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Mutations in Frizzled 6 Cause Isolated Autosomal-Recessive Nail Dysplasia

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Mutations in Frizzled 6 Cause Isolated Autosomal-Recessive Nail Dysplasia 15 March 2005 Use of Articles in the Pachyonychia Congenita Bibliography The articles in the PC Bibliography may be restricted by copyright laws. These have been made available to you by PC Project for the exclusive use in teaching, scholar- ship or research regarding Pachyonychia Congenita. To the best of our understanding, in supplying this material to you we have followed the guidelines of Sec 107 regarding fair use of copyright materials. That section reads as follows: Sec. 107. - Limitations on exclusive rights: Fair use Notwithstanding the provisions of sections 106 and 106A, the fair use of a copyrighted work, including such use by reproduction in copies or phonorecords or by any other means specified by that section, for purposes such as criticism, comment, news reporting, teaching (including multiple copies for classroom use), scholarship, or research, is not an infringement of copyright. 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We hope that making available the relevant information on Pachyonychia Congenita will be a means of furthering research to find effective therapies and a cure for PC. 2386 East Heritage Way, Suite B, Salt Lake City, Utah 84109 USA Phone +1-877-628-7300 • Email—[email protected] www.pachyonychia.org REPORT Mutations in Frizzled 6 Cause Isolated Autosomal-Recessive Nail Dysplasia Anne-Sophie Fro¨jmark,1 Jens Schuster,1,6 Maria Sobol,1,2,6 Miriam Entesarian,1,5,6 Michaela B.C. Kilander,3 Dana Gabrikova,1,7 Sadia Nawaz,4 Shahid M. Baig,4 Gunnar Schulte,3 Joakim Klar,1 and Niklas Dahl1,* 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 char- acterized 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 FZD6, the gene encoding Frizzled 6. FZD6 belongs to a family of highly conserved membrane-bound WNT receptors involved in developmental processes and differentiation through several signaling pathways. We expressed the FZD6 missense mutation and observed a quantitative shift in subcellular distribu- tion 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 À/À response was consistent with an effect on both canonical and noncanonical WNT-FZD signaling. A detailed analysis of the Fzd6 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 FZD6 levels and several nonfunctional WNT-FZD pathways. Congenital nail abnormalities are most often part of ecto- tions in the WNT-associated transcription factors dermal syndromes involving several epidermal append- LMX1B (MIM 602575) and MSX1 (MIM 142983), ages, whereas isolated and inherited nail dysplasias are involved in patterning and nail bed formation, cause very rare.1 Nail development is initiated at embryonic nail-patella (MIM 161200) and Witkop syndrome (MIM week 9 by mesenchymal condensation in the dorsal 189500), respectively.3,13,14 part of the distal digital tip. This is followed by the forma- To gain insight into molecular mechanisms regulating tion of a transverse nail fold while the underlying matrix nail development, we investigated two consanguineous primordium expands. The matrix induces the nail bed Pakistani families (F1 and F2) affected by autosomal-reces- and, subsequently, the formation of the nail plate.2 The sive isolated nail dysplasia (Figure 1A). Family F1 included formation of nails is initiated in the upper limb and four affected individuals, and family F2 included seven then proceeds to the hind limb, and the morphogenesis affected individuals. The affected individuals from family is similar in primates and rodents. The molecular mecha- F1 presented with a more severe nail dysplasia compared nisms underlying these processes are poorly understood, to affected individuals from family F2 (Figures 1B and but recent studies have shown that WNT-FZD signaling 1C). All affected individuals showed a variable degree of is important for the formation of ectodermal appendages, onychauxis (thick nails), hyponychia, and onycholysis of including nails.3–6 In humans, mutations in the WNT- fingernails and toenails. Fingernails had a claw-like appear- signaling regulator PORCN (MIM 300651) are associated ance. No other disorders or anomalies of ectodermal tissues with focal dermal hypoplasia (FDH) (MIM 305600),7 (i.e., hair, teeth, sweat glands, or skin) were noted and indi- and mutations in the FZD agonists RSPO4 (MIM viduals with dysplastic nails had normal hearing, normal 610573) and RSPO1 (MIM 609595) are identified in psychomotor development and reported normal sweating both isolated anonychia (MIM 206800)8 and palmoplan- as well as normal hair growth. Four affected individuals tar hyperkeratosis with sex reversal,9 respectively. Further- from each family were available for clinical examinations. more, WNT10A (MIM 6062689) mutations are associated Available parents to individuals with nail dysplasia pre- with odontoonychodermal dysplasia (OODD) (MIM sented with normal nail morphology. Informed consent 257980) and ectodermal syndromes,10–12 whereas muta- was obtained from all individuals who participated in 1Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden; 2Department of General and Molecular Genetics, National Taras Shevchenko University of Kyiv, Kiev 03680, Ukraine; 3Department of Physiology and Pharmacology, Section for Receptor Biology and Signaling, Karolinska Institutet, 171 76 Stockholm, Sweden; 4Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad 38000, Pakistan; 5Current address: Department of Women’s and Children’s Health Center for Molecular Medicine, Karolinska University Hospital, 171 76 Stockholm, Sweden 6These authors contributed equally to this work 7Current address: Department of Biology, Faculty of Natural Sciences, University of Presov, Presov 08001, Slovakia *Correspondence: [email protected] DOI 10.1016/j.ajhg.2011.05.013. Ó2011 by The American Society of Human Genetics. All rights reserved. 852 The American Journal of Human Genetics 88, 852–860, June 10, 2011 A F1 F2 I I II II III III 1 2 1 2 3 4 5 D8S521 3434 D8S521 23 31 2331 31 D8S1046 2121 D8S1046 11 11 1111 11 D8S1834 5452 D8S1834 13 33 1333 33 D8S385 1213 D8S385 41 12 3112 12 D8S1784 2223 D8S1784 11 12 1112 11 IV IV 3 3 5 5 6 1 2 3 4 1 2 3 4 5 D8S521 43 33 3213 D8S521 43 4313 12 33 D8S1046 12 22 2432 D8S1046 21 2111 11 11 D8S1834 25 55 5315 D8S1834 23 2333 31 33 D8S385 31 11 1121 D8S385 21 2111 23 11 D8S1784 32 22 2132 D8S1784 31 3111 21 11 V V 3 1 2 3 4 5 1 2 D8S521 33123333 32 D8S521 2333 D8S1046 22342222 34 D8S1046 1111 D8S1834 55135555 13 D8S1834 1333 D8S385 11211111 21 D8S385 4111 D8S1784 22312222 31 D8S1784 1111 B C Figure 1. Pedigrees and Phenotypes of Families Affected by Nail Dysplasia (A) Both families are consanguineous Pakistani pedigrees, and individuals who were examined and sampled for genetic analysis are indi- cated with numbers. Affected individuals are shown as filled symbols. Marker haplotypes on chromosome 8 spanning FZD6 locus are shown below the symbols and were generated as described.16,17 (B) Hands and feet of individual V:1 in family F1 showing onychauxis, hyponychia, and onycholysis of both finger- and toenails. Finger- nails are claw-shaped. (C) Hands and feet of individual III:5 in family F2. Onychauxis and onycholysis of both fingernails and toenails are less severe in indi- vidual III:5 than in individuals from family F1. this study, and the protocol was approved by the local the long arm of chromosome 8 (1570 SNPs). Within this ethical board at NIBGE, Faisalabad, Pakistan. region, affected individuals of family F2 were homozygous Blood samples were collected for DNA extraction from 22 over 800 kb (66 SNPs) (Figure S1A, available online). We per- available members of families F1 and F2, and we initially formed genetic linkage analysis by using polymorphic mi- genotyped DNA samples from the four affected family crosatellite markers16,17 on the long arm of chromosome members in family F1 by using the GeneChip Human 8 and obtained a maximum cumulative two-point LOD Mapping 250K SNP Array. Autozygosity mapping15 re- score of 3.87 (Q ¼ 0). The analysis confirmed homozygosity vealed one large homozygous region spanning 17 Mb on for the region in affected family members, and each family The American Journal of Human Genetics 88, 852–860, June 10, 2011 853 had a distinct haplotype.
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