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

Author:

Keselman Ana Claudia1,Martin Ayelen1,Scaglia Paula Alejandra1,Sanguineti Nora María1,Armando Romina2,Gutiérrez Mariana1,Braslavsky Débora1,Ballerini María Gabriela1,Ropelato María Gabriela1,Ramirez Laura1,Landi Estefanía1,Domené Sabina1,Castro Julia F1,Cassinelli Hamilton1,Casali Bárbara1,del Rey Graciela1,Barros Ángel Campos3,Nevado Blanco Julián3,Domené Horacio1,Jasper Héctor1,Arberas Claudia2,Rey Rodolfo A1,Lapunzina-Badía Pablo3,Bergadá Ignacio1,Pennisi Patricia A1

Affiliation:

1. 1Centro de Investigaciones Endocrinológicas ‘Dr. César Bergadá’ (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina

2. 2Servicio de Genética, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina

3. 3INGEMM, IdiPAZ, Hospital Universitario La Paz, Madrid & CIBERER (U753), ISCIII, Madrid, Spain

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.

Publisher

Bioscientifica

Subject

Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism

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