X-Linked and Mitochondrial disorders

Sex-Linked Traits

• only on sex chromosomes

• can be dominant or recessive (male are hemizygous)

Hemizgyous

males only have 1 copy of the gene as they only have 1 X chromosome

Sex Limited Traits

• a phenotype only observed in 1 sex

• X-linked or autosomal

Sex-Influenced Traits 

• alleles are dominant in one sex and recessive in the other

• X-linked or autosomal

e.g the baldness allele is dominant in males and recessive in females

How do males and females display x linked traits | Males

• males always express the trait (express whatever is on their single X chromosome)

How do males and females display x linked traits | Females 

• females can show a dominant or recessive phenotype (heterozygous or homozygous)

Features of X Linked Dominant

• affected father passes it to all daughters but no sons

• 50% chance affected (heterozygous) female passes it to children

• 2:1 prevalence affected females to males (2:1 X chromosomes)

• severity = homozygous females > hemizygous males > heterozygous females

• affected children usually have one affected parent

X-Linked Recessive

• knight's move pedigree pattern

• parents and children of the affected person are normally healthy

• never transmitted from father to son (maternal grandfather → male)

• affects mostly males

• ½ that subsequent brothers of affected boys are affected?

• ½ that the sisters of affected boys are carriers?

Colour Blindness | what 2 genes encode opsins (pigment proteins)?

1. OPN1LW (yellow/ orange)

2. OPN1MW (yellow/ green)

Colour Blindness | Recessive or Dominant

X-linked recessive

Colour Blindness | Incidence in Females to Males

1/12 → males

1/200 → females

Colour Blindness | Genetic Defect

unequal crossing-over

Colour Blindness | Chances of having affected children

¾ of normal children

50% sons are affected → females are protected by 2nd X Chromosome

Hypophosphatemic Rickets | Why bones weaken

hypophosphatemia → decreased bone calcium deposition → bones weaken and soften

Hypophosphatemia Rickets | More info about why bones weaken

kidneys cannot efficiently reabsorb phosphate → Leads to Low levels of phosphate in the blood (hypophosphatemia) → to a lower amount of calcium being deposited in the bones, which weaken and become softer (Osteomalacia).

Hypophosphatemic Rickets | Mutation and Gene

PHEX gene → increase FGF23 - reducing phosphate reabsorption from kidneys.

Hypophosphatemic Rickets | Dominant OR Recessive

X-linked dominant

Hypophosphatemic Rickets | Clinical Features

• bowing of the legs

• pigeon-breast deformity

• curvature of the spine

• tendency for bones to break easily

• squaring off and flattening of the skull

• teeth take longer to appear and the enamel is softer

Hypophosphatemic Rickets | Incidence and Ratio of Sex 

1/20,000 newborns

Affected Female to Affected Male | 2:1 

Duchenne Muscular Dystrophy | Normal Gene and Gene Product

DMD gene

dystrophin → attaches to a small cluster of other muscle proteins and is part of a complex (DSC) that spans the membrane and attaches to tissue outside the fibre

Duchenne Muscular Dystrophy | Location of Protein and Function

→ under the sarcolemma

Function → 

• forms part of the dystrophin-sarcoglycan complex (DSC)

• critical structural protein

Duchenne Muscular Dystrophy | Dominant or Recessive

X-Linked Recessive

Duchenne Muscular Dystrophy | Affected Organs

skeletal and cardiac muscle

Duchenne Muscular Dystrophy | Sex effected with DMD

Almost exclusively male

→ because

• females still have a functional dystrophin gene (heterozygous)

• random X-inactivation results in some dysfunctional cells but rarely causes a problem

DMD | Aspects that females aren’t protected from

cardiac muscle weakness

DMD | What causes mutation in females vs males

Females → inheritance of the defective allele from both parents (homozygous)

Males → mostly de novo (as DMD-affected males rarely reproduce)

DMD | Clinical Features

• Gower's manoeuvre to rise from the ground because occurs because muscle weakness starts in the pelvic girdle

• pseudohypertrophy of the calf muscles because of  ineffective muscle repair → deposition of fat and fibrous tissue

DMD | Progression

• apparently normal muscles up to 1-3 years old → wheelchairs at 10-12 → death at 20

• weakness progresses from proximal muscles of the pelvic girdle → shoulder → face

• milestones delayed

DMD | Common Cause of Death

cardiac muscle/ respiratory failure

DMD | Therapies | Exon Skipping

1. use antisense oligonucleotides (AO ) complementary to exon recognition sequences

2. splice acceptor/ donor sites and exonic splicing enhancer sites

3. alter RNA processing to exclude target exon(s) from the mRNA

Exon Skipping | What types of mutations does it target

• remove nonsense mutations

• restore the reading frame around frame-shifting mutations

Difference | Exon Skipping (AO) and RNAi

AO targets pre-mRNA and siRNA targets mRNA

• use antisense RNA to block exons and keep coding past them (AO's modulate pre-mRNA splicing to induce exon skipping), thus restoring the reading frame and producing a functional protein

DMD | Therapies | Reading Through Stop Codon

replace tRNA such that coding continues past the stop codon and protein truncation is avoided

Becker muscular dystrophy | Mild DMD

• a mild form of DMD

Onset → 2nd decade of life

Haemophilia | What is gene affected

• F8 gene (clotting factor VIII deficiency) → haemophilia A

• F9 gene (clotting factor IX deficiency) → haemophilia B

Haemophillia | Dominant or Recessive

X-linked recessive

Haemophillia | Severity

1. Haemophilia A

2. clotting factor VIII is downstream of both the intrinsic and extrinsic pathways

3. in haemophilia B, the extrinsic pathway is still fully functional

Note → the intrinsic pathway is triggered when a blood vessel is damaged and the extrinsic pathway is triggered when tissues are damaged

Haemophillia | Treatment

1. old

   • blood transfusions

   • infusions of anti-haemophilic factor

2. modern

   • recombinant clotting factors

Kenendy’s Disease | Gene and Mutation

1. AR gene

2. CAG repeats (>35) in the AR protein

KD | Management 

Treatment of symptoms, such as medications to reduce muscle cramps
and tremors, gentle and regular aerobic exercise, regular stretching to help reduce
muscle cramping, pain management, speech therapy, occupational therapy &
physiotherapy

KD | Clinical Features

• swallowing & speech difficulties,

• hand tremors

• muscle weakness and wasting,

• muscle cramps

• areas of numbness

• enlarged breast tissue
  (gynaecomastia)

• impotence

• low sperm count

• shrunken testicles

• reduced sex
  drive

Kennedy’s Disease | Consequence of Mutation 

1. toxic gain-of-function

• protein aggregates are toxic to motor neurons → spinal and bulbar muscle atrophy

• progressive muscular atrophy disorder of motor neurons in the spinal cord

KD | Diagnosis

Diagnosed by elevated serum creatine kinase (CPK) an indicator of muscle damage
& and genetic testing

KD | Clinical Features in Males 

infertility and gynecomastia

KD | Dominant or Recessive

X-linked recessive

KD | Onset and Incidence

Onset → 30s-50s

Incidence → 1 in 150,000 males

KD | Quality of Life and Life Expectancy  

normal life expectancy

severely affected quality of life

KD  | What group is usually asymptomatic?

1. heterozygote females

2. protected by a 2nd (functional) X chromosome and random X inactivation

KD | What group usually has milder phenotype? Clinical Features ? Why? 

1. homozygous females

2. muscle cramps and occasional tremors

3. due to lower androgen levels in females

KD | What Is kennedy’s misdiagnosed as?

amyotrophic lateral sclerosis (ALS)

Mitochondrial DNA | Inheritance

exclusively maternal

why → sperm mitochondria are in the midpiece not the head and any sperm mitochondria that get through are ubiquitinated and degraded through lysosomal system early in development

Mitochondrial DNA | How big?

37 genes (16,569 bp)

What is mitrochondrial DNA | How is it stored?

as a single circular chromosome

What does Mitochondrial DNA encode?

ribosomes and OXPHCS proteins

Why does mitochondrial dna have higher mutation rate than nuclear dna?

mtDNA is always open and exposed (not supercoiled into chromatin with histones)

what does mitochondrial protein import refer to?

• mitochondria require nuclear-encoded proteins to function (symbiotic relationship)

• proteins are brought to the correct mitochondrial compartment by mitochondrial signal peptides in the N-terminus

This is significance of this in regards to mitochondrial mutations because mitochondrial mutations may be caused by mutations in nuclear genes so mitochondrial mutations are not exclusively inherited maternally

what are the features of mitochondrial inheritance?

• all children of an affected female will inherit the disease

• no children of an affected male will inherit the disease

how does mitochondrial segregation explain exceptions to mitochondrial inheritance?

• during the development of the germline, maternal mtDNA is sampled into oocytes → can allow rare alleles to dominate the mtDNA pool in cells

• may or may not express the disease phenotype depending on the proportion of defective mitochondria

Heteroplasmy

a cell or organism where all copies of the mitochondrial genome (mtDNA) are not the same

Homoplasmy 

a cell or organism where all copies of mitochondrial genome (mtDNA) are exactly the same

how does heteroplasmy relate to disease penetrance/ severity?

the proportion of mutant (disease associated) mtDNA copies determine the penetrance and expressivity of mitochondrial diseases (spectrum of disease)

Mitochondrial Segregation

During development ofthe germline, many mitochondrial DNA(mtDNA) types are sampled into smaller numbers.

Can allow rare alleles to dominate the mtDNA pool in cells

why do mitochondrial diseases affect different organ systems differently?

• different organ systems contain different amounts of diseased mitochondria

• therefore, tissues with $\uparrow$ diseased mitochondria will be functionally impaired

why can mitochondrial diseases be difficult to diagnose?

• mutations in a number  of mitochondrial genes/ mitochondria lead to the same defect

• there are multiple copies of mtDNA per mitochondria

Leigh Disease | Commonly mutated gene

MTATP6 (encodes ATP synthase 6)

Leigh Disease | how does a mutation in this gene affect function?

deficiencies in ATP production and oxidative phosphorylation

Leigh Disease | Treatment

• oral sodium bicarbonate or sodium citrate for management of lactic acidosis

• thiamine (vitamin B) if deficiency of pyruvate dehydrogenase is proven/ suspected