Mutations in Frizzled 6 Cause Isolated Autosomal-Recessive Nail Dysplasia

Abstract

Inherited and isolated nail malformations are rare and heterogeneous conditions. We identified two consanguineous pedigrees in which some family members were affected by isolated nail dysplasia that suggested an autosomal-recessive inheritance pattern and was characterized by claw-shaped nails, onychauxis, and onycholysis. Genome-wide SNP array analysis of affected individuals from both families showed an overlapping and homozygous region of 800 kb on the long arm of chromosome 8. The candidate region spans eight genes, and DNA sequence analysis revealed homozygous nonsense and missense mutations in FZD(6), the gene encoding Frizzled 6. FZD(6) belongs to a family of highly conserved membrane-bound WNT receptors involved in developmental processes and differentiation through several signaling pathways. We expressed the FZD(6) missense mutation and observed a quantitative shift in subcellular distribution from the plasma membrane to the lysosomes, where the receptor is inaccessible for signaling and presumably degraded. Analysis of human fibroblasts homozygous for the nonsense mutation showed an aberrant response to both WNT-3A and WNT-5A stimulation; this response was consistent with an effect on both canonical and noncanonical WNT-FZD signaling. A detailed analysis of the Fzd(6)(-/-) mice, previously shown to have an altered hair pattern, showed malformed claws predominantly of the hind limbs. Furthermore, a transient Fdz6 mRNA expression was observed in the epidermis of the digital tips at embryonic day 16.5 during early claw morphogenesis. Thus, our combined results show that FZD6 mutations can result in severe defects in nail and claw formation through reduced or abolished membranous FZD(6) levels and several nonfunctional WNT-FZD pathways.

Epithelium-Derived Wnt Ligands Are Essential for Maintenance of Underlying Digit Bone

“…Nonetheless, not all mutation in Wnt related genes result in the deformation of the both nail and terminal phalanx. In such case, mutation in Fzd6, which is expressed in the keratogenous zone in humans, results in nail abnormalities but not in digit bone malformation (Frojmark et al , 2011; Naz et al , 2012). Therefore, further investigation, such as Wnt ligand secretion, in these mutant mice may help elucidate the relationship between the formation of nail and terminal phalanx during embryogenesis.…”

Whole exome sequencing identifiesLRP1as a pathogenic gene in autosomal recessive keratosis pilaris atrophicans

“…Analysis and sorting of homozygous genomic regions were performed as described previously with the dedicated software AutoSNPa 8 9. A cut-off of >127 consecutive homozygous SNPs was used for the selection of candidate regions.…”

The molecular genetic analysis of the expanding pachyonychia congenita case collection

“…23 These individuals present with 20-nail dystrophy from birth or shortly afterwards in the form of thickened, discoloured, claw-shaped nails. There is no involvement of other ectodermal tissues.…”