Disruption of ALX1 Causes Extreme Microphthalmia and Severe Facial Clefting: Expanding the Spectrum of Autosomal-Recessive ALX-Related Frontonasal Dysplasia

Abstract

We present an autosomal-recessive frontonasal dysplasia (FND) characterized by bilateral extreme microphthalmia, bilateral oblique facial cleft, complete cleft palate, hypertelorism, wide nasal bridge with hypoplasia of the ala nasi, and low-set, posteriorly rotated ears in two distinct families. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this clinical entity to chromosome 12q21. In one of the families, three siblings were affected, and CNV analysis of the critical region showed a homozygous 3.7 Mb deletion containing the ALX1 (CART1) gene, which encodes the aristaless-like homeobox 1 transcription factor. In the second family we identified a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene, providing evidence that complete loss of function of ALX1 protein causes severe disruption of early craniofacial development. Unlike loss of its murine ortholog, loss of human ALX1 does not result in neural-tube defects; however, it does severely affect the orchestrated fusion between frontonasal, nasomedial, nasolateral, and maxillary processes during early-stage embryogenesis. This study further expands the spectrum of the recently recognized autosomal-recessive ALX-related FND phenotype in humans.

Delayed neurogenesis with respect to eye growth shapes the pigeon retina for high visual acuity

“…The fact that Pax2 and Hes1 belong to this set strengthens the idea that the closure of the optic fissure and optic disc formation are regulated independently of cell differentiation. In humans, the loss of ALX1 or mutations in SOX2 lead to craniofacial dysplasia characterised, among other defects, by microphthalmia (Fantes et al, 2003;Taranova et al, 2006;Uz et al, 2010), while in birds the Alx1 haplotype contributes to diversification of beak shapes among Darwin's finches (Lamichhaney et al, 2015). Similar expression dynamics of Alx1 and Sox2 in pigeon and chick highlights how the growth of the retina is coordinated with the increase in eye size and face development irrespective of the time of onset of neurogenesis.…”

Enlarged parietal foramina: a review of genetics, prognosis, radiology, and treatment

“…The genetic aspects of FND are not well defined. Aristaless-related homeobox genes like ALX1, ALX3, and ALX4 are thought to play a role in the development of structures derived from craniofacial mesenchyme, first branchial arch, and the limb bud [24,26]. Two Turkish families, with histories of consanguinity, with a autosomal recessive inherited, homozygous nonsense mutation of ALX4 were described to have total alopecia, a large skull defect, coronal craniosynostosis, hypertelorism, agenesis of the corpus callosum, and mental retardation [10].…”

“…Two Turkish families, with histories of consanguinity, with a autosomal recessive inherited, homozygous nonsense mutation of ALX4 were described to have total alopecia, a large skull defect, coronal craniosynostosis, hypertelorism, agenesis of the corpus callosum, and mental retardation [10]. ALX4-related FND has also been associated with genital abnormalities [24]. Heterogeneous mutations in ALX4 were shown to cause cranium bifidum, but associated with a less severe phenotype compared to the autosomal recessive inheritance [26].…”

Sub-circuits of a gene regulatory network control a developmental epithelial-mesenchymal transition

“…In vertebrates, alx1 (also known as cart1) mutations have long been associated with craniofacial defects and neural tube defects without any known involvement in EMT (Zhao et al, 1996;Uz et al, 2010). However, recent vertebrate evidence shows a role for alx1 in EMT; in ovarian cancer cells, alx1 is reported to be upstream of snail-promoting EMT (Yuan et al, 2013).…”