title: 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.
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Fröjmark
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Schuster
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden; Department of General and Molecular Genetics, National Taras Shevchenko University of Kyiv, Kiev 03680, Ukraine.
authors.forename: Maria
authors.initials: M
authors.lastname: Sobol
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden; Current address: Department of Women's and Children's Health Center for Molecular Medicine, Karolinska University Hospital, 171 76 Stockholm, Sweden.
authors.forename: Miriam
authors.initials: M
authors.lastname: Entesarian
authors.affiliation: Department of Physiology and Pharmacology, Section for Receptor Biology and Signaling, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Michaela B C
authors.initials: MBC
authors.lastname: Kilander
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Dana
authors.initials: D
authors.lastname: Gabrikova
authors.affiliation: Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad 38000, Pakistan.
authors.forename: Sadia
authors.initials: S
authors.lastname: Nawaz
authors.affiliation: Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad 38000, Pakistan.
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Baig
authors.affiliation: Department of Physiology and Pharmacology, Section for Receptor Biology and Signaling, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schulte
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Klar
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden. Electronic address: niklas.dahl@igp.uu.se.
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D018389:Codon, Nonsense; D051157:Frizzled Receptors / Q000235:genetics* / Q000378:metabolism; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006614:Hindlimb / Q000002:abnormalities; D006724:Hoof and Claw / Q000002:abnormalities; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009260:Nail Diseases / Q000151:congenital / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D018389:Codon, Nonsense; C484687:FZD6 protein, human; D051157:Frizzled Receptors; C111048:Fzd6 protein, mouse; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; C555510:WNT3A protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse