1. Sex-linked and Nontraditional Modes of Inheritance
Chapter 5
Sex-linked and Nontraditional Modes of Inheritance

2. X Inactivation Inactivation of one X-chromosome of female
Tunesian wedge-faced calico
X Inactivation
Inactivation of one X-chromosome of female

3. X Inactivation evidence of X inactivation Causes X Inactivation
Tunesian wedge-faced calico
X Inactivation
evidence of X inactivation
female mice → dappled coloring of fur
female calico cat → black and orange patches of fur
albinism (a X-linked recessive disease): female heterozygotes → pigment patches
two different variants of enzymes in famales
Barr bodies (inactive X-chromosome)
Causes
mRNA of XIST gene (X inactivation gene of X chromosome)
due to heavy methylation of CG repeats of X chromosome
due to histone acetylation

4. X-linked Recessive Inheritance
hemophilia A, Duchenne muscular dystrophy, fragile X syndrome, red-green color blindness
Charateristics
heterozygote female: 50% of the normal level of gene product → a normal phenotype
dominant or recessive : only to female
hemizygous male → abnormal
skipped generation : affected father → carrier daughter → affected grandson
Manifesting heterozygotes (in female) : inactivation of most normal X chromosome (eg. 5% of female hemophilia A)

5. Inheritance of an X-linked Recessive Trait
X-linked Recessive Inheritance
Inheritance of an X-linked Recessive Trait

6. Punnett Square Representations of X-linked Recessive Inheritance

7. Additional Examples of X-Linked Recessive Disorders
X-linked Recessive Inheritance
Additional Examples of X-Linked Recessive Disorders

8. X-linked Dominant Inheritance
hypophosphatemic rickets, incontinentia pigment type 1, Rett syndrome
Charateristics
heterozygous female: milder expression of X-linked dominant traits than hemizygous male
twice common in females
no father-son transmission

9. X-linked Dominant Inheritance
Pedigree demonstrating the inheritance of an X-linked dominant trait

10. Comparison of the Major Attributes of X-Linked Dominant and X-Linked Recessive Inheritance Patterns

11. Y-linked Inheritance
Pedigree demonstrating the inheritance of a Y-linked trait. 

12. Mitochondrial Inheritance
Mitochondrial genes (16,569 bp): 2 rRNAs, 22 tRNAs, 13 polypeptides for oxidative phosphorylation
lack of DNA repair mechanism and damage from free radicals produced during the oxidative phosphorylation → 10 times higher mutation rate than nuclear DNA
organs with large ATP requirement (high threshold) → seriously affected
Characteristics
inherited through the maternal line
heteroplasmy by replicative segregation (via chance variation or a selective advantage)

13. Human mitochondrial DNA
Mitochondrial Inheritance
Human mitochondrial DNA

14. Mitochondrial Inheritance
A pedigree showing the inheritance of a disease caused by a mitochondrial DNA mutation.

15. Mitochondrial Inheritance
Missense mutations of protein-coding genes: Leber hereditary optic neuropathy (LHON)
Single-base mutations of tRNA genes: myoclonic epilepsy with ragged-red fiber disease (MERRF), mitochondrial encephalomyophathy and strokelike episodes (MELAS)
Duplication and deletion: Kearns-sayre disease, chronic progressive external ophthalinoplegia (CPEO), Pearson syndrome, diabetes, deafness, Alzheimer disease

16. Genomic Imprinting
Genomic Imprinting
differential activation of genes, depending on the parent from which they are inherited
eg. a deletion on the long arm of chromosome 15
Prader-Willi syndrome: from father, a protein involved in ubiquitin-mediated protein degradation
Angelman syndrome: from mother, a small nuclear riboprotein expressed in the brain (SNRPN)
the degree of methylation of the gene ↔ transcriptional inactivation

17. Genomic Imprinting
Genomic Imprinting

18. Genomic Imprinting Genomic Imprinting
Schematic of the organization of several imprinted genes on chromosome 11p15.5 that are involved in the pathogenesis of Beckwith-Wiedemann syndrome and Russell-Silver syndrome.

19. Anticipation
Anticipation
earlier onset and/or more severe expression in more recent generation of a pedigree
eg. Myotonic dystrophy
AD, progressive muscle deterioration, pleiotropic, locus heterogeneity
expanded CTG repeats in 3´ untranslated region of DMPK (myotonic dystrophy protein kinase) in  19q (5-30: normal, : mildly affected, >100: severe)
expansion of CCTG in 3´ untranslated region of ZNF9 gene on chromosome 3q21
eg.  Huntington’s disease: CAG repeat, fragile X syndrome: CGG repeat, spinocerebellar ataxia type I: CAG repeat

20. Anticipation Anticipation
A three-generation family affected with myotonic dystrophy
Myotonic dystrophy pedigree illustrating anticipation

21. Diseases Associated with Repeat Expansions
Anticipation
Diseases Associated with Repeat Expansions
Disease
Description
Repeat Sequence
Normal Range; Disease Range
Parent in Whom Expansion Usually Occurs
Location of Expansion
Category 1
Huntington disease
Loss of motor control,
dementia, affective disorder
CAG
6-34;
More often through father
Exon
Spinal and bulbar
muscular atrophy
Adult-onset motor-neuron
disease associated with
androgen insensitivity
9-36; 38-62
Spinocerebellar
ataxia type 1
Progressive ataxia,
dysarthria, dysmetria
6-39; 40-82
ataxia type 2
Progressive ataxia, dysarthria
15-24; -
ataxia type 3
(Machado-Joseph
disease)
Dystonia, distal muscular
atrophy, ataxia, external
ophthalmoplegia
13-36; 61-84
ataxia type 6
Progressive ataxia, dysarthria, nystagmus
4-19; 20-33
ataxia type 7
Progressive ataxia, dysarthria,
retinal degeneration
4-35;
ataxia type 17
Progressive ataxia, dementia,
bradykinesia, dysmetria
25-42; 47-63
Dentatorubral-
pallidoluysian atrophy
(Haw River syndrome)
Cerebellar atrophy, ataxia,
myoclonic epilepsy,
choreoathetosis, dementia
7-34; 49-88

22. Anticipation

23. Fragile X Syndrome Characteristics
40% of all X-linked mental retardation
1/4,000 male (80% penetrance), 1/8,000 female (30% penetrance)
larger ears and long face, hypermobile joints, macroorchidism
A perplexing pattern of X-chromosome-mediated inheritance (Sherman paradox)
normal transmitting males (NTM)
Mothers of NTM (carrier) had a much lower proportion of affected sons than did daughters of NTM (carrier).
Daughters of NTM (carrier, not affected) produced affected sons.

24. Inheritance of Typical X-linked Genetic Diseases and Fragile X Syndrome
Typical X-linked disease Fragile X syndrome
NTM
5-9%
16-40%
16-50%

25. Fragile X Syndrome Causes DNA diagnosis for X fragile syndrome
expansion and methylation of CGG repeats in 5´ region of FMR1 gene
expansion and methylation of CGG repeats 5´ region of FRAXE gene (FMR2)
DNA diagnosis for X fragile syndrome
CGG expansion and methylation degree in FMR1 or FRAXE
cytogenetic analysis of the long arm of the X chromosome

26. Hemophilia A

27. Duchenne muscular dystrophy

28. Fragile X syndrome

29. Hypophosphatemic rickets
Cause
by a mutation in the fibroblast growth factor 23 (FGF23)
X-linked dominant
Symptoms
excessive loss of phosphate in the urine
poorly formed bones (rickets), bone pain, and tooth abscesses.
Diagnosis
Blood tests reveal low levels of phosphate (hypophosphatemia)
abnormal levels of vitamin D
Treatment
increasing phosphate intake and high doses of vitamin D

30. Incontinentia pigmenti
Cause
By a deletion of exons 4 through 10 of IKBKG (Inhibitor of Kappa Light Polypeptide Gene Enhancer in B Cells Gamma Kinase)
Symptoms
Characteristic skin lesions, Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails
Retinal defects, cognitive delays/mental retardation
Diagnosis
molecular genetic testing of IKBKG (NEMO)

31. Rett syndrome Cause Symptoms Diagnosis
By sporadic mutations in the gene MECP2 (methyl CpG binding protein 2) located on the X chromosome
Symptoms
a deceleration of the rate of head growth and small hands and feet.
cognitive impairment
Diagnosis
molecular genetic testing of MECP2 mutations

32. Leber’s hereditary optic neuropathy (LHON)
Cause
mutations at nucleotide positions G to A, 3460 G to A and T to C, respectively in the ND4, ND1 and ND6 subunit genes : complex I (NADH dehydrogenase) of the oxidative phosphorylation chain in mitochondria
1:30,000 to 1:50,000 in Europe
Symptoms
degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision
affecting predominantly young adult males
only transmitted through the mother
Diagnosis and Treatments
a neuro-ophthalmological evaluation and/or blood testing for DNA assessment
avoiding optic nerve toxins
no convincing treatments yet

33. Myoclonic epilepsy with ragged-red fiber disease (MERRF)
Cause
by a maternally-inherited mutation at position 8344 in the mitochondrial genome : disruption of the mitochondrial gene for tRNA-Lys
disrupting synthesis of proteins essential for oxidative phosphorylation
Symptoms
progressive myoclonic epilepsy
clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "ragged-red fibers" when muscle is stained with modified Gomori trichrome stain
short stature
Diagnosis and Treatments
blood testing for DNA assessment
no convincing treatments yet

34. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
Cause
mutations in the MT-ND1(over 80%), MT-ND5, MT-TH, MT-TL1, and MT-TV mitochondrial genes
Symptoms
muscle weakness, altered consciousness, vision abnormalities, seizures, and severe headaches
Repeated stroke-like episodes
lactic acidosis : vomiting, abdominal pain, fatigue, muscle weakness, and difficulty breathing
Diagnosis and Treatments
molecular diagnosis, no known treatment (managements according to symptoms)

35. Kearns-Sayre syndrome (KSS)
Cause
by a 5,000 base deletion in the mitochondrial DNA
Heteroplasmic, not maternally inherited (sporadic)
start before the age of 20
Symptoms
vision loss, dysphagia, proximal weakness, hearing loss, cerebellar ataxia and cardiac conduction defects
Diagnosis and Treatments
molecular diagnosis
no cures, only palliative medications

36. Chronic progressive external ophthalmoplegia (CPEO)
Cause
by deletions or mutations to segments of mtDNA lead to defective function of oxidative phosphorylation
Symptoms
ptosis or drooping lids
some muscle weakness
Diagnosis and Treatments
muscle biopsy, molecular tests
no defined treatment
surgery to raise the lids

37. Pearson syndrome Cause Symptoms Diagnosis and Treatments
a deletion in mitochondrial DNA
Symptoms
Sideroblastic anemia of childhood
Pancytopenia
Exocrine pancreatic failure
Diagnosis and Treatments
Bone marrow examination reveals ringed sideroblasts, normoblasts with excessive deposits of iron in mitochondria detected by iron stains.
blood testing for DNA assessment
no cures