ALX4 gain-of-function mutations in nonsyndromic craniosynostosis

Abstract

Craniosynostosis is the early fusion of one or more sutures of the infant skull and is a common defect occurring in approximately 1 of every 2,500 live births. Non-syndromic craniosynostosis accounts for approximately 80% of all cases and is thought to have strong genetic determinants that are yet to be identified. ALX4 is a homeodomain transcription factor with known involvement in osteoblast regulation. By direct sequencing of the ALX4 coding region in sagittal or sagittal-suture-involved non-syndromic craniosynostosis probands, we identified novel, nonsynonymous, familial variants in three of 203 individuals with NSC. Using dual-luciferase assay we show that two of these variants (V7F and K211E) confer a significant gain-of-function effect on ALX4. Our results suggest that ALX4 variants may have an impact on the genetic etiology of NSC.

Frontonasal Dysplasia: Towards an Understanding of Molecular and Developmental Aetiology

“…Parietal foramina 1 (OMIM 168500) is caused by a heterozygous mutation in the MSX2 gene [Wilkie et al, 2000;Spruijt et al, 2005] and parietal foramina 1 and 2 are clinically indistinguishable [Mavrogiannis et al, 2006]. Further, activating mutations in both MSX2 and ALX4 have been implicated in craniosynostosis [Jabs et al, 1993;Ma et al, 1996;Yagnik et al, 2012;Florisson et al, 2013]. This highlights the involvement of calvarial development defects in the pathogenic presentation of FND and also supports the contention that FND, parietal foramina and craniosynostosis may represent components of a phenotypic spectrum [Yagnik et al, 2012].…”

“…Further, activating mutations in both MSX2 and ALX4 have been implicated in craniosynostosis [Jabs et al, 1993;Ma et al, 1996;Yagnik et al, 2012;Florisson et al, 2013]. This highlights the involvement of calvarial development defects in the pathogenic presentation of FND and also supports the contention that FND, parietal foramina and craniosynostosis may represent components of a phenotypic spectrum [Yagnik et al, 2012].…”

“…The homeodomain is a hallmark of this class of transcription factors, exhibiting very high levels of homology within related family members [D'Elia et al, 2001]. Mutations in a range of homeodomain class transcription factors are associated with congenital anomalies in humans and missense mutations within the homeodomain can cause both gain and loss of DNA-binding activity as has been observed for both ALX4 and MSX2 [Ma et al, 1996;Wilkie et al, 2000;Wuyts et al, 2000;Yagnik et al, 2012;Florisson et al, 2013]. The ALX4 deletion resulting in the Contemporary Burmese FND phenotype also occurs within the homeodomain [Lyons et al, 2016].…”

Genetic advances in craniosynostosis

“…Gain-of-function variants in the coding region of ALX4 , account for about 1.5% of sNCS patientes [Yagnik et al, 2012]. Since these ALX4 variants were also found in an unaffected parent, they may represent low penetrance mutations that, as is the case of SMAD6 [Timberlake et al, 2016], require predisposing variants at a second locus.…”

Closing the Gap: Genetic and Genomic Continuum from Syndromic to Nonsyndromic Craniosynostoses

“…In one case of sagittal NSC, the FGFR2 Ala315Thr mutation was reported [33]. Two cases with sagittal NSC were found to carry Ser494Thr and Cys592Tyr mutations in LRIT3, a protein believed to regulate maturation and signaling of FGFR1 [28]; another three sagittal NSC cases had Val7-Phe, Lys211Glu, and Pro306Leu mutations in ALX4, a homeobox containing transcription factor regulating calvarial development through interactions with Wnt and bone morphogenetic proteins (BMPs) [31]. TWIST1 mutations, Ala186Thr, Ser201Tyr, and Ser188Leu in the TWIST Box domain, were found in two cases of the isolated sagittal synostosis and in one case of isolated left coronal synostosis, respectively [29, 30].…”