11. PWS and AS Flashcards
What is the phenotype of PWS?
Hypotonia, dev delay, characteristic facial features, hypogonadism, infertility
What causes PWS? What causes AS?
PWS - loss of expression from PATERNAL allele
AS - loss of expression from MATERNAL allele
Which genes are involved in PWS and AS?
PWS - SNURF/SNRPN, MKRN2, MAGEL2, NDN expressed from PATERNAL allele only. Loss of SNRPN enough to cause PWS
AS - UBE3A expressed from MATERNAL allele only in the brain. Encodes E6AP, essential for synapse development
What are the molecular mechanisms behind PWS?
- De novo 15q11-q13 deletion of paternal allele (70-75%)
- Maternal UPD15 (25-30%)
- Imprinting defect without ICR deletion (1%)
- PWS IC deletion - only cause PWS when inherited from father
What are the molecular mechanisms behind AS?
- De novo 15q11-q13 deletion of maternal allele (75%)
- Paternal UPD15 (1-2%)
- Imprinting defect without ICR deletion (3%)
- AS IC deletion - only cause AS when inherited from mother
- UBE3A mutation
How are PWS and AS tested for?
MS-MLPA - MLPA determines whether cause is 15q11-q13 deletion or ICR deletion
2-tube protocol:
1. Undigested reaction used for copy number determination.
2. Digested with HhaI - digests unmethylated double-stranded probe–DNA complexes.
Hypermethylation of SNRPN = PWS
Hypomethylation of SNRPN = AS
No deletion = UPD or imprinting defect without ICR deletion
Normal methylation = PWS unlikely, UBE3A sequencing for AS
UPD by microsatellite analysis (requires parental DNA)
Where is the PWS critical region?
What is the pattern of gene expression in normal individuals?
15q11-13
Genes are expressed from one parental allele only - functionally haploid
What is the phenotype of AS?
Dev delay, speech impairment, gait ataxia, LD, epilepsy, microcephaly, ‘happy demeanour’
What is the recurrence risk associated with different causes of PWS & AS?
Deletions, UPD, imprinting defect (without IC deletion) = <1%
IC deletion = 50% if inherited from father (PWS) or mother (AS)
