Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification

@article{Wilkie2000FunctionalHO,
  title={Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification},
  author={Andrew O. M. Wilkie and Zequn Tang and Navaratnam Elanko and Sinead Walsh and Stephen R F Twigg and Jane A. Hurst and Steven Arthur Wall and Krystyna H Chrzanowska and Robert E. Maxson},
  journal={Nature Genetics},
  year={2000},
  volume={24},
  pages={387-390}
}
The genetic analysis of congenital skull malformations provides insight into normal mechanisms of calvarial osteogenesis. Enlarged parietal foramina (PFM) are oval defects of the parietal bones caused by deficient ossification around the parietal notch, which is normally obliterated during the fifth fetal month. PFM are usually asymptomatic, but may be associated with headache, scalp defects and structural or vascular malformations of the brain. Inheritance is frequently autosomal dominant, but… 
The roles of the homeobox genes ALX4 and MSX2 in skull development
TLDR
Analysis of compound mutants demonstrated that the two loci exert roughly additive effects on the skull vault while protein interaction assays did not indicate any physiological interaction between Alx4 and Msx2, which appears to regulate proliferation, differentiation, or survival of osteoblast precursors and pre-osteoblasts through parallel pathways.
The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500)
TLDR
Mutation analysis of the ALX4 gene in three unrelated FPP families without the MSX2mutation identified mutations in two families, indicating that mutations in ALx4 could be responsible for these skull defects and suggesting further genetic heterogeneity of FPP.
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TLDR
PFM caused by mutations in ALX4 and MSX2 have a similar prevalence and are usually clinically indistinguishable, and mutation screening has a high pickup rate in PFM, especially in familial cases, but is not indicated in CRS.
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TLDR
Interestingly, this is the first time that a mutation in the MSX2 gene is responsible for PFM associated with headache and venous anomaly, although the latter has been reported twice in clinical PFM cases, and raises the question whether MSx2 is directly linked to craniovascular development or whether the loss of parietal bone permits abnormal vascular morphogenesis.
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Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects
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AlX4, which encodes a paired-related homeodomain transcription factor, is identified as the PFM disease gene in P11pDS.
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Findings reveal an additional mechanism for the pathogenesis of CCD, particularly with regard to the regulation of MSX2, and indicate that CNVs in non-coding regions can cause developmental defects.
Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2 gene triplication
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DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1
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It is proposed that TBX1 in humans is a key gene in the etiology of DGS/VCFS, with mice heterozygous for the mutation having a high incidence of cardiac outflow tract anomalies, thus modeling one of the major abnormalities of the human syndrome.
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References

SHOWING 1-10 OF 36 REFERENCES
A human MSX1 homeodomain missense mutation causes selective tooth agenesis
TLDR
It is suggested that MSX1 functions are critical for normal development of specific human teeth, and an Arg31 Pro missense mutation in the homeodomain of MSx1 in all affected family members is proposed.
Haploinsufficiency of MSX1: a Mechanism for Selective Tooth Agenesis
TLDR
It is proposed that the phenotype of affected individuals with selective tooth agenesis is due to haploinsufficiency, andMsx1(R31P) appears to be inactive and does not affect the action of wild-type Msx1.
The molecular basis of Boston-type craniosynostosis: the Pro148-->His mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences.
TLDR
Using gel shift and binding site selection analyses, it is shown that the Pro148-->His mutation enhances the affinity of Msx2 for a set of known Ms x2 target sequences but has little or no effect on the site specificity ofMsx2 binding.
Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation
TLDR
It is demonstrated that Msx2 is essential at multiple sites during organogenesis, including in the axial and appendicular skeleton, and post-natal deficits in Pth/PthRp receptor (Pthr) signalling and in expression of marker genes for bone differentiation indicate that MsX2 is required for both chondrogenesis and osteogenesis.
Mutations Involving the Transcription Factor CBFA1 Cause Cleidocranial Dysplasia
Msx2 gene dosage influences the number of proliferative osteogenic cells in growth centers of the developing murine skull: a possible mechanism for MSX2-mediated craniosynostosis in humans.
TLDR
It is shown that general overexpression of Msx2 under the control of the broadly expressed CMV promoter causes the calvarial bones to invade the sagittal suture, and that an important early event in MSX2-mediated craniosynostosis in humans is a transient retardation of osteogenic cell differentiation in the suture and a consequent increase in the pool of osteogenesis cells.
A comprehensive screen for TWIST mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1.
TLDR
The results identify a new microdeletion disorder that maps to chromosome band 7p21.1 and that causes a significant proportion of Saethre-Chotzen syndrome.
TWIST gene mutation in a patient with radial aplasia and craniosynostosis: further evidence for heterogeneity of Baller-Gerold syndrome.
TLDR
This report reports on a patient with unilateral radial aplasia and bicoronal synostosis without additional malformations and without chromosome breakage, who fits this narrow definition of Baller-Gerold syndrome, and identifies a novel TWIST gene mutation.
Aplasia cutis congenita and enlarged parietal foramina (Catlin marks) in a family
TLDR
In the authors' patients, ACC and also the vascular and morphological findings indicated a possible vascular process during a specifically vulnerable period of embryo development, which may explain the unifying theory of some conditions with ACC.
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