Alternative titles; symbols
HGNC Approved Gene Symbol: MESP2
Cytogenetic location: 15q26.1 Genomic coordinates (GRCh38) : 15:89,776,332-89,778,754 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q26.1 | Spondylocostal dysostosis 2, autosomal recessive | 608681 | Autosomal recessive | 3 |
The MESP2 gene, a member of the basic helix-loop-helix (bHLH) family of transcriptional regulatory proteins essential to a vast array of developmental processes, is critical for normal somitogenesis in humans.
Saga et al. (1997) isolated a novel bHLH protein gene, called Mesp2 for 'mesoderm posterior 2,' that cross-hybridizes with Mesp1 (608689) expressed in early mouse mesoderm. Mesp2 is expressed in the rostral presomitic mesoderm, but downregulated immediately after the formation of the segmented somites.
Whittock et al. (2004) identified the MESP2 gene in the working draft of the human genome sequence. The MESP2 gene is predicted to produce a transcript of 1,191 bp encoding a protein of 397 amino acids. Human MESP2 protein shares approximately 58% identity with mouse Mesp2 and approximately 47% identity with human MESP1. The MESP2 protein contains an N-terminal bHLH region and a unique CPXCP motif immediately C-terminal to it. The N- and C-terminal regions are separated by a 13-repeat GQ region. Alignment of MESP2 homologs from human, mouse, Xenopus, and chick indicated a highly divergent C terminus between species.
The Notch (see 190198) signaling pathway is important in establishing metameric pattern during somitogenesis. In mice, the lack of either of 2 molecules involved in the Notch signaling pathway, Mesp2 or presenilin-1 (PS1; see 104311), results in contrasting phenotypes: caudalized versus rostralized vertebra. Takahashi et al. (2000) adopted a genetic approach to analyze the molecular mechanism underlying establishment of rostro-caudal polarity in somites. By focusing on the fact that the expression of a Notch ligand, Dll1, is important for prefiguring somite identity, Takahashi et al. (2000) found that Mesp2 initiates establishment of rostro-caudal polarity by controlling 2 Notch signaling pathways. Initially Mesp2 activates the Ps1-independent Notch signaling cascade to suppress Dll1 expression and specify the rostral half of the somite. Ps1-mediated Notch signaling is required to induce Dll1 expression in the caudal half of the somite. Therefore, Mesp2- and Ps1-dependent activation of Notch signaling pathways might differentially regulate Dll1 expression, resulting in the establishment of the rostro-caudal polarity of somites.
Morimoto et al. (2005) visualized endogenous levels of Notch1 activity in mice, showing that it oscillates in the posterior presomitic mesoderm but is arrested in the anterior presomitic mesoderm. Somite boundaries formed at the interface between Notch1-activated and -repressed domains. Genetic and biochemical studies indicated that this interface is generated by suppression of Notch activity by Mesp2 through induction of the lunatic fringe gene (LFNG; 602576). Morimoto et al. (2005) proposed that the oscillation of Notch activity is arrested and translated in the wavefront by Mesp2.
Yasuhiko et al. (2006) found that Tbx6 (602427) was essential for Mesp2 expression during somitogenesis in mouse. Tbx6 directly bound to the Mesp2 gene upstream region and mediated Notch signaling and subsequent Mesp2 transcription in the anterior presomitic mesoderm.
Matsuda et al. (2020) used human induced pluripotent stem cells for in vitro induction of presomitic mesoderm and its derivatives to model human somitogenesis, with a focus on the human segmentation clock. The authors observed oscillatory expression of core segmentation clock genes, including HES7 (608059) and DKK1 (605189), determined the period of the human segmentation clock to be around 5 hours, and demonstrated the presence of dynamic traveling wave-like gene expression in in vitro-induced human presomitic mesoderm. Identification and comparison of oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Knockout of genes mutated in patients with segmentation defects of vertebrae, including HES7, LFNG, DLL3 (602768), and MESP2, followed by analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization, or differentiation properties.
Whittock et al. (2004) stated that the MESP2 gene has 2 exons and spans approximately 2 kb.
Whittock et al. (2004) identified the MESP2 gene within the chromosome 15q26.1 region of the human genome working draft sequence.
Using a genomewide scanning strategy in a consanguineous family of Lebanese Arab origin with 2 offspring affected with spondylocostal dysostosis (SCDO2; 608681), Whittock et al. (2004) found a 4-bp duplication mutation in the MESP2 gene (605195.0001) that segregated with the disorder. No MESP2 mutations were found in a further 7 patients with related radiologic phenotypes in whom abnormal segmentation affected all vertebrae, nor in a further 12 patients with diverse phenotypes. Whittock et al. (2004) suggested that this form of spondylocostal dysostosis be called spondylocostal dysostosis type 2 (SCDO2) or spondylocostal dysostosis, MESP2 type.
In 12 Puerto Rican probands with SCDO2, Cornier et al. (2008) identified 3 different biallelic mutations in the MESP2 gene (605195.0002-605195.0004). The most common allele was E103X (605195.0002), consistent with a founder effect in this population.
Saga et al. (1997) generated mice deficient in Mesp2 by targeted disruption. The homozygous Mesp2 -/- mice died shortly after birth and had fused vertebral columns and dorsal root ganglia, with impaired sclerotomal polarity. The earliest defect in the homozygous embryos was the lack of segmented somites. Their disruption of the metameric features, altered expression of Mox1 (300225), Pax1 (167411), and Dll1 (see 602768), and lack of expression of Notch1 (190198), Notch2 (600275), and FGFR1 (136350) suggested that MesP2 controls sclerotomal polarity by regulating the signaling systems mediated by Notch-Delta and FGF (e.g., 131220), which are essential for segmentation.
Whittock et al. (2004) studied a consanguineous Lebanese Arab family in which 2 offspring were affected with spondylocostal dysostosis mapping to 15q26.1 (SCDO2; 608681). Affected individuals showed homozygosity for a 4-bp duplication mutation in the MESP2 gene. The 4-bp (ACCG) duplication was located in exon 1 and termed 500-503dup. The parents were heterozygous for the mutation and an unaffected sib was homozygous normal.
By in vitro functional expression studies, Cornier et al. (2008) demonstrated that the 4-bp dup mutant protein lacked transcriptional activity.
In a 12-year-old girl of Puerto Rican origin with a severe form of spondylocostal dysostosis (SCDO2; 608681), Cornier et al. (2008) identified a homozygous 307G-T transversion in exon 1 of the MESP2 gene, resulting in a glu103-to-ter (E103X) substitution in the basic helix-loop-helix domain. The mutation was predicted to produce a nonfunctional protein and be susceptible to nonsense-mediated RNA decay. The patient also had scoliosis, a tethered spinal cord, and malrotation of the right kidney. In 10 of 12 additional Puerto Rican probands with the disorder, the authors identified homozygosity for the E103X mutation. One patient was compound heterozygous for the E103X and L125V (605195.0003) mutations, and 2 sibs, who were third cousins of an E103X homozygous proband, were compound heterozygous for the E103X and E230X (605195.0004) mutations. Heterozygous carriers were unaffected. In general, E103X homozygotes were more severely affected than compound heterozygotes. The findings were consistent with a founder effect in the Puerto Rican population. In vitro functional expression studies showed that the mutant protein lacked transcriptional activity.
In a patient of Puerto Rican origin with spondylocostal dysostosis (SCDO2; 608681), Cornier et al. (2008) identified compound heterozygosity for 2 mutations in the MESP2 gene: a 373C-G transversion resulting in a leu125-to-val (L125V) substitution, and E103X (605195.0002). Both substitutions occurred in the basic helix-loop-helix domain. In vitro functional expression studies showed that the L125V-mutant protein lacked transcriptional activity.
In 2 sibs of Puerto Rican origin with spondylocostal dysostosis (SCDO2; 608681), Cornier et al. (2008) identified compound heterozygosity for 2 mutations in the MESP2 gene: a 688G-T transversion in exon 1 resulting in a glu230-to-ter (E230X) substitution in the C-terminal domain, and E103X (605195.0002).
Cornier, A. S., Staehling-Hampton, K., Delventhal, K. M., Saga, Y., Caubet, J.-F., Sasaki, N., Ellard, S., Young, E., Ramirez, N., Carlo, S. E., Torres, J., Emans, J. B., Turnpenny, P. D., Pourquie, O. Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin syndrome. Am. J. Hum. Genet. 82: 1334-1341, 2008. [PubMed: 18485326] [Full Text: https://doi.org/10.1016/j.ajhg.2008.04.014]
Matsuda, M., Yamanaka, Y., Uemura, M., Osawa, M., Saito, M. K., Nagahashi, A., Nishio, M., Guo, L., Ikegawa, S., Sakurai, S., Kihara, S., Maurissen, T. L., and 10 others. Recapitulating the human segmentation clock with pluripotent stem cells. Nature 580: 124-129, 2020. [PubMed: 32238941] [Full Text: https://doi.org/10.1038/s41586-020-2144-9]
Morimoto, M., Takahashi, Y., Endo, M., Saga, Y. The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity. Nature 435: 354-359, 2005. [PubMed: 15902259] [Full Text: https://doi.org/10.1038/nature03591]
Saga, Y., Hata, N., Koseki, H., Taketo, M. M. Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation. Genes Dev. 11: 1827-1839, 1997. [PubMed: 9242490] [Full Text: https://doi.org/10.1101/gad.11.14.1827]
Takahashi, Y., Koizumi, K., Takagi, A., Kitajima, S., Inoue, T., Koseki, H., Saga, Y. Mesp2 initiates somite segmentation through the Notch signalling pathway. Nature Genet. 25: 390-396, 2000. [PubMed: 10932180] [Full Text: https://doi.org/10.1038/78062]
Whittock, N. V., Sparrow, D. B., Wouters, M. A., Sillence, D., Ellard, S., Dunwoodie, S. L., Turnpenny, P. D. Mutated MESP2 causes spondylocostal dysostosis in humans. Am. J. Hum. Genet. 74: 1249-1254, 2004. [PubMed: 15122512] [Full Text: https://doi.org/10.1086/421053]
Yasuhiko, Y., Haraguchi, S., Kitajima, S., Takahashi, Y., Kanno, J., Saga, Y. Tbx6-mediated Notch signaling controls somite-specific Mesp2 expression. Proc. Nat. Acad. Sci. 103: 3651-3656, 2006. [PubMed: 16505380] [Full Text: https://doi.org/10.1073/pnas.0508238103]