Genomic Imprinting: Prader-Willi and Angelman Syndromes

parent-of-origin effect

expression of certain autosomal genes only from the allele found on the chromosome from a specific parent

- phenotype will occur if the mutation resides on the parental chromosome which is normally expressed

- not if the mutation is on the parental chromosome that is normally imprinted

monoallelic expression

expression of a gene from only ONE of the two alleles

biallelic expression

expression of a gene from BOTH alleles

imprint reset

an individual's maternal and paternal imprinted genes are reset during gametogenesis to match the imprinting pattern consistent with their gender (i.e. imprints are erased & reestablished during meiosis )

genetic imprinting

some gene alleles have different expression depending on parent-of-origin

imprinting

allele that is not expressed or "off"

- mediated by DNA methylation and epigenetic silencing

imprint & disease expression

- if disease-causing mutant allele is imprinted = disease not expressed

- if mutant allele on active chromosome = disease will be expressed

autosomal dominant paraganglioma

slowly growing, mostly benign tumors of the parasympathetic ganglia (usually in head & neck region)

- autosomal dominant

- maternally imprinted, paternally expressed (only manifests when mutation inherited from father)

Beckwith-Wiedemann syndrome (BWS)

an overgrowth syndrome- infants are larger than normal; growth may be asymmetric

- autosomal dominant

- paternally imprinted, maternally expressed (only manifests when mutation inherited from mother)

- most cases are spontaneous (~85%)

defective imprinting

leads to over or under expression of a gene but not in a parent-of-origin specific manner

Angelman Syndrome (AS)

lack of maternal contribution of 15q11-13

- rarely inherited thus neither dominant or recessive

- important gene: UBE3A (brain-specific ubiquitin ligase)

Angelman Syndrome (AS)

clinical presentations:

- severe intellectual disability (mental retardation)

- seizures (high risk for epilepsy)

- spasticity

- coarse facies

- short stature

- happy demeanor ("happy puppet syndrome" = derogatory)

- hyperactivity

UBE3A

brain-specific ubiquitin ligase gene implicated in Angelman Syndrome

Prader-Willi Syndrome (PWS)

lack of paternal contribution of 15q11-13

- rarely inherited thus neither dominant or recessive

- important gene: SNRPN, HB (snoRNA assembly)

Prader-Willi Syndrome (PWS)

clinical presentations:

- in infancy: poor feeding, hypotonia

- moderate intellectual disability

- polyphagia, obesity (type II diabetes)

- behavioral problems

- hypopigmentation (variable)

SNRPN

snoRNA assembly implicated in Prader-Willi Syndrome

UBE3A normal imprinting

expressed only from the maternal chromosome (paternally imprinted)

SNRPN normal imprinting

expressed only from the paternal chromosome (maternally imprinted)

OCA2 normal

biallelic gene expression

oculocutaneous albinism type 2

homozygous OCA2 loss-of-function

- autosome revessive

OCA2

gene associated with autosomal recessive oculocutaneous albinism type 2

UBE3A loss-of-function

causes Angelman Syndroms (AS) via:

- deletion of 15q11-13 on maternal chromosome

- paternal uniparental disomy = both chromosomes are paternal

- imprinting defect= paternal imprinting on maternal chromosome

- loss-of-function

SNRPN loss-of-function

causes Prader-Willi Syndrome (PWS) via:

- deletion of 15q11-13 on paternal chromosome

- maternal uniparental disomy = both chromosomes are maternal (maternal nondisjunction = more common)

- imprinting defect= maternal imprinting on paternal chromosome

- loss-of-function

Southern blot

method to detect methylation patterns using methylation-sensitive restriction enzymes

- NotI = methylation sensitive, will not cut imprinted alleles

- Xbal = no sensitive, will but either allele

- SNRPN probe (paternally expressed = unmethylated = cut by NotI; maternally imprinted = methylated = not cut by NotI)

uniparental disomy (UPD)

inheritance of 2 copies of a chromosome from one parent

trisomic rescue

mechanism by which UPD occurs

- trisomic conceptus occurs due to nondisjunction during parental meiosis

- trisomic cells can undergo several more divisions resulting in daughter trisomic cells

- if a mitotic nondisjunction then occurs, then it will result in disomic and tetrasomic daughter cells

- only the DISOMIC cell will develop into an embryo

uniparental isodisomy

UPD in which the 2 chromosomes from the same parent are identical

- the original nondisjunction occurred in meiosis II

- can result in homozygosity for a recessive allele with only on heterozygous parent

uniparental heterodisomy

UPD in which the 2 chromosomes from the same parent are different

- the original nondisjunction occurred in meiosis I

- if contributing parent is heterozygous, offspring will also be heterozygous

- no chromosome are contributed from the other parent