Imprinting and Uniparental Disomy (copy)

mechanisms and associated disorders

Imprinting mechanism

DNA methylation, post-translational histone modification, chromatin structure, noncoding RNAs (RNAi)

Uniparental disomy occurrence

can occur as a random event during the formation of egg or sperm cells or may happen early in fetal development, UPD for some chromosomes have no adverse effect on an individuals but can result in abnormality through aberrant genomic imprinting

UPD definition

two copies or parts of a chromosomes inherited from one parent

heterodisomy: same parental source, 2 chromosome

isodisomy: same parental source, same chromosome

When UPD is associated with phenotypic abnormalities

chromosome or chromosome segment involved carrier genes are imprinted

genes express autosomal recessive condition from a single carrier parent

CFTR gene location

chromosome 7

In prenatal sample

aneuploid cell line with gain/loss of chromosome

not all mosaicisms have potential to become UPD

other UPD cytogenetic warnings

robertsonian translocation, inversion, unusual heteromorphic chromosomal pattern, knowledge of parental translocation/inversion

Mechanism

• triaomic rescue

• Monosomic rescue

• Segmental UPD

• Gametic complementation

Trisomic rescue (most common)

Mechanism: early mitotic loss of 1 of trisomy —> become disomic

maternal upd more likely since nondisjunction happens more frequently in oogenesis

2/3 —> loss becomes normal phenotype

1/3 —> loss leads to UPD

UPD type: mixture of heteroisodisomy and isodisomy

Pericentromeric region:

1. Heterpdosomy → origin from meiosis 1 → Mosaicism present

2. 2 isodisomy → meiosis 2 → present

Monosomic rescue

one chromosome from a normal gamete is duplicated when paired with nullisomic gamete to restore euploidy

Upd type: complete isodisomy

Pericentromeric region: isodisomy

Origin: mitosis

Mosaicism: absent

nondisjunction at meiosis II —> isodisomic

Gametic complementation (post-fertilization error)

fusion of 2 particular gametes, both coincidentally abnormal, one nullisomic other disomic for same chromosome

rare, can expect heterodisomic and isodisomic lines

Mechanism:

1. Mitotic non-disjunction with dup → upd type complete isodisomy → pericenteomeric region isodisomy → origin mitosis → Mosaicism present

2. Mitotic recombination of gene conversion → segmental isodisomy → isodisomy or biparental → mitosis → present

segmental UPD

somatic recombination where exchanged region is imprinted

Mechanism: fertilization of disomic and nullisomic gametes

Upd type: mixture of hereroisodisomy and isodisomy

Pericenteomeric region:

1. Heterodisomy → origin: meiosis 1 → Mosaicism absent

2. Isodisomy → meiosis 2 → absent

Strategies for detecting UPD

• examine more than one recessive disorder

• Lacking deletion

• Focus on chro with imprinted genes

• Examine with apparent balanced trans or chro rearr with ab phenotype

• Chromost often involve in germ cell, look for UPD, spontaneous abortuses w/ recessive disorders

UPD in Prader-Willi

Maternal 15q11-13, SNRPN and ZNF127

Maternal UPD is also confirmed by the inheritance of both copies of maternal chro 15 loci in the affected child

Absence of paternal alleles at GABRB3 and D15S113

Prader-Willi molecular analysis

Absence of paternal alleles

maternal UPD also confirmed by inheritance of both copies of maternal 15 in child

UPD in Angelman

paternal 15q11-13, unknown gene

actual mutations detected in UBE3A, SNRPN not methylated and expressed

UPD in Silver-Russell Syndrome

chromosome 7, unknown genesS

low birth rate d/t intrauterine growth retardation, short stature, triangular shaped face, scaphocephaly (long narrow head at birth), normal head size appearing large b/c reduced body length/weight, 5th finger clinodactyly (incurving), poor appetite, developmental delays

UPD in Beckwith-Wiedemann

paternal, 11p15.5 often segmental, candidate imprinted genes are IGF2(pat) and H19(mat)

macroglossia (large tongue), giantism and organomegaly, abdominal wall defects, ear creases, renal abnormalities, predisposition for developing Wilms’ Tumor

Maternal UPD chromosome 14

14p32, include reciprocally imprinted DLK1 and GTL2 genes

low birth weight, developmental delay, precocious puberty, small hands, scoliosis, broad forehead, fleshy nasal tip, otitus media

Summary

UPD results from 2 simultaneous/ subsequent aberrations in cell division leading to the developing zygotehaving 2 copies of himiligousgenetic material from the same parent

Trisomic rescue is the most common

UPD has been observed in nearly every chro number except 12, 18, 19 and Y

The most common UPD chr is 15

UPD does not necessarily lead a an Ab phenotype

A normal phenotype result from UOD of imprinted genes

Imprinted genes have diff expression/methylation patterns on maternal vs paternal homologous generic segments