-ND5
- MT-TH
- MT-TL1
- MT-TV
expressivity of MELAS
heteroplasmic, highly VARIABLE IN EXPRESSION
symptoms of MELAS
appear in childhood
- muscle weakness and pain
- HA
- vomiting
- seizures
- stoke like episodes that can damage brain
what causes leigh syndrome?
mutation in mitochondrial ATP6 gene
symptoms of leigh syndrome
ARISE IN 1ST YEAR OF LIFE 1. progressive loss of motor skills 2. vomiting 3. diarrhea 4. dysphagia 5. weak muscle tone USUALLY FATAL WITHIN FIRST FEW YEARS OF LIFE
