A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency

Abstract

Background IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation. Results We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from −1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth. Conclusion The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.

A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency

“…As expected, in the patient with the deletion of exons 4 and 5 serum IGF1 was undetectable (4), but the case with the p.Val92Met mutation showed an extremely high IGF1 concentration as measured by radioimmunoassay (5). In the French patient with partial IGF1 deficiency serum IGF1 concentrations varied between assays (10), while in the Argentinian case IGF1 concentrations showed unexplained variations using the same assay (1).…”

“…The deceased brother of the patient described by our group (5) had a similar phenotype. Thus, in contrast to the suggestion aroused by the title of the paper by Keselman et al (1), their observations have not really broadened the clinical phenotype, but rather confirmed it. The clinical features of this condition have confirmed the findings in Igf1-knockout mice (6, 7) that IGF1 is a key factor in intrauterine growth and brain and inner ear development and provided the insight that IGFI secretion is independent of GH in utero.…”

“…For the two siblings described by our group, we showed that there was no dominant negative effect of the truncated protein (16). Further, relatives of a patient with a homozygous IGF1 mutation who are heterozygous carriers of the mutation are relatively short (1,4), which was statistically confirmed in the large pedigree studied by our group, in which mutation carriers had a mean height SDS of −1.0 vs −0.4 in carriers of the wild-type gene (P = 0.04) (5). In addition, the heterozygous IGF1 splicing variant described by Fuqua et al segregated in a large pedigree with short stature (14).…”

“…In contrast, the adult with the Val92Met mutation just had a mild glucose intolerance (fasting glucose 6.2 mmol/L, insulin 13 mU/L, HbA1c 5.7%), though functional studies showed that binding or activation of both insulin receptor isoforms was not detectable even at micromolar concentrations (12). The patient described by Keselman et al (1) and the patient carrying the Arg84Gln mutation did not show insulin resistance (10).…”

Identifying therapeutic drug targets for rare and common forms of short stature

“…Entire gene deletions and/or mutations causing loss of protein function in SHOX, IGF1R, NPPC, NPR2 have been reported in familial short stature with various degrees of severity (Table 1, Supplementary Table 6). 15,[30][31][32][33] Conversely, duplications, deletions of repressor regions, translocations and missense mutations leading to GoF in these genes were reported in individuals with tall stature or overgrowth. [34][35][36][37][38] GoF mutations are hard to identify from in-silico predictions and usually require functional validation.…”