Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype

D. B. Sparrow, G. Chapman, M. A. Wouters, N. V. Whittock, S. Ellard, D. Fatkin, P. D. Turnpenny, Kenro Kusumi, D. Sillence, S. L. Dunwoodie

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

The spondylocostal dysostoses (SCDs) are a heterogeneous group of vertebral malsegmentation disorders that arise during embryonic development by a disruption of somitogenesis. Previously, we had identified two genes that cause a subset of autosomal recessive forms of this disease: DLL3 (SCD1) and MESP2 (SCD2). These genes are important components of the Notch signaling pathway, which has multiple roles in development and disease. Here, we have used a candidate-gene approach to identify a mutation in a third Notch pathway gene, LUNATIC FRINGE (LFNG), in a family with autosomal recessive SCD. LFNG encodes a glycosyltransferase that modifies the Notch family of cell-surface receptors, a key step in the regulation of this signaling pathway. A missense mutation was identified in a highly conserved phenylalanine close to the active site of the enzyme. Functional analysis revealed that the mutant LFNG was not localized to the correct compartment of the cell, was unable to modulate Notch signaling in a cell-based assay, and was enzymatically inactive. This represents the first known mutation in the human LFNG gene and reinforces the hypothesis that proper regulation of the Notch signaling pathway is an absolute requirement for the correct patterning of the axial skeleton.

Original languageEnglish (US)
Pages (from-to)28-37
Number of pages10
JournalAmerican Journal of Human Genetics
Volume78
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Fingerprint

Phenotype
Mutation
Genes
Gene Components
Glycosyltransferases
Cell Surface Receptors
Missense Mutation
Phenylalanine
Skeleton
Embryonic Development
Catalytic Domain
Jarcho-Levin syndrome
Enzymes
Autosomal recessive spondylocostal dysostosis

ASJC Scopus subject areas

  • Genetics

Cite this

Sparrow, D. B., Chapman, G., Wouters, M. A., Whittock, N. V., Ellard, S., Fatkin, D., ... Dunwoodie, S. L. (2006). Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. American Journal of Human Genetics, 78(1), 28-37. https://doi.org/10.1086/498879

Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. / Sparrow, D. B.; Chapman, G.; Wouters, M. A.; Whittock, N. V.; Ellard, S.; Fatkin, D.; Turnpenny, P. D.; Kusumi, Kenro; Sillence, D.; Dunwoodie, S. L.

In: American Journal of Human Genetics, Vol. 78, No. 1, 01.2006, p. 28-37.

Research output: Contribution to journalArticle

Sparrow, DB, Chapman, G, Wouters, MA, Whittock, NV, Ellard, S, Fatkin, D, Turnpenny, PD, Kusumi, K, Sillence, D & Dunwoodie, SL 2006, 'Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype', American Journal of Human Genetics, vol. 78, no. 1, pp. 28-37. https://doi.org/10.1086/498879
Sparrow, D. B. ; Chapman, G. ; Wouters, M. A. ; Whittock, N. V. ; Ellard, S. ; Fatkin, D. ; Turnpenny, P. D. ; Kusumi, Kenro ; Sillence, D. ; Dunwoodie, S. L. / Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. In: American Journal of Human Genetics. 2006 ; Vol. 78, No. 1. pp. 28-37.
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