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

J Med Genet 2003;40:913-917

The 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 post-natal 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 T[right arrow]A, which disrupts the normal consensus sequence for the polyadenylation site in the 3' 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 report

The 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 (-4SD), length was 41 cm (-6.5 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 120 cm tall (-1SD). The analysis of familial pedigree did not show the presence of a short stature condition segregating in the family. The clinical evaluation of the patient at the age of 19 months showed a weight of 4750 kg (-6.2 SD), a length of 64 cm (-6.2 SD), a head circumference of 40.5 cm (<5th percentile), a body mass index of 11.7 …