20.03.10 Imprinted chromosomes and syndromes Flashcards
What is imprinting?
Epigenetic phenomenon that leads to parent-specific differential expression of a subset of mammalian genes
Summary of imprinting gene facts
- over 90 imprinted genes
- Can be complete or tissue specific
- Imprinted genes tend to form clusters (about 1Mb in length) which are rick in CpG islands and contain both mat and pat expressed genes
- Expression of these clusters is controlled by imprinting control regions (ICRs)
- Process controlled by DNA methylation
- ICRs are differentially methylated - i.e. DNA is only methylated on one parental allele
- Normally these patterns of methylation are stable once they are established - they are copied during cell division
- Methylation pattern is only reset during gametogenesis (to reflect the new parental sex)
5 mechanisms that can lead to imprinting disorders
1) UPD - both chromosomes come from the same parent
2) Deletion - loss of gene expression due to deletion of expressed gene on that allele or due to deletion of ICR
3) Duplication - doubles the expression of an imprinted gene
4) Mutation on the active allele
5) Epimutation - Specific hypomethylation or hypermethylation at an ICR (but DNA sequence is left unchanged)
What are the 6 imprinted regions linked to disease?
1) 6q24.6 - Transient neonatal diabetes
2) 7 - SRS
3) 11p15.5 - BWS/SRS
4) 14q32 - Temple syndrome/Kagami-Ogata syndrome
5) 15q11.2 - PWS/AS
6) 20q13.2 - Pseudohypoparathyroidism type 1b
What are the general phenotypic effects of imprinting disorders that are common across syndromes?
- Most imprinted genes are linked to growth and development of embryos, placental formation and metabolism
- Mat imprinted genes - linked to undergrowth
- Pat imprinted genes - linked to overgrowth
- ?some suggestions that assisted reproductive technologies could be linked to increased chance of imprinting disorder - as ART tends to happen around the time methylation patterns are established
BWS - background
- dysregulation of imprinted growth genes at 11p15.5
- 85% sporadic, 15% inherited
- Paediatric overgrowth disorder with variable symptoms - can include neonatal hypoglycemia, macrosomia (big at birth), macroglossia (large tongue), hemihyperplasia (half of body larger than other half), abdominal wall defect and embryonal tumors
- Critical region contains 2 domains - imprinting centre 1 and 2 (IC1 and IC2)
- Domain 1 - IC1 - regulates IGF2 (pat) and H19 (mat) expression. IC1 is methylated on paternal allele and unmethylated on maternal allele. ICR is H19DMR. So IGF2 is exp from pat allele and H19 is exp from mat allele.
- Domain 2 - IC2 - regulates CDKN1C (mat), KCNQ10T1 (pat) and KCNQ1 (mat) expression. IC2 is methylated on maternal allele but not on the paternal. ICR is KvDMR1. So KCNQ1OT1 is exp from pat allele and CDKN1C and KCNQ1 is exp from mat allele.
- In BWS you get increased expression of IGF2 and reduced expression of CDKN1C
BWS - causes (5)
- Loss of methylation of IC2 on maternal allele - get hypomethylation of KvDMR1 (40-50% of sporadic cases)
- Gain of methylation of IC1 on maternal allele - get hypermethylation of H19DMR (5-8% of sporadic cases)
- Paternal UPD (hypometh of KvDMR1 and hypermeth of H19DMR (20% of sporadic cases)
- CDKN1C LoF mutation on maternal allele (40% of familial cases and 5-10% of sporadic cases)
- Cytogenetic abnormality (dup, inv, trans involving 11p15.5)
SRS - background
- Clinically heterogeneous disorder - can have asymmetrical gestational growth restriction, small for age, relative macrocephaly, postnatal growth failure, feeding difficulties
- Mostly caused by maternal UPD7 or imprinting alternation at 11p15.5
SRS - causes (2)
1) Mat UPD7 - reduced expression of pat expressed genes or over expression of mat expressed genes on chromosome 7
- Two important regions:
7p11.2p13 - contains imprinted gene GRB10
7q31 - get segmental UPD7q - contains 3 imprinted genes (MEST, CPA4 and COPG2) and 2 imprinted non-coding RNAs
2) Imprinting alteration at 11p15.5
- Can get biallelic expression of H19 and biallelic silencing of IGF2 due to mat UPD11 (causes opposite phenotype to BWS - i.e. growth retardation)
- Can also get loss of methylation of IC1 on paternal allele causing increased H19 expression (30-50% of cases)
- Can also get cytogenetic abnormality (dup, inv, trans involving 11p15.5)
PWS - background
- Caused by loss of PATERNAL contribution at 15q11q13 (matUPD)
- Severe neonatal hypotonia, FTT, hyperphagia, mild-mod MR, hypogonadism, short stature, behavioural issues
- Deletions of paternal alleles - 75-80% cases
- matUPD - 20-25%
- Imprinting errors - 1-2%
AS - background
- Caused by loss of MATERNAL contribution at 15q11q13 (patUPD)
- Severe MR, ataxia, absent speech, inappropriate laughter, microcephaly, seizures
- Deletions of maternal alleles - 70-75% cases
- patUPD - 3-7%
- Imprinting errors - 2-3% (30-40% are mosaic)
- Point mutations - 14% in UBE3A gene
- 10% with no abnormalities detected
PWS/AS mechanisms
- Majority of genes in region are pat expression (SNURF-SNRPN, IPW, MAGEL2, MRKN3)
- Only mat expressed genes are UBE3A and ATP10A
- PWS IC - contains promotor and exon 1 for SNURF-SNRPN gene. Methylated on mat allele and unmethylated on pat allele
- AS IC - represses the activity of the PWS IC on the maternal allele.
Transient neonatal diabetes mellitus type 1 (TNDM) - background
- Form of neonatal diabetes that presents soon after birth
- Get spontaneous remission during infancy but can relapse
- Often get IUGR
- Get abnormal development/absence of pancreas or pancreatic islets and B-cells - leads to reduced or absent insulin
- Get over expression of two imprinted genes (PLAGL1 and ZAC/HYMAI). Normally only expressed on pat allele as promotor region is methylated on mat allele
- ZAC - zinc finger that regulates processes involved in production of insulin, and over expression can cause apoptosis of B-cells
TNDM - causes
1) PatUPD6 (40% of cases)
2) Duplication of 6q24 region on pat allele (32%)
3) Hypomethylation of maternal ZAC/HYMA1 (28%) - gene is normally silenced but here it is expressed. This can be just epigenetic loss of methylation or can be caused by mutation in ZFP57 - causes reduced binding of ZFP57 to TNDM locus, therby activating PLAG1
4) Hypomethylation of other imprinted loci scattered throughout genome can cause TNDM
UPD14 - background
- Get aberrant expression of genes at 14q32.2
- Pat expressed genes - DLK1 and RTL1
- Mat expressed genes - MEG3, RTL1as, MEG8
- IG-DMR - methylated on pat allele
- MEG3-DMR - unmethylated on mat allele
- Can get UPD, deletions, and epimutations in both disorders linked to UPD14
