The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus

Abstract

T-associated maternal effect (Tme) is the only known maternal-effect mutation in the mouse. The defect is nuclear-encoded and embryos that inherit a deletion of the Tme locus from their mother die at day 15 of gestation. There are many genomically imprinted regions known in the mouse genome but so far no imprinted genes have been cloned. The Tme locus is absent in two chromosome-17 deletion mutants, Thp and the tLub2, and its position has been localized using these deletions to a 1-cM region. We report here that the genes for insulin-like growth factor type-2 receptor (Igf2r) and mitochondrial superoxide dismutase-2 (Sod-2) are absent from both deletions. Probes for these genes and for plasminogen (Plg) and T-complex peptide 1 (Tcp-1) were used in pulsed-field gel mapping to show that Tme must lie within a region of 800-1,100 kb. We also demonstrate that embryos express Igf2r only from the maternal chromosome, and that Tcp-1, Plg and Sod-2 are expressed from both chromosomes. Therefore Igf2r is imprinted and closely linked or identical to Tme.

M6P/IGF2R is mutated in squamous cell carcinoma of the lung

“…Genomic imprinting is an epigenetic form of gene regulation that results in the expression of only one parental allele, and a number of imprinted genes have been determined to be oncogenic targets (Falls et al, 1999;. The M6p/Igf2r gene is imprinted in both mice (Barlow et al, 1991;Wang et al, 1994) and rats (Mills et al, 1998), whereas imprinting of the M6P/IGF2R is a polymorphic trait in humans with most adults expressing both alleles (Falls et al, 1999;. Thus, imprinting of the M6P/IGF2R could result in allelic inactivation, a postulate supported by the discovery that 50% of patients with Wilms' tumor are imprinted at this locus (Xu et al, 1997).…”

Genomic imprinting and its relevance to genetic diseases

“…Heterozygotes for a mutant insulin-like growth factor II gene (/g/'2) that is mapped to a distal imprinted region of mouse chromosome 7 showed growth deficiency when the mutant allele came from the father, while those whose mutant allele was derived from the mother represented normal growth, the result indicating that the mouse /if2 is a maternally imprinted (or paternally expressing) gene (DeChiara et al, 1991). On the other hand, the gene for the receptor of Igf-II, Igf2r, was identified to be paternally imprinted, and this gene is responsible for ThP/Trne (Barlow et al, 1991). Thus, /gf2 and Igf2r is reversely imprinted.…”

“…A half of the offspring of a T hp mother are lethal, while those of a T hp father have a hairpin-like short tail. This "T-associated maternal effect, Trne" is caused by a DNA deletion on chromosome 17 (Barlow et al, 1991). It was suggested that the presence of a maternal copy of Tree is essential for normal development of the mouse embryo, namely, Tme is the maternally expressing locus and the paternal Tree copy is inactive in offspring.…”

Intragenomic conflict and cancer

“…The main function of mannose 6-phosphate receptors is the transportation of molecules to lysosomes for degradation (35). The IGF-2 type 2 receptor is paternally imprinted, so that it is exclusively expressed by the maternal genome (36). Apparently, the IGF-2r functions to degrade IGF-2 (37).…”