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• Mutation in IGF-1 polyadenylation signal is a polymorphism in the Brazilian population
  Alexander A Jorge
  Published on: 27 April 2016

• Published on: 27 April 2016

  Mutation in IGF-1 polyadenylation signal is a polymorphism in the Brazilian population

  • Alexander A Jorge, Clinical end genetic researcher
  • Other Contributors:
    • Debora C. C. Liborio

  Dear Editor

  Bonapace et al. (1) analyzed the IGF-1 gene in one SGA child that presented clinical and laboratory findings compatible with isolated IGF-1 deficiency. Molecular study of the IGF-1 gene in this patient disclosed a homozygous nucleotide substitution (AATATA > AAAATA) in the upstream core polyadenylation signal (UCPAS) located in IGF-1 exon 6 3’ UTR. The fact that this was the only mutation found within...

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  Dear Editor

  Bonapace et al. (1) analyzed the IGF-1 gene in one SGA child that presented clinical and laboratory findings compatible with isolated IGF-1 deficiency. Molecular study of the IGF-1 gene in this patient disclosed a homozygous nucleotide substitution (AATATA > AAAATA) in the upstream core polyadenylation signal (UCPAS) located in IGF-1 exon 6 3’ UTR. The fact that this was the only mutation found within the entire coding region and the absence of this finding in 100 unrelated healthy controls led the authors to conclude that this mutation was responsible for the patient’s clinical findings.

  We recently sequenced the IGF-1 gene of 118 SGA children and identified 4 children (approximately 2% of alleles) who carried the same mutation described by Bonapace et al. in heterozygous state. To assess this mutation in our control population, we sequenced 90 healthy controls and surprisingly identified 5 individuals who carried this same mutation, 2 in homozygous and 3 in heterozygous state, which corresponds to 4% of studied alleles. The heights of the 2 male homozygous individuals were 191 and 177 cm, respectively (Height SDS of 2.5 and 0.3).

  It is noteworthy that the AATATA > AAAATA mutation yields an alternative AATATA motif 2 bp downstream from the physiological UCPAS hexamer (2). Bonapace et al. attempted to assess the mutation effect on mRNA transcription and maturation by RT-PCR. Although the sequences for the two RT-PCR primers were not provided in the original publication, it may be inferred that the 2 primers must have targeted the 5’ end of exon 6 and sequences downstream of the pre-mRNA cleavage site of IGF-1 gene. For this reason, the RT-PCR performed was unable to amplify products from 1.1 kb mRNA and assess the effect of AATATA > AAAATA mutation on mRNA processing. In the experiment depicted by Bonapace et al., 2 distinct amplification products (340 and 450 bp) were obtained. As discussed by Chen et al., in a recent review about variants in the 3’ regulatory regions, the 340 bp RT-PCR product obtained by Bonapace et al. probably derived from non-specific PCR amplifications and the 450 bp product corresponds to a cDNA sequence amplified from the normally expressed 7.6 kb IGF-1 mRNA species (2).

  In conclusion, our finding of the AATATA > AAAATA alteration in normal height controls implies that this mutation in the IGF-1 UCPAS region is not responsible for the clinical and laboratory findings described in IGF-1 deficiency children, and actually represents a polymorphism. In view of these findings, the molecular basis of the IGF-1 deficiency etiology in the patient described by Bonapace et al. remains to be elucidated.

  References

  1. Bonapace G, Concolino D, Formicola S, Strisciuglio P 2003 A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency. J Med Genet 40:913-7

  2. Chen JM, Ferec C, Cooper DN 2006 A systematic analysis of disease-associated variants in the 3' regulatory regions of human protein-coding genes I: general principles and overview. Hum Genet 120:1-21

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  Conflict of Interest:
  None declared.

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