Mutations in POFUT1, Encoding Protein O-fucosyltransferase 1, Cause Generalized Dowling-Degos Disease Ming Li, Ruhong Cheng, Jianying Liang, Heng Yan,

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Mutations in POFUT1, Encoding Protein O-fucosyltransferase 1, Cause Generalized Dowling-Degos Disease Ming Li, Ruhong Cheng, Jianying Liang, Heng Yan, Hui Zhang, Lijia Yang, Chengrang Li, Qingqing Jiao, Zhiyong Lu, Jianhui He, Jin Ji, Zhu Shen, Chunqi Li, Fei Hao, Hong Yu, Zhirong Yao The American Journal of Human Genetics Volume 92, Issue 6, Pages 895-903 (June 2013) DOI: 10.1016/j.ajhg.2013.04.022 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Family Pedigrees and Clinical Photographs of Individuals with Generalized DDD (A and B) Pedigrees of families 1 (A) and 2 (B). The squares and circles denote males and females, respectively. Affected individuals are shown in black. The probands are denoted by arrows. (C–F) Clinical photographs of individual III:11 in family 1. Reticular hyperpigmentation on the wrists (C) and inguinal regions (D), reticular hyperpigmentation and hyperkeratotic dark-brown papules on the neck (E), and reticular hypopigmentation on the abdomen (F) are shown. (G–J) Clinical photographs of individual II:3 in family 2. Reticular hyperpigmentation and hypopigmentation on the bilateral axillae with hyperkeratotic dark-brown papules (G and H), reticular hyperpigmentation and hypopigmentation on the neck (I), and reticular hypopigmentation on the abdomen (J) are shown. The American Journal of Human Genetics 2013 92, 895-903DOI: (10.1016/j.ajhg.2013.04.022) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Electron Microscopy of Skin from DDD Individual III:11 in Family 1 and a Control (A) Ultrathin section from the individual with DDD shows a few melanosomes in the melanocytes. Of note, premelanosomes are rarely seen. Abbreviations are as follows: M, melanocyte; K, keratinocyte; and N, nucleus. (B and C) In contrast with control skin (C), the melanocyte of the individual with DDD (B) is small in size, has lighter cytoplasm, and lacks melanosomes. (D) Normal keratin filaments and their interaction with hemidesmosomes and desmosomes of the individual with DDD. The American Journal of Human Genetics 2013 92, 895-903DOI: (10.1016/j.ajhg.2013.04.022) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 Identification of the Disease-Causing POFUT1 Mutations in Two Families Affected by Generalized DDD (A) Haplotype analysis of family 1. Haplotype indicates heterozygosity between rs1293713 and rs244123 in affected family members. The recombination events defined the susceptibility region in 20p11.21–20q13.12 to a 14.79 cM interval. Red bars indicate the chromosomal region shared by affected members of the pedigree. (B) Output of the multipoint-LOD-score analysis for chromosome 20. (C and D) POFUT1 mutations in the two families: c.430G>T (p.Glu144∗) in family 1 (C) and c.482delA (p.Lys161Serfs∗42) in family 2 (D). The black arrows indicate mutations. (E) The normal POFUT1 transcripts from the DDD individual and control skin. The American Journal of Human Genetics 2013 92, 895-903DOI: (10.1016/j.ajhg.2013.04.022) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 4 Identification of the Effectiveness of pofut1 Knockdown and the Effect of Tyrosinase Activity and Melanin Protein Contents of Zebrafish by Knockdown of Pofut1 Expression (A and B) Effectiveness of pofut1 knockdown was confirmed by RT-PCR and Sanger sequencing. The expression of pofut1 decreased obviously in 72 hpf (A), and compared to the wild-type cDNA sequence, the cDNA sequence of the pofut1-MO group showed a lack of 105 bp from exon 2 (B). MO∗ indicates the pofut1-MO group. (C and D) Zebrafish phenotype observation at 48 and 72 hpf. The melanin contents in the zebrafish tail at 48 hpf (C) and in both the tail and body axis at 72 hpf (D) decreased significantly in the pofut1-MO group compared with controls, and the melanin distribution in the zebrafish tail was presented as dispersion in the pofut1-MO group (D). The black arrow indicates abnormal melanin distribution in the zebrafish fin. (E) Detection of tyrosinase activity and melanin protein contents at 48 and 72 hpf. Both tyrosinase activity and melanin protein contents were lower in the pofut1-MO group at 48 and 72 hpf, respectively, than in controls. The results are shown as the mean ± SD (n = 5), and similar results were obtained when the experiments and measurements were repeated three times. Error bars indicate the mean ± SD. ∗∗∗p < 0.001, ∗∗p < 0.01, ∗p < 0.05. (F) RT-PCR analyses of pofut1 expression in zebrafish from 6 to 72 hpf. Pofut1 was knocked down in all pofut1-MO groups from 12 to 72 hpf. The size of the amplified cDNA fragment containing exon 2 was 722 bp, and a product generated from cDNA without part of exon 2 of the pofut1-MO group was 617 bp in size. The American Journal of Human Genetics 2013 92, 895-903DOI: (10.1016/j.ajhg.2013.04.022) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 5 Analysis of Pofut1 Knockdown in Zebrafish and Reduced POFUT1 in HaCaT Cells (A and B) RNA expression levels of pofut1, notch1, notch2, hey1, krt5, tyr, and mitf were determined by quantitative real-time PCR at 48 and 72 hpf in zebrafish. Morpholino knockdown of pofut1 in zebrafish resulted in a corresponding decrease in the expression of pofut1, notch2, hey1, krt5, tyr, and mitf at 48 (A) and 72 (B) hpf. The expression of notch1 decreased at 48 hpf, but not at 72 hpf. The results are shown as the mean ± SD (n = 3); one representative experiment of two is shown. Error bars indicate the mean ± SD. ∗∗p < 0.01, ∗p < 0.05. (C) RNA expression levels of POFUT1, NOTCH1, NOTCH2, HES1, and KRT5 were determined by quantitative real-time PCR in HaCaT cells. The shRNA knockdown of POFUT1 in HaCaT cells resulted in a corresponding decrease in the expression of POFUT1, NOTCH1, NOTCH2, HES1, and KRT5. The results are shown as the mean ± SD (n = 3); one representative experiment of two is shown. Error bars indicate the mean ± SD. ∗∗∗p < 0.001, ∗∗p < 0.01, ∗p < 0.05. The American Journal of Human Genetics 2013 92, 895-903DOI: (10.1016/j.ajhg.2013.04.022) Copyright © 2013 The American Society of Human Genetics Terms and Conditions