Levels of IGFBP7 Protein May Aid in Managing Growth Hormone Therapy

A protein that interacts with insulin growth factor 1 (IGF1) may be important in managing children with Prader–Willi syndrome (PWS) on growth hormone therapy, a study has found.

The levels of that protein, called IGFBP7, were found to be higher than normal in PWS children who carry deletions in a gene known to cause the disease, and to return to normal with the therapy’s use.

The study, “SNORD116 and growth hormone therapy impact IGFBP7 in Prader–Willi syndrome,” was published in the journal Genetics in Medicine.

Children with PWS have low levels of growth hormone, so that treatment with this hormone is often recommended. However, its use may lead to a marked increase in IGF1, which is similar in structure to insulin — the hormone that regulates glucose (sugar) levels in the blood. As such, besides fueling growth, IGF1 has some ability to lower glucose levels in the blood.

Some proteins, called growth hormone binding proteins, can regulate growth hormone levels, including those of IGF1, under growth hormone therapy. One such protein is IGFBP7.

Researchers wondered if tweaking the levels of IGFBP7  might be a means of better managing PWS in children being given growth hormone therapy. They also wondered if IGFBP7 itself might be regulated by SNORD116, a gene located in chromosome 15. Loss of genes in a particular region of chromosome 15 can cause PWS, and small deletions in the SNORD116 gene have been found to be enough to cause the key symptoms of the disease.

“We aimed to clarify the role of SNORD116 in cellular and animal models with regard to growth hormone therapy,” the researchers wrote.

First, they looked at the effects of growth hormone therapy in 21 children new to this treatment. Their mean age at the start of therapy was 2.1 years. After one year of treatment, started at a dose of 0.035 mg/kg each day, a fourfold rise in IGF1 levels was seen.  In the 11 children for whom bone densitometry data were available, fat mass was decreased and lean mass was increased.

Researchers also looked at blood plasma levels of IGFBP7 in 13 of the enrolled children. Initial measurements found their IGFBP7 levels were nearly twice as high as those of age-matched healthy children as a control group. After one year of therapy, however, they had normalized to the levels of those healthy children. IGFBP7 was inversely correlated with IGF1, meaning that the lower the levels of IGFBP7, the higher the levels of IGF1.

Next, the researchers collected fibroblast cells from the skin of PWS and healthy children. In the laboratory, they converted those fibroblasts into immature, stem-like cells to later develop into mature neurons. Those neurons retained the genetic characteristics of the original source, which in the case of PWS children included deletions — large or small— in the SNORD116 gene.

When the scientists treated the neurons with IGF1, the levels of IGFBP7 decreased, especially in cells with a small deletion in the SNORD116 gene. In control neurons derived from healthy children, no changes were noted in IGFBP7 levels.

To understand the reason behind these differences, the investigators looked at genes involved in correctly processing hormones, as it could affect the production of an intact IGFBP7. The levels of all three tested genes (PCSK1, PCSK2, and NHLH2) were lower in PWS neurons than in control neurons.

Finally, a mouse model of PWS, in which a piece of genetic information homologous to that of the human SNORD116 is missing, was used to confirm the findings with IGFBP7. These mice show impaired growth, mild hyperphagia (excessive eating), impaired satiation (feeling full), and low levels of IGF1 — much as is seen in patients.

Similar to the findings in PWS children, IGFBP7 blood levels in the mice were approximately double those of control mice. The levels of messenger RNA, which provides the information to make the IGFBP7 protein, were higher in the brain, but not in liver, heart, and fat tissue.

“Increased IGFBP7 expression is specifically observed in PWS neuronal cells and decreased under IGF1. High IGFBP7 levels may be involved in degenerative mechanisms and, indeed, PWS is now considered as a degenerative disease,” the researchers wrote.

“Therefore, decreasing IGFBP7 levels under [growth hormone therapy] may have positive effects on the cognition of PWS patients,” they added.