The Principles of Clinical Cytogenetics - Extra Materials - Springer

518 Jin-Chen Wang
(50) and IGF2 (paternal allele active) (51,52), both located on the short arm of chromosome 11 at
band 11p15. In the case of IGF2, although it is the paternal allele that is active, the maternal allele is
hypomethylated and the paternal allele is methylated at the 5' portion of exon 9, similar to the findings
in mouse studies. Unlike this gene in mice, the human IGF2R gene is not imprinted (53).
A difference in DNA replication timing of maternal and paternal alleles of imprinted genes has
also been observed (54–57). Cell cycle replication timing has been shown to correlate with gene
activity: genes that are expressed generally replicate earlier (58,59). Furthermore, most genes on
homologous chromosomes replicate synchronously (60). This is not the case for imprinted genes.
Using fluorescence in situ hybridization (FISH) (see Chapter 17) on interphase nuclei and scoring for
the stage of the two alleles in the S-phase, Kitsberg et al. (54) showed that the imprinted genes H19,
Igf2, Igf2r, and Snrpn in mice and their corresponding positions in the human genome all replicate
asynchronously, with the paternal allele replicating early. Studies of genes in the 15q11-q13 region in
humans demonstrated that most show a paternal-early/maternal-late pattern, with some exhibiting the
opposite pattern (55,56). Therefore, it appears that imprinted genes are embedded in DNA domains
with differential replication patterns, which might provide a structural imprint for parental identity (55).
Thus, the process of genomic imprinting is very complex, and although DNA methylation plays a
critical role in genomic imprinting, the process is much more complex than simply inactivating a
gene by methylation. It could involve an interaction among DNA methylation, chromatin compaction
(61), DNA replication timing, and potentially other mechanisms (62).
GENOMIC IMPRINTING AND HUMAN DISEASES
Genomic imprinting provides an explanation for the observation that the transmission of certain
genetic diseases cannot be explained by traditional Mendelian inheritance, but that the phenotype
depends on whether the gene involved is maternally or paternally inherited. Conversely, the existence
of such diseases provides evidence that genomic imprinting occurs in man. Human conditions
that fall into this category include certain deletion/duplication syndromes, a number of cancers, and
many situations arising from uniparental disomy (UPD). In addition, imprinted genes could also
contribute to modification of disease phenotype, such as is observed in Albright hereditary osteodystrophy,
language development, and some psychiatric disorders and complex behavioral phenotypes,
including bipolar affective disorder and catatonic schizophrenia (63–65).
Chromosome Deletion/Duplication Syndromes
Prader–Willi Syndrome/Angelman Syndrome
The best-studied examples of genomic imprinting in human disease are the Prader–Willi and
Angelman syndromes. These are clinically distinct disorders; both map to the chromosome 15q11q13
region (66–68), but they involve different genes (69,70). The etiologies of these disorders
include (1) the absence of a parent-specific contribution of this region as a result of either deletion
(71–74) or UPD (75–79), (2) disruptions in the imprinting process (80–84), and (3) mutations
within the gene (70,85).
The clinical phenotype of PWS has been well characterized (86). Briefly, it includes hypotonia
during infancy, obesity, hyperphagia, hypogonadism, characteristic facies, small hands and feet,
hypopigmentation, and mental deficiency. Approximately 70% of cases have an interstitial deletion
of a 4-Mb sequence at 15q11-q13 on the paternally derived chromosome 15 (61). Approximately
25% of cases are the result of maternal UPD for chromosome 15 (75,78), and 2% or so as a result of
an abnormality of the imprinting process, causing a maternal methylation imprint on the paternal
chromosome 15 (82,83). Many paternally expressed transcripts have been identified in a cluster in
the proximal part of the 15q11-q13 region. These include ZNF127, NDN, MAGEL2 (NDNL1),
SNURF/SNRPN, PAR-5, IPW, PAR-1, PWCR1, and at lease seven additional transcripts (reviewed in
ref. 87,88–90). This clustering of paternally expressed transcripts suggests strong regional control of