Identification of a novel heterozygous IGF1 splicing mutation in a large kindred with familial short stature

John Fuqua, Michael Derr, Ron G. Rosenfeld, Vivian Hwa

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background/Aims: Insulin-like growth factor (IGF)-I is critical for normal human growth. Extremely rare homozygous mutations of the IGF1 gene severely impair intrauterine growth, intellectual development and postnatal growth. Case/Method: A young male presented with postnatal growth retardation (-4.0 height SDS). His serum IGF-I concentration was low (115 μg/l, -2.21 SDS) and increased minimally to 130 μg/l (-1.82 SDS) on GH therapy, and he was analyzed for defect(s) in the GH-IGF-I axis. Severe short stature could be traced back several generations. Results: From the proband and 4 other severely short-statured family members, two novel, heterozygous, variants were identified in the IGF1 gene: c.207G>A in exon 3 and c.402+1G>C in the donor splice site of intron 4. The IGF1 gene was normal in 11 normal stature family members, and, interestingly, in 5 other short-statured family members. Study of IGF1 mRNA indicated c.402+1G>A induced splicing out of exon 4, leading to a predicted frameshift and protein truncation. Conclusions: A novel heterozygous IGF1 splicing variant is associated with familial short stature in an extended family. Although it remains unclear whether this heterozygous mutation is the cause of the growth failure, the extreme rarity of IGF1 gene defects makes these cases of considerable interest.

Original languageEnglish
Pages (from-to)59-66
Number of pages8
JournalHormone Research in Paediatrics
Volume78
Issue number1
DOIs
StatePublished - Aug 2012

Fingerprint

Insulin-Like Growth Factor I
Mutation
Growth
Genes
Exons
RNA Splice Sites
Growth and Development
Introns
Messenger RNA
Serum
Proteins
Therapeutics

Keywords

  • Growth retardation
  • IGF-1 gene
  • Mutation analysis
  • Short stature

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Pediatrics, Perinatology, and Child Health

Cite this

Identification of a novel heterozygous IGF1 splicing mutation in a large kindred with familial short stature. / Fuqua, John; Derr, Michael; Rosenfeld, Ron G.; Hwa, Vivian.

In: Hormone Research in Paediatrics, Vol. 78, No. 1, 08.2012, p. 59-66.

Research output: Contribution to journalArticle

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