Craniosynostosis with extra copy of <i>MSX2</i> in a patient with partial 5q‐trisomy

Shiihara, Takashi; Kato, Mitsuhiro; Kimura, Toshiyuki; Hayasaka, Kiyoshi; Yamamori, Shunji; Ogata, Tsutomu

doi:10.1002/ajmg.a.20552

Cited by 36 publications

(40 citation statements)

References 16 publications

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“…Subsequent karyotyping with improved resolution of other patients allowed to exclude band 7p15 and to subsequently narrow down the locus for craniosynostosis to subband 7p21.1 [Bianchi et al, 1981;Fryns et al, 1985;Marks et al, 1985;Motegi et al, 1985;García-Esquivel et al, 1986;Schömig-Spingler et al, 1986;Speleman et al, 1989;Zackai and Stolle, 1998]. Similarly, loci for craniosynostosis on chromosome arms 2q, 5q, 9p, 11q, 14q, 17p, 17q, and 19p have been identified [Rutten et al, 1978;Lippe et al, 1980;Fryns et al, 1986;Stratton et al, 1986;Lucas et al, 1987;Lewanda et al, 1995;Thomas et al, 1996;Lemyre et al, 1998;Shiihara et al, 2004;Lyon et al, 2015]. These findings indicate that several genes may be involved in regulating proper closure of cranial sutures during development.…”

Section: Craniosynostosis Gene Identificationmentioning

confidence: 99%

Structural Genome Variations Related to Craniosynostosis

Poot¹

2018

Mol Syndromol

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Craniosynostosis refers to a condition during early development in which one or more of the fibrous sutures of the skull prematurely fuse by turning into bone, which produces recognizable patterns of cranial shape malformations depending on which suture(s) are affected. In addition to cases with isolated cranial dysmorphologies, craniosynostosis appears in syndromes that include skeletal features of the eyes, nose, palate, hands, and feet as well as impairment of vision, hearing, and intellectual development. Approximately 85% of the cases are nonsyndromic sporadic and emerge after de novo structural genome rearrangements or single nucleotide variation, while the remainders consist of syndromic cases following mendelian inheritance. By karyotyping, genome wide linkage, and CNV analyses as well as by whole exome and whole genome sequencing, numerous candidate genes for craniosynostosis belonging to the FGF, Wnt, BMP, Ras/ERK, ephrin, hedgehog, STAT, and retinoic acid signaling pathways have been identified. Many of the craniosynostosis-related candidate genes form a functional network based upon protein-protein or protein-DNA interactions. Depending on which node of this craniosynostosis-related network is affected by a gene mutation or a change in gene expression pattern, a distinct craniosynostosis syndrome or set of phenotypes ensues. Structural variations may alter the dosage of one or several genes or disrupt the genomic architecture of genes and their regulatory elements within topologically associated chromatin domains. These may exert dominant effects by either haploinsufficiency, dominant negative partial loss of function, gain of function, epistatic interaction, or alteration of levels and patterns of gene expression during development. Molecular mechanisms of dominant modes of action of these mutations may include loss of one or several binding sites for cognate protein partners or transcription factor binding sequences. Such losses affect interactions within functional networks governing development and consequently result in phenotypes such as craniosynostosis. Many of the novel variants identified by genome wide CNV analyses, whole exome and whole genome sequencing are incorporated in recently developed diagnostic algorithms for craniosynostosis.

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Section: Craniosynostosis Gene Identificationmentioning

confidence: 99%

Structural Genome Variations Related to Craniosynostosis

Poot¹

2018

Mol Syndromol

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“…Msx2 knock-out mice exhibit multiple abnormalities, such as persistent calvarial foramen, defective endochondral bone formation, and defective organogenesis in tooth, hair follicle, and mammary gland (8). Partial deletion mutations of MSX2 cause parietal foramina in humans (20,21). Msx2 transgenic mice exhibit craniosynostosis with increased pools of proliferative osteogenic cells in the calvaria (22).…”

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confidence: 99%

“…Msx2 transgenic mice exhibit craniosynostosis with increased pools of proliferative osteogenic cells in the calvaria (22). Some MSX2 trisomy patients also exhibit craniosynostosis, which indicates that the function of Msx2 is conserved in human (20,21). Studies of Msx2 transgenic mice, which exhibit suture overgrowth and overlap without suture, have indicated that the mechanism of premature suture closure in these mice is due to a specific incremental increase in osteogenic cell proliferation (22,23).…”

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confidence: 99%

The Boston-type Craniosynostosis Mutation MSX2 (P148H) Results in Enhanced Susceptibility of MSX2 to Ubiquitin-dependent Degradation

Yoon

Cho

et al. 2008

Journal of Biological Chemistry

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Boston-type craniosynostosis is caused by a single amino acid substitution, P148H, in the transcription factor MSX2. The increased binding affinity of MSX2 (P148H) to the response element has led many to hypothesize that the substitution is a gainof-function mutation. However, there have been conflicting reports on the function of MSX2, and by extension, the nature of the P148H mutation remains unclear. In this study, we have examined the molecular mechanism of MSX2 function and the nature of the P148H mutation. During cranial suture closure of rodent, Msx2 expression was detected in the suture space. Overexpression of wild type MSX2 in mesenchymal cells stimulated cell proliferation and cyclin D1 expression, whereas P148H mutant did not. These results indicated that MSX2 is involved in maintaining the suture space by stimulating suture mesenchymal cell proliferation and that P148H is defective in this process. The protein levels of P148H were lower than wild type Msx2 (Msx2-WT), and pulse-chase experiments indicated that the mutant protein has a shorter half-life than the Msx2-WT protein. The ubiquitylation level of P148H was greater than that of Msx2-WT. The degradation of Msx2 was mediated by Praja1, and the P148H mutant was degraded more effectively than WT. The ubiquitylation of Msx2-WT was higher in the presence of Msx2 (P148H), which indicated that P148H functions as a dominant-negative mutant. Collectively, the primary function of MSX2 in suture closure is the induction of cell proliferation and suture maintenance, and the mutation results in an increased susceptibility of both wild type and mutant MSX2 to proteasomal degradation.

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“…Molecular testing did not reveal any mutations in the common genes related to syndromic craniosynostosis [49]. A possible relationship to dosage of the MSX2 gene, as suggested by Shiihara [50], remains to be verified.…”

Section: Bisutural Synostosismentioning

confidence: 94%

Nonsyndromic Craniosynostoses

Collmann¹,

Solomon²,

Schweitzer³

et al. 2011

Monographs in Human Genetics

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The subtypes of nonsyndromic ('isolated') craniosynostosis are denominated according to the predominant deformity resulting from premature fusion of one of the major cranial sutures: scaphocephaly, trigonocephaly, anterior plagiocephaly, brachycephaly, posterior plagiocephaly, and oxycephaly. In most cases the underlying causes remain unknown although there is some overlap with syndromic craniosynostosis suggesting heterogeneous etiologies. In contrast to the oversimplified nomenclature, isolated craniosynostosis may involve two or more sutures at the same time or may progress with increasing age, thus indicating that the basic nature of craniosynostosis is a failure of growth regulation of the skull rather than a malformation.

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Craniosynostosis with extra copy of MSX2 in a patient with partial 5q‐trisomy

Cited by 36 publications

References 16 publications

Structural Genome Variations Related to Craniosynostosis

Structural Genome Variations Related to Craniosynostosis

The Boston-type Craniosynostosis Mutation MSX2 (P148H) Results in Enhanced Susceptibility of MSX2 to Ubiquitin-dependent Degradation

Nonsyndromic Craniosynostoses

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