This phenomenon is explained by genomic imprinting. Imprinting is an epigenetic phenomenon, a nonheritablechange in the DNA that causes an alteration in gene expressionbased on parental origin of the gene. PWS is caused by deficiency of the protein product of the gene SNRPN (small nuclearribonucleoprotein). Although present on both maternally andpaternally derived chromosome 15, SNRPN is expressed onlyin the paternally derived chromosome. Expression is blocked inthe maternal chromosome because the bases of the open readingframe are methylated; this physical change in the DNA preventsgene expression. PWS results whenever a paternal chromosome15 is missing, either through deletion or through UPD.
AS results from a lack of expression of ubiquitin-protein ligase E3A (UBE3A), a second gene in the chromosome 15q11.2 region. UBE3A is normally expressed only in the maternally derived chromosome 15. Although present in paternal chromosome 15, UBE3A is methylated, and gene expression is blocked. Therefore, if either the critical region of maternal chromosome 15 is deleted, or paternal UPD occurs, the individual will manifest symptoms of AS.
Expansion of a Trinucleotide Repeat
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More than 50% of human DNA appears as repeat sequences, two or three bases repeated over and over again. Disorders caused by expansion of trinucleotide repeats include Fragile X syndrome, Huntington disease, myotonic dystrophy, Friedreich ataxia, and the spinocerebellar ataxias. Although an increase in the number of the three repeated bases is at the heart of each disorder, the molecular mechanism differs.
Fragile X syndrome (FRAX), which occurs with a frequency of approximately 1 in 2000 children, is the most common cause of inherited intellectual disability. Features include characteristic craniofacial findings (large head; prominent forehead, jaw, and ears); macro-orchidism with testicularvolume twice normal in adulthood; a mild connective tissue disorder, including joint laxity, patulous eustachian tubes, and mitral valve prolapse; and a characteristic neurobehavioral profile, including intellectual disability (ranging from mild to profound) and autism spectrum disorders.
Positional cloning in the Xq27 region identified a tripletrepeat region composed of one cytosine and two guanineresidues (CGG). These repeats occur in the CpG island, apart of the promoter region of a gene that has been calledFMR1. Unaffected individuals who have no family historyof FRAX have 0 to 45 CGG repeats (most have 25 to 35). Inindividuals with FRAX, the number of repeats is greater than200; such people are said to have a full mutation. Between these two categories, a third group has 56 to 200 repeats;always phenotypically normal, these individuals are premutation carriers.
FRAX results from a failure to express FMRP, the protein product of the FMR1 gene. “Fragile X Mental Retardation Protein” (FMRP) shuttles mRNA between the nucleus and cytoplasm in the central nervous system and other areas (e.g., the developing testis) during early embryonic development. Although FMRP is produced in unaffected individuals and premutation carriers, in those with the full mutation, FMRP transcription of the protein is blocked because the large number of CGG repeats in the CPG island become methylated (an epigenetic phenomenon). Thus, FRAX occurs as a consequence of a loss-of-function mutation—the failure of expression of FMRP because of methylation of the promoter sequence.