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Polymorphisms Identified in the Upstream Core Polyadenylation Signal of IGF1 Gene Exon 6 Do Not Cause Pre- and Postnatal Growth Impairment

Unidade de Endocrinologia do Desenvolvimento (D.C.C., R.R.D.C., E.M.F.C., B.B.M., I.J.P.A., A.A.L.J.), Laboratorio de Hormonios e Genetica Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina, and Unidade de Endocrinologia Pediátrica (D.D.), Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Ambulatorio de Seguimento de Prematuros da Santa Casa de Sao Paulo (P.R.P.), 01221-020 Sao Paulo, Brazil; and Unidade de Endocrinologia Pediatrica (M.C.S.B.), Departamento de Pediatria, Hospital de Clinicas da Universidade Federal do Parana, 01221-020 Curitiba, Brazil

Address all correspondence and requests for reprints to: Alexander A. L. Jorge, Hospital das Clinicas, Laboratorio de Hormonios, Av Dr Eneas de Carvalho Aguiar 155 PAMB, 2 andar Bloco 6, 05403-900 São Paulo, Brazil. E-mail: alexj{at}usp.br.

Background: Few children born small for gestational age (SGA) with IGF1 mutations have been reported. One of these patients presented a mutation at 3' untranslated region (UTR) at exon 6, probably affecting the polyadenylation process.

Objective: The objective of the study was to sequence the IGF1 gene of children born SGA.

Patients and Methods: IGF1 (exons 1–6) was directly sequenced in 53 SGA children without catch-up growth. Allelic variant frequency of the identified IGF1 polymorphisms was assessed in a total of 145 SGA children and in 180 controls born with adequate weight and length and adult height SD score greater than –2.

Results: No mutations were identified in the IGF1 coding regions in SGA children. In contrast, six allelic variants were identified in the upstream core polyadenylation signal located in IGF1 3' UTR at exon 6. The frequency of the different allelic variants was similar in SGA children and controls. It is noteworthy that the same allelic variant, previously described as causing severe IGF1 deficiency, was also observed in homozygous (n = 4) and heterozygous state (n = 6) in normal height controls, corresponding to 4% of studied alleles. The three most frequently identified allelic variants of IGF1 3' UTR showed no effect on height SD score of adult controls as well as on birth characteristics in SGA children.

Conclusion: The polymorphisms identified in the upstream core polyadenylation signal at IGF1 exon 6 do not cause IGF1 deficiency as well as pre- and postnatal growth impairment, in contrast to previously reported data.