Genomic imprinting: genetic mechanisms and phenotypic consequences in Prader-Willi and Angelman syndromes

Chromosomal 15q11-q13 region is of great interest in Human Genetics because many structural rearrangements have been described for it (deletions, duplications and translocations) leading to phenotypes resulting in conditions such as the Prader-Willi (PWS) and Angelman (AS) syndromes which were the first human diseases found to be related to the differential expression of parental alleles (genomic imprinting). Contrary to Mendelian laws where the parental inheritance of genetic information does not influence gene expression, genomic imprinting is characterized by DNA modifications that produce different phenotypes depending on the parental origin of the mutation. Clinical manifestation of PWS appears when the loss of paternally expressed genes occurs and AS results from the loss of a maternally expressed gene. Different genetic mechanisms can lead to PWS or AS, such as deletions, uniparental disomy or imprinting mutation. In AS patients an additional class occurs with mutations on the UBE3A gene. Studies of PWS and AS patients can help us to understand the imprinting process, so that other genomic regions with similar characteristics can be located, and different syndromes can have their genetic mechanisms elucidated. Departamento de Biologia, Instituto de Biociências, USP, Caixa Postal 11.461, 05422-970 São Paulo, SP, Brasil. Send correspondence to C.F. Fax: +55-11-818-7419. E-mail: [email protected] 716 Fridman and Koiffmann occur between 1 and 6 years of age (Butler, 1990; Holm et al., 1993) and marks the second phase of the syndrome, characterized by neuropsycomotor delay, hyperphagia with obesity, short stature, short hands and feet and mental retardation with learning disabilities (Figure 1A) (q.v. Fridman, 1997). Some individuals present hypopigmentation, high pain threshold (Ledbetter et al., 1981; Butler, 1990), obsessivecompulsive disorder, depression, violent episodes and inappropriate social behavior (Holm et al., 1993; Cassidy, 1997). Einfeld et al. (1999) found that anti-social and psychopathological behavior was more frequent in PWS individuals than in a control group of mentally deficient patients. PWS patients show a higher degree of irritability, as well as stubbornness, a tendency to be argumentative, possessive, and persevering, and have a tendency to steal and to lie. Although many clinical manifestations of PWS seem to be the result of hypothalamic deficit, no structural defect in the brain have been found, so any such deficit must be functional, but its exact nature remains unknown (Cassidy, 1997). Genetically, PWS is caused by the absence of paternal alleles that are normally active in the 15q11-q13 region, with the maternal alleles normally being inactive due to the genomic imprinting. Paternal deletion of the 15q11q13 region (70% of cases) or maternal uniparental disomy (UPD) (20-25% of cases) can lead to the absence of paternal alleles (Robinson et al., 1991; Mascari et al., 1992). Translocations or other structural anomalies of chromosome 15 are found in about 5% of cases, resulting in paternal deletion or UPD15 (Rivera et al., 1990; Smeets et al., 1992; Qumsiyeh et al., 1992; Donnai, 1993; Freeman et al., 1993; Reeve et al., 1993; Smith et al., 1993, 1994; Vickers et al., 1994). About 1-5% of cases, including families, have imprinting center (IC) mutations (Reis et al., 1994; Sutcliffe et al., 1994; Buiting et al., 1995; Dittrich et al., 1996; Saitoh et al., 1996, 1997). The absence of patients with point mutations in a single gene suggests that PWS is a contiguous gene syndrome, caused by the loss of two or more paternally expressed genes (Nicholls, 1993b, 1994; Ohta et al., 1996). Clinical comparisons between deleted and UPD patients have not revealed significant differences, although hypopigmentation occurs in patients with deletion and increased maternal age is a factor in UPD cases (Butler, 1989; Robinson et al., 1991; Gillessen-Kaesbach et al., 1995) due to the known correlation between maternal age and nondisjunction events (Robinson et al., 1991, 1993). The nonimprinted P gene responsible for oculocutaneous albinism (OCA2) maps on the distal part of the 15q11-q13 and is deleted in the majority of PWS cases with deletion (Spritz et al., 1997).