A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency

Abstract

T he insulin-like growth factors (IGFs; somatomedins) comprise a family of peptides that play important roles in mammalian growth and development. The principal members of this family are IGF1 and IGF2. IGF1 (somatomedin C), a 70 residue basic polypeptide, mediates many of the growth promoting actions of growth hormone (GH) and has metabolic and mitogenic effects.1 The major source of circulating IGF1 is the liver, but it is also produced in a wide variety of tissues and has endocrine and paracrine modes of action. The mature IGF1 peptide has A, B, C, and D domains with homology to insulin, and is highly conserved.2 It is produced as an inactive precursor, pre-pro-IGF1, with an additional carboxyterminal E region that plays an important role in the maturation of normal IGF1 peptide. This regulatory region is obtained by alternative splicing of the last two exons. IGF1 resides on the long arm of chromosome 12 (12q 22-24.1), 3 and several molecular studies have demonstrated that the structure of this gene is very complex. The gene contains six exons, which extend over more than 85 kb on chromosomal DNA. For human IGF1, two potential primary translation products exist: IGF1A and IGF1B, with sizes of 153 and 195 amino acids respectively. The two precursors are synthesised from distinct messenger RNAs produced by alternative splicing of the primary transcript. IGF1A mRNA contains exons 1, 2, 3, 4, and 6 of the human IGF1 gene while IGF1B is encoded by exons 1, 2, 3, 4, and 5. It has been speculated that IGF1B plays the major role during intrauterine growth, while the same function during postnatal growth is taken over by IGF1A. 4 Recent studies have focused attention on the genetic causes of growth alterations. Mutations involving the molecular structure of GH 5 or the function of the GH receptor 6 have been described. Recently, a partial deletion of the gene for IGF1, resulting in intrauterine growth failure plus severe post-natal growth retardation, sensorineural deafness, and mental retardation has been found. 7 In this study, we describe a new case of IGF1 deficiency associated with sensorineural deafness, severe pre-and post-natal growth failure, and delayed psychomotor development produced by a novel transversion TRA, which disrupts the normal consensus sequence for the polyadenylation site in the 39 untranslated region of exon 6 of IGF1, leading to altered mRNA processing, which could account for the extremely low IGF1 circulating levels and for the clinical findings. METHODS Case reportThe patient was born at 39 weeks' gestation by caesarean section because of poor fetal growth. The pregnancy had until then been uneventful. The birth weight was 1480 kg (24SD), length was 41 cm (26.5 SD), and the head circumference was 26.5 cm (,5th percentile). Hypoglycaemia and icterus were not reported. His parents were second cousins and the family history showed several miscarriages. His mother was 153 cm tall (5th percentile) and his father was 163 cm (5th percentile). His healthy sister, at the age of 9 years, was ...

Genetic disorders in the GH–IGF-I axis in mouse and man

“…Audiograms of the three patients with complete IGF-I deficiency due to a homozygous deletion or mutation of the IGF-I gene demonstrate severe bilateral sensorineural deafness (13)(14)(15). This is confirmed by absent brainstem evoked potentials in one of the patients (14).…”

“…In contrast, an IGF-I gene deletion or mutation results in severe intrauterine growth retardation as is demonstrated in the patient described by Woods et (K4 and K6.5 SDS respectively) (13)(14)(15). The finding that genetically determined low IGF-I levels, due to polymorphisms in the IGF-I promoter region, result in a reduced birth weight and length support the role of IGF-I in fetal growth (16,17).…”

Insulin‐like growth factor 1 has multisystem effects on foetal and preterm infant development

“…The severity of the foetal growth restriction is illustrated with birth weight standard deviation scores (SDS) ranging from −2.5 to −3.5 (Table 1) 36, 37, 38, 39, 40.…”

Older men with low serum IGF-1 have an increased risk of incident fractures: The MrOS Sweden study

“…(1)(2)(3)11) A role of IGF-1 in bone metabolism is supported by the fact that patients with IGF deficiency as a result of IGF1 gene deletion or inactivating mutation display osteopenia. (12)(13)(14) The association between serum IGF-1 and BMD has been evaluated in several cohorts but with conflicting results. (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) A positive association has been reported in some studies, (15,17,(20)(21)(22)(23)25,26) whereas no association has been found in other studies.…”