Imprinting Disorders

Two other microdeletion syndromes, Prader-Willi syndrome (PWS) and Angelman syndrome (AS), exhibit parent-of-origin, or "imprinting," effects. For many years, it has been known that cytogenetically detectable deletions of chromosome 15 occur in a proportion of patients with PWS, as well as in those with AS. This seemed curious, as the clinical manifestations of the two syndromes are very dissimilar. PWS is characterized by obesity, hypogonadism, and mild to moderate mental retardation, whereas AS is associated with microcephaly, ataxic gait, seizures, inappropriate laughter, and severe mental retardation. New insight into the pathogenesis of these disorders has been provided by the recognition that parental origin of the deletion determines which phenotype ensues: if the deletion is paternal, the result is PWS, whereas if the deletion is maternal, the result is AS (Fig. 63-2). This scenario is complicated further by the recognition that not all individuals with PWS or AS carry the chromosome 15 deletion. For such individuals, the parental origin of the chromosome 15 region is again the important determinant. In PWS, for example, nondeletion patients invariably have two maternal and no paternal chromosomes 15 [maternal uniparental disomy (UPD)], whereas for some nondeletion AS patients the reverse is true (paternal UPD). This indicates that at least some genes on chromosome 15 are differently expressed, depending on which parent contributed the chromosome. Additionally, this means that normal fetal development requires the presence of one maternal and one paternal copy of chromosome 15. Approximately 70% of PWS cases are due to paternal deletions of 15q11-q13, whereas 25% are due to maternal UPD, and about 5% are caused by mutations in a chromosome 15 imprinting center. In AS, 75% of cases are due to maternal deletions, and only 2% are due to paternal UPD. The remaining cases are presumably caused by imprinting mutations (5%), or mutations in the UBE3A gene, which is associated with AS. The UPD cases are mostly caused by meiotic nondisjunction resulting in trisomy 15, subsequently followed by a normalizing mitotic nondisjunction event ("trisomy rescue") resulting in two normal chromosomes 15, both from the same parent. UBE3A is the only maternally imprinted gene known in the critical region of chromosome 15. However, several paternally imprinted genes, or expressed-sequence tags (ESTs), have been identified, including ZNF127, IPW, SNRPN, SNURF, PAR1, and PAR5. Chromosomal regions that behave in the manner observed in PWS and AS are said to be imprinted. This phenomenon is involved in differential expression of certain genes on different chromosomes. Chromosome 11 is one of these with an imprinted region, since it is known that a small proportion of individuals with the Beckwith-Wiedemann overgrowth syndrome have two paternal but no maternal copies of this chromosome

Reff:

Harrison's Internal Medicine > Chapter 63. Chromosome Disorders >