MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

Abstract

The Msx1 transcription factor is involved in multiple epithelial-mesenchymal interactions during vertebrate embryogenesis. It has pleiotropic effects in several tissues. In humans, MSX1 variants have been related to tooth agenesis, orofacial clefting, and nail dysplasia. We correlate all MSX1 disease causing variants to phenotypic features to shed light on this hitherto unclear association. MSX1 truncations cause more severe phenotypes than in-frame variants. Mutations in the homeodomain always cause tooth agenesis with or without other phenotypes while mutations outside the homeodomain are mostly associated with non-syndromic orofacial clefts. Downstream effects can be further explored by the edgetic perturbation model. This information provides new insights for genetic diagnosis and for further functional analysis of MSX1 variants.

Tooth agenesis and orofacial clefting: genetic brothers in arms?

“…Intriguingly, not only the disrupted gene but even the location of the mutations within the gene can lead to diverse phenotypes. A recently published review (Liang et al 2016 ) shows how the location of mutations in the MSX1 homeodomain always causes TA with or without other phenotypes while mutations outside the homeodomain are mostly associated with non-syndromic OFCs. Following this hypothesis, it would be interesting for further functional studies to expand the molecular investigation to different protein domains in relation to different spectra of phenotypes, thus improving the diagnostic potential of these gene panels and the knowledge of molecular pathogenic mechanisms affecting the orofacial region.…”

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…Also DLX homeobox genes function in early NC development, and in the late specification of NC-derived structures [McLarren et al, 2003;Ruest et al, 2003], and they play key roles in skull and brain development [Jones and Rubinstein, 2004;Kraus and Lufkin, 2006;Vincentz et al, 2016]. In particular, MSX1 encodes a transcriptional repressor specifically involved in odontogenesis [Cohen, 2000;Alappat et al, 2003], and hence it is mutated in orofacial clefting and tooth agenesis [Liang et al, 2016]. MSX1 is a direct downstream target of DLX5 during early inner ear development [Sajan et al, 2011].…”

Application of high‐resolution array platform for genome‐wide copy number variation analysis in patients with nonsyndromic cleft lip and palate

“…36 Therefore, cumulative effect of microdeletions in the copy number of MSX1 could represent a mechanism of deregulation in MSX1 proteins, which are responsible to maintain the growth of the primary palate during mammalian palatogenesis through expression regulation of growth factors such as Bmp4. 37 In the same direction, the effect of microduplication reported in the chromosome region involving the three genes TERT, MIR4457, CLPTM1L may be responsible for an increase in the expression of these genes, promoting an overexpression of apoptotic pathways during the palate morphogenesis. 31 And also, the effect of microduplication of PHF8 may promote a disrupt catalytic of PHF8 activity, which is histone modifying enzyme oxygen dependent, that under conditions of associated hypoxia may be related with chromatin regulated gene expression including of homeobox genes during the development and fusion of facial prominences.…”

“…In nonsyndromic forms of oral clefts, in which there is no involvement of causal genes strongly associated with risk, it is hypothesized that multiple genetic alterations with modest individual effects on risk may be capable of disrupting normal craniofacial development under specific circumstances given by exposure to environmental risk factors . Therefore, cumulative effect of microdeletions in the copy number of MSX1 could represent a mechanism of deregulation in MSX1 proteins, which are responsible to maintain the growth of the primary palate during mammalian palatogenesis through expression regulation of growth factors such as Bmp4 . In the same direction, the effect of microduplication reported in the chromosome region involving the three genes TERT, MIR4457, CLPTM1L may be responsible for an increase in the expression of these genes, promoting an overexpression of apoptotic pathways during the palate morphogenesis .…”