Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]

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Sex-linked and Mitochondrial

inheritance

Chapter 5



Human X and Ychromosomes - these

are homologous overonly a tiny portion oftheir length (at oneend). Most of the DNAis different between

the chromosomes.The X has manygenes whose functionis not related to sex-determination, while

the few Y-linked genesare mostly involvedwith sex determination.



Sex-linked genes in humans

• Some genes on X-chromosome code for female

traits; some genes on Y chromosome code for

male traits

• X chromosome has 164 million bases; Y

chromosome has 59 million bases

• Current estimate of X-linked genes range from

729-748

• Current estimate of Y-linked genes is 78



LYON HYPOTHESIS

• 1961 English geneticist Mary Lyonproposed this hypothesis to describe Xinactivation

• Consists of 5 tenants – 1. Condensed X chromosome isgenetically inactive

– 2. X inactivation in humans occurs early indevelopment when embryo consists ofabout 32 cells. 1 or 2 days followingfertilization



5 TENANTS OF LYON HYPOTHESIS

• 3. At this stage in each of the 32 cellsone of the X chromosomes is randomlyinactivated

• 4. Inactivation is a mitotically stableprocess

• 5. Net effect of this is to equalize (genedosage) phenotypes in males and

females for genes that are carried onthe X chromosome

RESULTS IN VARIABLE EXPRESSION OFHETEROZYGOTES (X* X)

-MOSAICISM (e.g. COAT COLOUR GENES)



Human Chromosomes

• One X chromosome in females is inactivated early inembryonic development.



PART OF THE X CHROMOSOME IS NOT

INACTIVATED• End-to-end attachment of the short arms of the XY form

bivalent at diplotene-metaphase I.• This is due to 2.6 mb homologous region between X and

Y chromosome with obligatory cross-over during male

meiosis. This region is called pseudoautosomal region(PAR1)• Genes in PAR1 are expressed whether they are on the

active X chromosome or the inactive X chromosome• Another homology region between X and Y PAR2 exist

near the telomere of the long-arm of both X and Y, 320kb, recombination frequency in this region is 2% of malemeiosis, genes in PAR2 also escape inactivation infemale cells



Xist – X inactive-specific transcript

Avner and Heard, Nat. Rev. Genetics 2001 2(1):59-67



X-linked recessive (XR)

Heterozygous normal mother

(carrier)

Hemizygous normal father

50% risk for an affected male

50% for a normal male

100% chance for normal female:

50% carrier female

50% homozygous normal female

Males and females NOT equallyaffected



X-l i n ked r ecessi v e (XR )

Homozygous dominant = normal female (XAXA)

Heterozygous dominant = normal female carrier (XAXa)

Homozygous recessive = affected female (XaXa)

Hemizygous dominant = normal male (XAY)

Hemizygous recessive = affected male (X

a

Y)



Basic pattern ofinheritance of X-Y-

linked genes.Note thatmales are technicallyhemizygous.



X-linked recessive inheritance (XR)

– Affects almost exclusively men

– Affected men born from carrier mother, with 50% risk of disease

– No male to male transmission



X-linked dominant (XD)

One trait, 2 alleles

A = dominant abnormal allelea = recessive normal allele

Must consider which parent has the

abnormal gene when assessing risk



X-L inked D om in an t (XD )

For heterozygous affected females:

50% risk for affected son

50% risk for affected daughter

For hemizygous affected males:

100% risk for affected daughter

0% risk for affected son

Males and females NOT equally

affected

Affected

Father

Normal

Mother

Affected Normal Affected Normal

female male female male



X-l i n ked dom i n an t (XD )

Homozygous dominant = affected female (XAXA)

Heterozygous dominant = affected female (XA

Xa

) Homozygous recessive = normal female (XaXa)

Hemizygous dominant = affected male (XAY)

Hemizygous recessive = normal male (XaY)



XD Pedi gr ee

Affected females risk affected

sons and affected daughters

Affected males risk affected

daughters

No male to male transmission

Difficult to distinguish from

autosomal dominant



X-linked dominant traits

- on average, twice as many females afflicted as males

- males are often more severely affected.

- typically associated with miscarriage or lethality in males.



X-linked dominant inheritance (XD)

– More females than males

– All daughters of affected males are affected, but no sons

– A child of an affected female has 50% risk of disease



Y-linked inheritance (Y)

– Affects only males

– Affected males always have affected fathers

– All sons of an affected male are affected



Hemophilia

• Hemophilia A: X-linked recessive

- Inability to form blood clots, caused by lack of clottingfactor VIII.

- Severe bleeding from wounds

- hemorrhages in the joints and muscles.- Bruising is frequent.

- Variable expression (nonsense vs missense mutations)

• Hemophilia B (Christmas disease) : Clotting defectcaused by lack of factor IX.

• Willebrand disease: AR, mutation in the carrier protein ofFactor VIII





Duchennes Muscular Dystrophy (DMD)

-X-linked recessive-1 in 3500 males afflicted

- 5-10% of carrier females have muscle weakness, afew have severe disease- age on onset between 1 and 6 yrs

- confined to wheel chair by age 11 and death by age 20

-The disease is caused by a defect in a gene that codes for a

protein called dystrophin (most mutations are deletions)-Dystrophin stabilizes cytoskeleton during muscular

contraction-Mutations in dystrophin leads to progressive weaknessand loss of muscle

-Creatine kinase: elevated about 20 times above the upper

limit: Used in diagnosis of DMD



Becker Muscular Dystrophy (BDM)

- X-linked recessive

- has partially functional dystrophin

- later age of onset, milder symptomsand longer life span

• DMD and BDM are different allelic

forms of the same disease.



Color blindness

8% males have red-green color blindness

red color blindness – can’t see red

green color blindness – can’t see greens

both are X-linked recessive traits

(map to the X chromosome)

Blue color blindness

autosomal recessive

maps to chromosome 7



Hypophosphatemic rickets

X-linked dominant traitKidneys are impaired in their ability to reabsorb phosphateAbnormal ossification, with bending and distortion of thebones



Incontinentia Pigmenti type I

• X-linked dominant

• Abnormal skin pigmentation

• Missing teeth• Ocular abnormalities

• Neurological abnormalities

• Seen only in females• Lethal to males before term



Rett syndrome

• X-linked dominant

• Autistic behavior

• Mental retardation• Seizures

• Gait ataxia

• Caused by mutations in MECP2 gene

• 1 in 10,000-15,000 females affected

• Mostly lethal in males before term



Fragile X Syndrome

Note elongated face, prominent ears





Clinical Features in Fragile X Males

• Delayed developmental

– Walk (20.6 months)

– First clear words (20 months)

• Pre-pubertal:

– Developmental delay (especially speech)

– Mental retardation (IQ 30-50)



Mitochondrial inheritance



Mitochondrion • Organelle providing cellularenergy.

• Contains small circular DNA.

• No crossing over or DNA

repair.

• Many copies of themitochondrial genome per cell.

• 37 genes, no histones, nointrons.

• Maternal inheritance



Mitochondrial Inheritance

- mitochondria are maternally inherited

-oocyte cytoplasm to egg transmission

Key features of mitochondrial inheritance

- only females can transmit defected genes to offspring

- both male and female offspring can be affected

- phenotype often related to defect in energy production.




• Mitochondria and their genome are transmittedfrom a mother to all of her offspring.



tRNA Gene Organization in Human Mitochondrial Genome

• 22 tRNA genes

• Separate polypeptide-encoding genes

• The primary transcripts are cleaved on either sideof each tRNA gene to produce monocistronictranscripts



Mitochondrial DNA• maternally inherited

• No recombination

• mtDNA encodes 13 of 67 components of theOXPHOS system



Heteroplasmy = different % of normal &

abnormal mitochondria in single cells or tissues

and or and

x x x x x x

o o o o o o

o o o o o o

O o o

x x x x

o o o o o

x x o o o

o o o ox

o o o o o

o o o o

x x x x x

o o o

Homoplasmic – cells contain one type of mtDNA



The mitochondrial genome is a

hotspot for mutations• 93% of mtDNA is coding DNA

• Respiratory chain and the oxidative

damage to mtDNA• mtDNA is not protected by histones

• Many round of replication

• Some DNA damage cannot be repaired(like thymidine dimer).




Disease phenotype dependent upon:

gene(s) involved type of mutation

(missense/nonsense/deletion)

% normal vs abnormal mitochondria

tissue involved



Proportion of

mutant mtDNA

and tissue in

which theyreside influence

phenotype



“Mitochondrial Theory” of Aging

• Normal mitochondrial function generates

significant oxidative stress

• This oxidative damage mutates themtDNA

• Mutated mtDNAabnormal energy

metabolism MORE oxidative stress!



Examples of Mitochondrial Disorders



Mitochondrial disorders

Leber hereditary optic neuropathy (LHON)- Mainly in young adult males

- characterized by optic nerve degeneration resulting in lossof central vision.

- >90% of affected families have mutations at nucleotides11778, 3460 or 14484, that encode components ofcomplex I of the respiratory chain.



Myoclonic Encephalopathy with Ragged

Red Fibers (MERRF)• ataxia

• epilepsy

• muscle weakness

• lactic acidemia

• ragged red fibers seen in muscle biopsy

• abnormal energy metabolism in muscles

• Caused by missense mutation in the mt

tRNA lys gene (A8344G) in 80% of cases

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Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]