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Comparative Study
. 2004 Jun;74(6):1249-54.
doi: 10.1086/421053. Epub 2004 Apr 30.

Mutated MESP2 causes spondylocostal dysostosis in humans

Neil V Whittock  1 , Duncan B Sparrow, Merridee A Wouters, David Sillence, Sian Ellard, Sally L Dunwoodie, Peter D Turnpenny
Affiliations
Comparative Study

Mutated MESP2 causes spondylocostal dysostosis in humans

Neil V Whittock et al. Am J Hum Genet. 2004 Jun.

Abstract

Spondylocostal dysostosis (SCD) is a term given to a heterogeneous group of disorders characterized by abnormal vertebral segmentation (AVS). We have previously identified mutations in the Delta-like 3 (DLL3) gene as a major cause of autosomal recessive spondylocostal dysostosis. DLL3 encodes a ligand for the Notch receptor and, when mutated, defective somitogenesis occurs resulting in a consistent and distinctive pattern of AVS affecting the entire spine. From our study cohort of cases of AVS, we have identified individuals and families with abnormal segmentation of the entire spine but no mutations in DLL3, and, in some of these, linkage to the DLL3 locus at 19q13.1 has been excluded. Within this group, the radiological phenotype differs mildly from that of DLL3 mutation-positive SCD and is variable, suggesting further heterogeneity. Using a genomewide scanning strategy in one consanguineous family with two affected children, we demonstrated linkage to 15q21.3-15q26.1 and furthermore identified a 4-bp duplication mutation in the human MESP2 gene that codes for a basic helix-loop-helix transcription factor. No MESP2 mutations were found in a further 7 patients with related radiological phenotypes in whom abnormal segmentation affected all vertebrae, nor in a further 12 patients with diverse phenotypes.

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Figures

Figure 1
Figure 1
Pedigree of the family affected with SCD, MESP2 type, demonstrating disease-linked haplotype. Affected members II.2 and II.3 are indicated by fully blackened symbols.
Figure 2
Figure 2
Anteroposterior MRI of the spine of individual II.2. The morphology of the thoracic spine and the upper cervical spine is severely disrupted, with multiple hemivertebrae, whereas the remaining regions show less severe disruption.
Figure 3
Figure 3
Detection of the mutation 500–503dup by direct nucleotide sequencing. The sequence of a heterozygous individual (as indicated by the arrow) (top) is compared with the normal homozygous sequence (bottom).
Figure 4
Figure 4
Comparison of MesP2 (A) and MesP1 (B), both containing a bHLH domain. MesP1 and MesP2 contain a unique CPXCP motif immediately C-terminal to the bHLH domain. C, Predicted product of the human MesP2 frameshift mutant. Xenopus and zebrafish sequences (D) are shorter at the C-terminus and have the residues C6XC in place of the CPXCP motif.
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References

Electronic-Database Information

    1. Human Genome Working Draft, The, http://genome.ucsc.edu/
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/

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