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Biological Research

Print version ISSN 0716-9760

Biol. Res. vol.34 n.2 Santiago  2001

http://dx.doi.org/10.4067/S0716-97602001000200020 

Genomic imprinting and human chromosome 15

GABRIELA M. REPETTO

Department of Pediatrics, Facultad de Medicina, P. Universidad Católica de Chile, Santiago

Corresponding Author: Gabriela Repetto. Dept. of Pediatrics, Facultad de Medicina, P. Universidad Católica de Chile. Marcoleta 367, Santiago, Chile. FAX: (56-2) 638-4307. Phone: (56-2) 354-3753. Email: grepetto@med.puc.cl

Received: May 20, 2001. Accepted: July 10, 2001

ABSTRACT

Genomic imprinting is a reversible phenomenon that affects the expression of genes depending on their parental origin. The best characterized human disorders resulting from an alteration of the imprinting process are Angelman and Prader-Willi syndromes. They are due to the lack of active maternal or paternal genes, respectively, from chromosome region 15q11q13. Most cases arise via interstitial deletions. We review evidence that other common cytogenetic alterations of this region, interstitial and supernumerary duplications, could be the reciprocal products of the deletions and are also affected by the imprinting phenomenon, given the predominance of maternally-derived duplications in patients ascertained due to developmental delays or autistic features.

Key Terms: chromosome 15; chromosome 15 deletions/duplications; genomic imprinting

Genomic imprinting

Genomic imprinting is an epigenetic phenomenon that results in differential expression of alleles depending on their parental origin. Although this feature has been well known to biologists for years in different animal models and particularly through pronuclear transplantation experiments, its clinical consequences in humans have only recently begun to be elucidated (Hoppe and Illmensee 1977, Sapienza and Hall 1995). It is estimated than less than 1% of the human genome is subject to imprinting, and several clusters of imprinted genes have been identified. There is evidence that the process of preferential silencing of alleles occurs during meiosis, is mediated through DNA methylation, as well as allele-specific replication timing differences and is "reset" in each generation (Nicholls 1994, Knoll et al 1994, Ledbetter and Engel 1995). The process of imprinting and its alterations are now known to be involved in several human disorders including certain types of cancer; this review will focus only on the imprinted chromosome region 15q11q13.

Human chromosome 15q11q13 region

One of the best characterized human imprinted regions is located in the proximal long arm of chromosome 15. Several genes have been identified in this region, and at least seven genes and transcripts are known to be active only from the paternal copy: ZNF127, NDN, SNURF, SNRPN, IPW, PAR1 and PAR5 (Robinson et al 1997, Cassidy et al 2000). Only one gene in this region, UBE3A, has been shown to be expressed exclusively from the maternal allele (Kishino et al 1997, Matsuura et al 1997), and this differential expression is particularly evident in the brain (Rougeulle C et al 1997, Vu and Hoffman 1997). Murine studies have shown maternal-only expression of UBE3A in specific portions of the brain, such as Purkinje cells, regions of the hippocampus and the olfactory nerve (Albrecht et al 1997). In addition, studies of patients with small deletions or translocations have demonstrated the presence of a cis-acting imprinting center (Ohta et al 1999). One non-imprinted gene from this region, the P gene, involved in melanin biosynthesis, is worth mentioning due to the pigmentary abnormalities seen in some patients with cytogenetic alterations of this region (see below) (Lee et al 1994).

Human disorders due to imprinting effects of chromosome 15

"Missing active genes": Angelman and Prader-Willi syndromes

The clinical consequences of the imprinting process and its defects were first described in patients with Angelman (AS) and Prader-Willi (PWS) syndromes, two phenotypically distinct causes of mental retardation (MR). Patients with AS have severe MR, absent or minimal speech, seizures, ataxic gait, bouts of excessive laughter, micrognathia, and, in some cases, hypopigmentation (Williams et al 1995). In contrast, patients with PWS have neonatal central hypotonia, mild cognitive impairment, hyperphagia of childhood onset resulting in obesity, hypogonadotrophic hypogonadism, small hands and feet, characteristic facial features and some also have hypopigmentation (Holm et al 1993). Both syndromes, which clearly differ in their phenotypic features, share common etiologies: approximately 70% of patients have a deletion of 15q11q13, usually detectable with the use of techniques such as fluorescence in situ hybridization (FISH) (Cassidy et al 1996, 2000). The deletions involve the maternally-inherited copy in individuals with AS, whereas those with PWS have deletions of the paternal allele (Knoll et al 1989). The deletion of the P gene is thought to be the cause of the hypopigmentation. Molecular analysis of the deletions have shown that most patients share a common deleted region of about 4Mb, with proximal breakpoints between markers D15S18 and D15S541 or between D15S541 and D15S543, and distal breakpoints between D15S12 and D15S24 (Kuwano et al 1992, Christian et al 1995, Amos-Landgraf et al 1999). This clustering of breakpoints is suggestive of instability of the region.

Nearly 30 % of patients with PWS and 10% of those with AS have uniparental disomy (UPD) of chromosome 15, which is the inheritance of both homologues from the same parent (Nicholls 1993, Cassidy et al 2000). This abnormality appears to result from trisomy or monosomy rescue and leads to the absence of the normal biparental contribution of genes in this region (Ledbetter and Engel 1995). Uniparental disomy is routinely assessed in clinical laboratories either by microsatellite analysis, or by evaluating methylation status, either with Southern blot or methylation-specific PCR (Cassidy et al 1996, Kubota et al 1996).

Both mechanisms, microdeletions and UPD, appear to be sporadic events of low recurrence risk to siblings of affected patients. Some cases of recurrent AS and PWS in families have been reported. The underlying mechanisms have either been imprinting center mutations or deletions in PWS (Buiting et al 1994 and Ohta et al 1999) and in fact, mutations of the maternal copy of UBE3A in AS cases (Kishino et al 1997, Matsuura et al 1997) consistent with the notion that the latter is a monogenic condition. When the mother is a mutation carrier, the risk to her offspring of having AS is 50%. As stated above, UBE3A, which codes for a protein involved in ubiquitination, is the only known gene from the region that is expressed solely from the maternal copy. It is unclear whether the PWS phenotype is due to lack of one or several genes; the current thought is that it corresponds to a contiguous gene syndrome. In summary, an absence of contribution of paternal genes in the region results in PWS, an absence of maternally-active genes results in the AS phenotype, and several mechanisms could account for these phenomena.

"Extra genes": Supernumerary and Interstitial duplications

Other rearrangements can affect this chromosomal region, the most common being duplications, which can be either supernumerary or interstitial. The supernumerary duplications are frequently found as bisatellited dicentric chromosome 15 (dic (15)). These are one of the most common supernumerary markers, accounting for 50% of those found during routine karyotyping (Webb 1994). Based on the presence or absence of genes from the common AS/PWS region, these markers can be classified into small and large dic (15)s, that also differ in their clinical consequences (Webb 1994). Small dic (15)s can be familial, and in most cases are associated with a normal phenotypes, but large dic (15)s are usually seen in patients with developmental delays and autism or autistic-like features, usually accompanied by other findings such as hypotonia, seizures and characteristic facial appearance. Molecular analyses of these markers have shown that the small dic (15) have breakpoints similar to the proximal deletion breakpoint as described above, between D15S18 and D15S541 or D15S541 and D15S543. They generally do not contain extra copies of the imprinted genes, and they can be either of maternal or paternal origin. In contrast, there is a wider variation in the size of large dic (15)s, with some extending to the common distal deletion breakpoint between D15S12 and D15S24, but with some markers of even larger extension (Cheng et al 1994). This implies that these patients have tetrasomy for genes from the imprinted region. Surprisingly, most of the reported patients have dic (15)s derived from the maternal chromosomes, the majority derived from both homologues, suggesting that they originated in meiosis I (Wolpert et al 2000). Gene expression studies are lacking, probably due to the absence of exclusively maternal active genes that could be assessed in blood or other samples. One recent study using RT-PCR showed an apparent excess of transcript of SNRPN in an individual with a large dic (15) and autistic-like features compared to control sequences, suggesting that the excess genes may be able to escape the imprinting process (Muralidhar et al 1999). The relationship of this finding to the cognitive phenotype is unclear.

Studies of individuals with interstitial duplications that result in trisomy for the genes in the region also show breakpoints that are similar to the deletions. Patients with maternally derived duplications have been identified in the course of the evaluation of developmental delays, and it appears that paternal duplications are asymptomatic (Cook et al 1997, Repetto et al 1998).

The predominance of maternally-inherited duplications suggests that the events that lead to the duplications are either more common during female meiosis or that there is a bias of ascertainment, which may be due to a normal or milder phenotype or to early lethality of paternally derived duplications. Studies of patients ascertained in an unbiased fashion, for example, during prenatal diagnosis, will help clarify the significance of the observations.

CONCLUSIONS

Imprinting is a complex phenomenon that modifies simple Mendelian inheritance. Its implications for humans are only recently being recognized, particularly through the studies of diseases that result from abnormalities in the normal process of biparental inheritance. It is noteworthy that the described alterations of chromosome region 15q11q13 share common breakpoints, which suggests that there could be a common mechanism for these abnormalities. It is possible that the alterations result from unequal crossing-over events in meiosis, and that the deletions and duplications are reciprocal products. This has been described for other disorders, such as Charcot-Marie-Tooth type IA and hereditary neuropathy with liability to pressure palsies in chromosome 22 (Chance et al 1994). Clusters of repeat sequences have been described in the common breakpoints in chromosome 15, making this a plausible hypothesis (Amos-Landgraf et al 1999).

It is also evident that these disorders share the presence of varying degrees of cognitive dysfunction, although the specific phenotypes are quite different. This could be due to the clustering of genes that code for neurotransmitter receptors such as gamma amino butyric receptor subunits (Greger et al 1995, Cassidy et al 2000). Cytogenetic abnormalities of chromosome 15 are the single most common known cause of autistic disorder. In addition, linkage studies in individuals with this and other related disorders without cytogenetic abnormalities have shown positive results for markers in this region, suggesting the presence of susceptibility genes (Cook et al 1998). Clearly, much more is to be learned about the imprinting process, its implications for human disease and particularly the disorders described here that account for a significant proportion of causes of cognitive disabilities.

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