A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig.

Most traits and disorders have a multifactorial background indicating that they are controlled by environmental factors as well as an unknown number of quantitative trait loci (QTLs). The identification of mutations underlying QTLs is a challenge because each locus explains only a fraction of the phenotypic variation. A paternally expressed QTL affecting muscle growth, fat deposition and size of the heart in pigs maps to the IGF2 (insulin-like growth factor 2) region. Here we show that this QTL is caused by a nucleotide substitution in intron 3 of IGF2. The mutation occurs in an evolutionarily conserved CpG island that is hypomethylated in skeletal muscle. The mutation abrogates in vitro interaction with a nuclear factor, probably a repressor, and pigs inheriting the mutation from their sire have a threefold increase in IGF2 messenger RNA expression in postnatal muscle. Our study establishes a causal relationship between a single-base-pair substitution in a non-coding region and a QTL effect. The result supports the long-held view that regulatory mutations are important for controlling phenotypic variation.

Inhibin B predicts oocyte number and the ratio IGF-I/IGFBP-1 may indicate oocyte quality during ovarian hyperstimulation for in vitro fertilization.

PURPOSE: To perform a retrospective analysis of 62 age-matched IVF-treated women in order to investigate whether levels of inhibin B, IGF-I, and IGFBP-1 in serum 2 days before oocyte retrieval and in follicular fluid at the day of oocyte retrieval might be useful as indicators of the ovarian ability to produce oocytes (ovarian reserve). METHODS: Patients were allocated into three groups on the basis of the number of oocytes retrieved. Group 1 ("low responders") had 0-3 oocytes, group 2 ("normal responders") had 6-11 oocytes, and group 3 ("high responders") had 12 oocytes or more. Levels of inhibin B, IGF-I, and IGFBP-1 in follicular fluid and in serum obtained 2 days before oocyte retrieval were analyzed and correlated to clinical parameters including estradiol levels, progesterone levels, follicle size, follicle number, and oocyte number. RESULTS: We found significant differences in inhibin B levels in the three groups. Inhibin B levels in follicular fluid and serum was strongly correlated to the number of oocytes retrieved (p < 0.01). The number of oocytes retrieved were also correlated to total FSH dose (p < 0.05), to estradiol 2 days before and at ovum pick-up (p < 0.05), to progesterone at ovum pick-up (p < 0.0001), to progesterone at embryo transfer (p < 0.05), and to the number of follicles (size 12-15 mm, p < 0.001, size > 15 mm, p < 0.01). Serum inhibin B also correlated to follicular fluid inhibin B (p < 0.01). Inhibin B was not correlated to pregnancy. In contrast, the ratio IGF-I/IGFBP-1 in serum as well as in follicular fluid was significantly higher in women who became pregnant (p < 0.05). CONCLUSIONS: The results show that inhibin B in serum 2 days before oocyte retrieval predicts number of oocytes retrieved. Since inhibin B in serum before oocyte retrieval in ovarian hyperstimulation was strongly predictive of the number of oocytes retrieved, it appears useful as a marker for ovarian response. Inhibin B did not predict treatment outcome, whereas the ratio IGF-I/IGFBP-1 in serum and follicular fluid was significantly higher in women who became pregnant. The ratio IGF-I/IGFBP-1 may thus reflect oocyte quality.

Transforming growth factor-beta1 in fetal serum correlates with insulin-like growth factor-I and fetal growth.

OBJECTIVE: To estimate whether transforming growth factor-beta1 in fetal serum obtained by umbilical cord sampling at delivery is correlated with fetal growth. We also estimated whether transforming growth factor-beta1 is correlated with insulin-like growth factor-I and insulin-like growth factor binding protein-1, which have been shown to correlate with fetal growth. METHODS: The active form of transforming growth factor-beta1 was analyzed in serum from cord blood from 68 fetuses by the enzyme-linked immunosorbent assay technique. Of the 68 pregnant women, 12 had preeclampsia, 14 had preeclampsia and intrauterine growth restriction, 15 had intrauterine growth restriction alone, and seven had fetuses that were large for gestational age (LGA). Twenty pregnancies with fetuses appropriate for gestational age (AGA) served as controls. RESULTS: Transforming growth factor-beta1 concentrations were significantly correlated with birth weight. The average transforming growth factor-beta1 concentration in the following groups were: intrauterine growth restriction, 22.4 +/- 2.7 microg/L; intrauterine growth restriction plus preeclampsia, 22.9 +/- 2.0 microg/L; preeclampsia without intrauterine growth restriction, 28.8 +/- 2.1 microg/L; LGA, 30.3 +/- 4.3 microg/L; and AGA, 36.8 +/- 2.0 microg/L. Transforming growth factor-beta1 levels were significantly lower in pregnancies complicated by intrauterine growth restriction and showed a positive correlation with birth weight (r = 0.48, P <.001). Furthermore, there was a positive correlation between insulin-like growth factor-I levels and birth weight (r = 0.36, P <.01) and a negative correlation between insulin-like growth factor binding protein-1 and birth weight (r = -0.32, P <.01). There was also a correlation between transforming growth factor-beta1 and insulin-like growth factor-I (r = 0.29, P <.05) and between transforming growth factor-beta1 and insulin-like growth factor binding protein-1 (r = -0.25, P <.05). CONCLUSION: Transforming growth factor-beta1 might be related to fetal growth in pregnancy. The results also support previous data showing that insulin-like growth factor-I and insulin-like growth factor binding protein-1 are related to fetal growth.

Altered expression of low affinity insulin-like growth factor binding protein related proteins in hepatoblastoma.

Hepatoblastoma is a poorly understood rare pediatric liver tumour. We have previously shown that the IGF-axis is seriously disrupted in this tumour type. With the recent discovery that several other proteins also have the potential to bind to IGFs called insulin-like growth factor binding protein related proteins (IGFBP-rPs), we undertook an examination of several such genes in a series of hepatoblastomas with matched normal liver tissue. The expression profiles obtained reveal that the expression of these genes are also disturbed in these tumours, and may have implications for our understanding of the IGF-axis and its importance in this disease.