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OBSL1 mutations in 3-M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels

Celine Huber1, Mélanie Fradin, Thomas Edouard

  • 1University Paris Descartes, Department of Genetics and INSERM U781, Hospital Necker Enfants-Malades, Paris, France.

Human Mutation
|October 31, 2009
PubMed

Insights

3-M syndrome, a growth disorder, is linked to OBSL1 gene mutations. These mutations affect IGFBP2 and IGFBP5 expression, suggesting OBSL1

Area of Science:

  • Genetics and Molecular Biology
  • Endocrinology
  • Skeletal Dysplasias

Background:

  • 3-M syndrome is an autosomal recessive disorder causing severe growth retardation.
  • Genetic heterogeneity exists, with CUL7 previously identified as a disease gene.
  • Previous studies suggested other genetic factors contribute to 3-M syndrome.

Purpose of the Study:

  • To identify the second disease locus for 3-M syndrome.
  • To investigate the role of OBSL1 gene in 3-M syndrome pathogenesis.
  • To explore the relationship between OBSL1, CUL7, and insulin-like growth factor binding proteins (IGFBPs).

Main Methods:

  • Homozygosity mapping to identify a novel disease locus on chromosome 2q35-36.1.
  • Microarray analysis of fibroblast RNA to identify differentially expressed genes.
  • Direct sequencing of candidate genes and mutation analysis of OBSL1.
  • Real-time quantitative PCR (RT-PCR) to assess mRNA levels of OBSL1, CUL7, IGFBP2, and IGFBP5.

Main Results:

  • A second locus for 3-M syndrome was mapped to chromosome 2q35-36.1.
  • Nine distinct mutations were identified in the OBSL1 gene in 13 families.
  • OBSL1 mutations led to abnormal mRNA levels of IGFBP2 and IGFBP5, but not CUL7.
  • Patients with OBSL1 mutations showed altered IGFBP2 and IGFBP5 expression.

Conclusions:

  • OBSL1 is a second major gene involved in 3-M syndrome.
  • OBSL1 mutations disrupt the expression of IGFBP2 and IGFBP5.
  • OBSL1 likely modulates IGFBP protein expression, contributing to growth retardation in 3-M syndrome.

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