Fig. 4: IGFBP7 is elevated in the plasma and brain of PWScr^p−/m+ mice and proposed schema of IGFBP7 regulation by SNORD116 deletion.

(a) Schematic representation of the orthologous PWS region on mouse chromosome 7qC. Small nucleolar RNAs (snoRNA) genes are represented by bars (Snord116: 71 copies and Snord115: 136 copies), other genes locations are depicted with rectangles and ovals. Paternally expressed genes are indicated in blue, maternally expressed genes in pink. The imprinting center (IC) is shown by a gray oval. The orange line indicates the deleted area in the studied model of PWScr^p−/m+ mice. Drawing is not to scale. (b) Circulating Igfbp7 was 2.2-fold higher (P = 0.00034) in P7 PWScr^p−/m+ mice (n = 7) compared to wild-type (WT) littermates (n = 7). Normality was assessed by Shapiro–Wilk normality tests, and statistical differences were analyzed using the paired Student’s t-test. Data are expressed as mean ± SEM, ***P < 0.001. (c) Transcript levels of Igfbp7 in different mouse tissues PWScr^p−/m+ (n = 7) compared to WT littermates (n = 7). Igfbp7 were highly expressed in PWScr^p−/m+ brains. Data are shown as mean delta Ct values compared to pgk1 as the reference gene giving the more stable expression besides other housekeeping genes. A comparison was drawn by a 2-tailed Student’s t-test. Data are expressed as mean ± SEM. **P < 0.01, ***P < 0.001. (d) Proposed schema of IGFBP7 regulation by SNORD116 deletion and GHT in PWS. Both increased expression of IGFBP7 and proconvertase PCSK1/ PC1 deficiency could explain the raised IGFBP7 level in PWS patients, IGFBP7 being a potential target of PC1, which is downregulated in SNORD116-deleted neurons. Loss of SNORD116 results in an increase in IGFBP7 mRNA expression and a decrease in potential IGFBP7 cleavage by PC1, with high levels of secreted IGFBP7 in naive PWS patients. Growth hormone therapy (GHT) stimulates IGF1 production, which downregulates IGFBP7 mRNA expression and lowers its circulating level.