Parental genomic imprinting is the phenomenon in which the behavior of a gene is 
modified, depending on the sex of the transmitting parent [Peterson and Sapienza 
(1993): Annu Rev Genet 27:7-31]. Recent observations have revealed that the 
inheritance patterns, age-of-onset, severity, and etiology of certain human 
diseases can be explained by aberrations in the establishment or the maintenance 
of the imprint. Examples include the Prader-Willi, Angelman, and 
Beckwith-Wiedemann syndromes [Nicholls (1994): Am J Hum Genet 54:733-740], 
malignancy [Sapienza (1990): Biochim Biophys Acta 1072:51-61; Feinberg (1993): 
Nat Genet 4:110-113], and insulin-dependent diabetes mellitus (IDDM) [Julier et 
al. (1994) Nature 354:155-159; Bennett et al. (1995) Nat Genet 9:284-292]. We 
review the evidence that implicates an imprinted gene in the INS-IGF2 region of 
chromosome 11p15 in the etiology of IDDM (referred to as the IDDM2 locus) and 
show that in human fetal pancreas, INS is not imprinted, thus providing an 
argument against INS as the candidate gene. We also examine imprinting effects 
on the expression of IGF2 in components of the human immune system believed to 
be important in IDDM and show imprinted expression in fetal thymus as early as 
15 weeks gestation. We demonstrate further that in the circulating mononuclear 
cells of two individuals, lectin-stimulated IGF2 transcription was biallelic, 
indicating relaxation of imprinting, whereas in one individual, transcription 
was monoallelic. Finally, we review the current available data supporting a role 
for insulin-like growth factor-II (IGF-II) in the immune system and, more 
specifically, discuss the evidence supporting a role for the IGFs in the 
prevention of apoptosis. These data have led us to formulate a novel hypothesis 
that could mechanistically explain the involvement of the IDDM2 locus in the 
pathogenesis of IDDM.