• Mitochondrial DNA (mtDNA) contains genes that encode enzymes needed for oxidative phosphorylation → energy production.
• Mitochondrial DNA shows maternal inheritance.
• Reason:
  • ovum contains many mitochondria in its cytoplasm
  • sperm contains few or no mitochondria
  • therefore, the zygote receives its mitochondrial DNA essentially from the mother
• So: Affected mother → can transmit mitochondrial mutation to both sons and daughters
• But: Affected father → does not transmit mitochondrial genes to his children
• Mitochondrial genetic diseases are rare.
• Because mitochondria are important for energy production, mutations mainly damage tissues with high energy requirements, especially:
  • CNS
  • skeletal muscle
  • cardiac muscle
  • liver
  • kidney
• Leber hereditary optic neuropathy is the classic example.
• It is a neurodegenerative disorder causing: progressive bilateral loss of central vision → eventual blindness

KEY CONCEPT

• Mitochondrial disorders = maternal inheritance.
• Mother transmits mtDNA → sons + daughters.
• Father does not transmit mtDNA.
• mtDNA mutation → impaired oxidative phosphorylation → high-energy tissues affected most.
• Prototype → Leber hereditary optic neuropathy.

CONCEPTUAL EXAMPLES

• Mother has an mtDNA mutation → both her son and daughter may inherit it.
• Father has an mtDNA mutation → children do not inherit it from him.
• Mitochondrial energy production fails → highly energy-dependent nervous tissue is affected → progressive visual loss in Leber hereditary optic neuropathy.

Diseases Caused by Alterations of Imprinted Regions: Prader-Willi and Angelman Syndromes

• Normally, each autosomal gene has two copies:
  • one from the mother
  • one from the father
• For most genes, the maternal and paternal copies function similarly.
• However, some genes behave differently depending on which parent they came from.
• This parent-specific gene control is called genomic imprinting.
• Genomic imprinting = one parental copy of a gene is selectively silenced/inactivated during formation of sperm or ova.
• Maternal imprinting:
  • maternal allele is silenced
  • paternal allele remains active
• Paternal imprinting:
  • paternal allele is silenced
  • maternal allele remains active
• At the molecular level, gene silencing occurs mainly through:
  • DNA promoter methylation
  • modification of histone proteins
• These changes make the gene transcriptionally inactive.
• Imprinting occurs during gametogenesis:
  • in sperm
  • or in ova
• After fertilization, the imprint is maintained in the somatic cells of the offspring.
• Two classic disorders caused by abnormal imprinting are:
  • Prader-Willi syndrome
  • Angelman syndrome

KEY CONCEPT

• Genomic imprinting = parent-of-origin–specific gene silencing.
• Maternal imprinting → maternal allele OFF.
• Paternal imprinting → paternal allele OFF.
• Mechanism → DNA methylation + histone modification → gene silencing.
• Important examples → Prader-Willi and Angelman syndromes.

CONCEPTUAL EXAMPLE

• Same gene is inherited from both parents, but one copy is normally switched off.
• If the active parental copy is lost or abnormal, the remaining imprinted copy cannot compensate → disease develops.

FIG. 4.23 — TRIPLET REPEAT EXPANSION DISEASES

🧠 Simplest idea

Repeated DNA triplets become excessively expanded. The disease depends mainly on WHERE the repeat expands: UTR, intron, or exon.

Whole figure in one flow

Repeat expansion → abnormal gene expression/protein → disease

🎨 COLOR / STRUCTURE GUIDE

• 🔵 Dark blue = promoter / intron regions
• 🟡 Yellow = UTR (untranslated region)
• 🟢 Green = exon
• 🔺 Red triangles = site where repeat expansion occurs
• 5′ → 3′ = direction of the gene

1️⃣ CGG repeat in 5′ UTR → Fragile X

The red triangle points to a CGG triplet expansion in the 5′ UTR.

Full mutation

Large CGG expansion
→ DNA methylation
→ transcriptional silencing of FMR1
→ ↓ FMRP protein
→ loss of protein function

⬇️

Fragile X syndrome

🧠 Memory:

Fragile X = CGG → gene OFF

2️⃣ Smaller CGG expansion / premutation

The same FMR1 region can produce a different problem when the repeat is in the premutation range.

CGG premutation
→ abnormal ↑ transcription
→ excessive/toxic FMR1 mRNA
→ cellular toxicity

⬇️

Can cause:

• Fragile X–associated tremor/ataxia syndrome (FXTAS)
• Fragile X–associated primary ovarian insufficiency (FXPOI)

Key difference:

Full mutation → too little protein
Premutation → too much toxic mRNA

3️⃣ GAA repeat in INTRON → Friedreich ataxia

🔺 Red triangle in the intron

GAA repeat expansion
→ interferes with transcription
→ gene silencing
→ ↓ frataxin protein

⬇️

Friedreich ataxia

🧠 Memory:

Friedreich = GAA in intron → frataxin ↓

4️⃣ CAG repeat in EXON → Huntington disease

🔺 Red triangle lies inside an exon, so the repeat becomes part of the protein-coding sequence.

Why important?

CAG codes for glutamine (Q).

Therefore:

CAG CAG CAG…
→ many glutamines
→ polyglutamine tract
→ protein misfolding/aggregation
→ toxic gain of function

⬇️

Huntington disease

🧠 Memory:

Huntington = CAG → poly-Q → toxic protein

⭐ MOST IMPORTANT COMPARISON

Repeat + Location	Main mechanism	Disease
CGG — 5′ UTR	Gene silencing → protein loss	Fragile X syndrome
CGG premutation — 5′ UTR	Toxic mRNA	FXTAS / FXPOI
GAA — intron	Transcriptional silencing → frataxin loss	Friedreich ataxia
CAG — exon	Polyglutamine misfolding → toxic gain	Huntington disease

🧠 Fastest exam recall

CGG → Fragile X
GAA → Friedreich ataxia
CAG → Huntington

🔥 One-line memory

UTR CGG = gene OFF/toxic RNA; intron GAA = gene OFF; exon CAG = toxic protein.

Prader-Willi and Angelman Syndromes

• Prader-Willi syndrome is characterized by:
  • intellectual disability
  • short stature
  • hypotonia → reduced muscle tone
  • obesity
  • small hands and feet
  • hypogonadism
• In about 60%–75% of cases, there is deletion of chromosome 15: del(15)(q11;q13)
• In Prader-Willi syndrome, this deletion occurs on the paternally derived chromosome 15.
• Therefore: Paternal 15q11–q13 deletion → Prader-Willi syndrome
• Angelman syndrome involves deletion of the same chromosome 15 region, but the abnormal chromosome comes from the mother.
• Therefore: Maternal 15q11–q13 deletion → Angelman syndrome
• Angelman syndrome is characterized by:
  • intellectual disability
  • ataxic gait
  • seizures
  • inappropriate laughter
• Thus, the same chromosomal deletion causes different diseases depending on whether it comes from the father or mother.
• This demonstrates the parent-of-origin effect produced by genomic imprinting.

KEY CONCEPT

• Same deletion, different parent → different disease.
• Paternal deletion → Prader-Willi syndrome.
• Maternal deletion → Angelman syndrome.

Easy memory:

P = Paternal → Prader-Willi
M = Maternal → Angelman

CONCEPTUAL EXAMPLES

• Child loses the paternal 15q11–q13 region → Prader-Willi → hypotonia + obesity + hypogonadism.
• Child loses the maternal 15q11–q13 region → Angelman → intellectual disability + ataxia + seizures + inappropriate laughter.
• This difference proves that some genes on chromosome 15 are expressed differently depending on their parental origin.

Pathogenesis

• Prader-Willi and Angelman syndromes involve the same region of chromosome 15, but different genes are normally active depending on the parent of origin (Fig. 4.24).
• In the 15q12 region, a group of genes on the maternal chromosome is normally imprinted (silenced).
• Therefore, for these genes: Maternal copy OFF → paternal copy is the functional copy
• If the paternal 15q region is deleted: paternal active genes lost + maternal genes already silenced → no functional gene expression → Prader-Willi syndrome
• The most likely important genes in Prader-Willi syndrome are a cluster encoding small nucleolar RNAs (snoRNAs).
• snoRNAs help in RNA processing.
• A different gene in the same region, UBE3A, shows the opposite imprinting pattern.
• For UBE3A: Paternal UBE3A OFF → maternal UBE3A is active
• UBE3A encodes a ubiquitin ligase.
• Ubiquitin ligase: adds ubiquitin to cellular proteins → marks them for proteasomal degradation
• If the maternal UBE3A gene is deleted: maternal active UBE3A lost + paternal UBE3A already silenced → ↓ UBE3A → Angelman syndrome
• The neurologic manifestations of Angelman syndrome mainly result from lack of UBE3A expression in certain brain regions.
• Some patients have no visible chromosome deletion but still develop disease because of uniparental disomy.
• Uniparental disomy = both copies of a chromosome pair are inherited from one parent only.
• In Prader-Willi syndrome: two maternal chromosome 15s → no paternal active snoRNA genes → Prader-Willi syndrome
• In Angelman syndrome: two paternal chromosome 15s → no active maternal UBE3A → Angelman syndrome

KEY CONCEPT

• Prader-Willi: paternal gene expression is needed.
  Paternal deletion OR two maternal chromosome 15s → Prader-Willi.
• Angelman: maternal UBE3A expression is needed.
  Maternal deletion OR two paternal chromosome 15s → Angelman.
• Same chromosome region, but different parental origin → different disease because of genomic imprinting.

CONCEPTUAL EXAMPLES

• Maternal copy already OFF + paternal copy deleted → no functional Prader-Willi-region genes → Prader-Willi syndrome.
• Paternal UBE3A already OFF + maternal UBE3A deleted → no functional UBE3A → Angelman syndrome.
• Both chromosome 15 copies come from mother → maternal uniparental disomy → Prader-Willi.
• Both chromosome 15 copies come from father → paternal uniparental disomy → Angelman.

FIG. 4.24 — ANGELMAN vs PRADER-WILLI SYNDROME

🧠 Simplest idea

Same chromosome region (15q11–q13), but disease depends on whether the deletion comes from the MOTHER or FATHER.

Imprinted = gene is switched OFF / silenced

1️⃣ TOP — NORMAL CHROMOSOME 15

There are two copies:

• M = maternal chromosome 15
• P = paternal chromosome 15

But both copies are not equally active because of genomic imprinting.

🟦 Maternal chromosome

• Prader-Willi genes = imprinted → OFF
• Angelman gene (UBE3A) = active → ON

🟦 Paternal chromosome

• Prader-Willi genes = active → ON
• Angelman gene = imprinted → OFF

🧠 Key concept

For these genes, the body depends on only one parent’s active copy.

2️⃣ LEFT YELLOW ARROW — Deletion in MATERNAL chromosome

The maternal chromosome loses the important 15q region.

But remember:

Angelman gene

• Maternal copy = normally ACTIVE
• Paternal copy = normally IMPRINTED/OFF

So:

Maternal deletion
→ active UBE3A lost
→ paternal UBE3A is already silent
→ essentially no functional UBE3A

⬇️

ANGELMAN SYNDROME

🧠 Memory:

Angelman = Mother missing

A = Angelman → Active gene normally from mom

3️⃣ Why doesn’t maternal deletion cause Prader-Willi?

Because the maternal Prader-Willi genes were already imprinted/OFF.

The paternal chromosome still has:

Active Prader-Willi genes

So their function remains.

4️⃣ RIGHT YELLOW ARROW — Deletion in PATERNAL chromosome

Now the paternal 15q region is deleted.

Remember:

Prader-Willi genes

• Paternal copies = normally ACTIVE
• Maternal copies = normally IMPRINTED/OFF

So:

Paternal deletion
→ active Prader-Willi genes lost
→ maternal copies are already silent
→ no functional expression

⬇️

PRADER-WILLI SYNDROME

🧠 Memory:

Prader-Willi = Papa missing

P = Prader-Willi → Paternal genes normally active

5️⃣ Why doesn’t paternal deletion cause Angelman?

Because the paternal Angelman/UBE3A copy is normally imprinted/OFF.

The maternal chromosome still provides:

Active UBE3A

So Angelman syndrome does not result from this paternal deletion.

🎨 ARROW / COLOR GUIDE

• 🟦 Long chromosomes = chromosome 15
• M = maternal copy
• P = paternal copy
• 🟧 Orange triangles = important gene region / deletion site
• 🟨 Large yellow arrows = consequence of maternal vs paternal deletion
• 🟥 Left lower box = Angelman syndrome
• 🟦 Right lower box = Prader-Willi syndrome

⭐ MOST IMPORTANT COMPARISON

Deleted chromosome	Active gene lost	Disease
Maternal 15q	UBE3A / Angelman gene	Angelman syndrome
Paternal 15q	Prader-Willi genes	Prader-Willi syndrome

🧠 Fastest exam recall

Maternal deletion → Angelman

Mom’s active UBE3A gone

Paternal deletion → Prader-Willi

Papa’s active PWS genes gone

🔥 One-line memory

“Angelman = Mother missing; Prader-Willi = Papa missing.”