Congenital Anonychia and Uncombable Hair Syndrome: Coinheritance of Homozygous Mutations in RSPO4 and PADI3 Chao-Kai Hsu, Maria Teresa Romano, Arti Nanda,

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Congenital Anonychia and Uncombable Hair Syndrome: Coinheritance of Homozygous Mutations in RSPO4 and PADI3 Chao-Kai Hsu, Maria Teresa Romano, Arti Nanda, Ellie Rashidghamat, John Y.W. Lee, Hsin-Yu Huang, Chankiat Songsantiphap, Julia Yu-Yun Lee, Hejab Al-Ajmi, Regina C. Betz, Michael A. Simpson, John A. McGrath, Christos Tziotzios Journal of Investigative Dermatology Volume 137, Issue 5, Pages 1176-1179 (May 2017) DOI: 10.1016/j.jid.2016.12.015 Copyright © 2017 The Authors Terms and Conditions

Figure 1 Nail and hair abnormalities in the proband and extended pedigree. (a) Complete absence of all 20 nails in the proband; (b) the proband has somewhat sparse wavy scalp hair that is slow to grow and difficult to comb; (c) the proband (IV-3, arrow) is the third child of consanguineous parents with one unaffected sister and one unaffected brother. Three cousins (IV-5, IV-6, and IV-7) also have anonychia but no hair abnormalities. (d) The cousins of the proband (IV-5, IV-6, and IV-7) manifest anonychia without hair abnormalities. Journal of Investigative Dermatology 2017 137, 1176-1179DOI: (10.1016/j.jid.2016.12.015) Copyright © 2017 The Authors Terms and Conditions

Figure 2 Coinheritance of two separate autosomal recessive disorders accounts for the ectodermal dysplasia phenotype. (a) Sanger sequencing identifies a recurrent homozygous donor splice-site mutation in RSPO4 (IVS1+1G>A) in all subjects with anonychia, including the proband and three cousins; (b) Sanger sequencing confirms the proband’s homozygous missense mutation in PADI3 (c.1372C>A; p.Pro458Thr), originally identified by WES trio analysis. The proband is homozygous for the PADI3 mutation, whereas other unaffected family members are wild-type (WT) or heterozygous carriers; (c) verification of the mutation by HpyCH4III restriction enzyme digestion (New England BioLabs). The mutation c.1372C>A creates a new cut site such that the 452-bp band is cleaved into 300-bp and 152-bp products. For the patient (IV-3) two cleaved bands are present, whereas in carriers (III-3, III-4, and III-8) three discrete bands are seen. For the WT only the single undigested upper band is visible. (d) Schematic illustration of the PAD-3 protein and the mutations identified thus far (new mutation boxed in red); (e) immunoblot analysis of protein extracts from transiently transfected HaCaT cells shows a reduced expression of mutant PADI3 protein level compared with WT; immunoblotting was performed with anti-V5 antibody. (f) Immunofluorescence analysis in HaCaT cells transiently expressing WT and mutant PADI3 shows the homogeneous cytosolic expression of WT PADI3, whereas the mutant protein is observed in the form of large aggregates (scale bar = 10 μm). MW, molecular weight ladder; NC, negative control; PADI3, peptidyl arginine deiminase, type III; PC, positive control; RSPO4, R-Spondin 4; WES, whole exome sequencing. Journal of Investigative Dermatology 2017 137, 1176-1179DOI: (10.1016/j.jid.2016.12.015) Copyright © 2017 The Authors Terms and Conditions