Abstract for presentation at 11th International Congress of Human Genetics

Identification and functional analysis of mutations that cause spondylocostal dysostoses

  • Dr Duncan Sparrow, Victor Chang Cardiac Research Institute, Sydney, Australia
  • Dr Gavin Chapman, Victor Chang Cardiac Research Institute, Sydney, Australia
  • Dr Peter Turnpenny, Royal Devon & Exeter Hospital, Exeter, United Kingdom
  • Prof David Sillence, The Children’s Hospital at Westmead, Sydney, Australia
  • A/Prof Sally Dunwoodie, Victor Chang Cardiac Research Institute, Sydney, Australia

    • Spondylocostal dysostoses (SCD) is a heterogenous group of vertebral malsegmentation disorders arising during embryonic development, by a disruption of the vertebral precursors or somites. We have identified two genes causing a subset of autosomal recessive forms of this disease: DLL3 (SCDI; MIM 277300; Bulman et al, 2000. Nat Genet 24:438, Turnpenny et al, 2003. J Med Genet 40:333) and MESP2 (SCD2, MIM 608681; Whittock et al, 1994. Am J Hum Genet 74:1249). These genes are both important components of the Notch signalling pathway, which has multiple roles in embryonic patterning throughout evolution.
    Purpose: Since mutation in Dll3 and MESP2 are responsible for some 20% of SCD cases, we aimed to identify additional disease-causing genes. In addition, functional assays were developed in order to understand the impact of the mutations.
    Methods: Using a mouse model of SCD1 that lacks DLL3, we identified genes with deregulated expression in forming somites. One of the candidate genes, LUNATIC FRINGE (LFNG), was sequenced in an autosomal recessive SCD family.
    Results: In the proband, a homozygous missense mutation (c.564CrA) was detected, and in the parents the mutation was heterozygous; the mutation changed a highly conserved phenylalanine to a leucine. LFNG encodes a glycosyltransferase that modifies Notch receptors, a key step in the regulation of this signalling pathway. Functional analyses revealed that the mutant LFNG was unable to modify Notch signalling, this was due to the fact that all enzymatic activity was lost.
    Conclusions: This represents the first known mutation in the human LFNG gene (SCD3: MIM 609813; Sparrow et al 2006. Am J Hum Genet 78: 28) and reinforces the hypothesis that proper regulation of the Notch signalling pathway is an absolute requirement for the correct patterning of the axial skeleton. We are continuing to examine candidate genes for mutations that cause SCD, and to understand the functional consequences of known mutations on Notch signalling.

    Conference Organiser - ICMS Pty Ltd