Hannah Mandel, Revital Shemer, Zvi U

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SERKAL Syndrome: An Autosomal-Recessive Disorder Caused by a Loss-of-Function Mutation in WNT4 Hannah Mandel, Revital Shemer, Zvi U. Borochowitz, Marina Okopnik, Carlos Knopf, Margarita Indelman, Arie Drugan, Dov Tiosano, Ruth Gershoni-Baruch, Mordechai Choder, Eli Sprecher The American Journal of Human Genetics Volume 82, Issue 1, Pages 39-47 (January 2008) DOI: 10.1016/j.ajhg.2007.08.005 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree Structure and Pathological Features (A) Family pedigree and haplotype analysis using polymorphic microsatellite markers on 1p36.23-p35.1. The disease-associated haplotype is boxed in red. The position of the WNT4 gene is indicated. (B–I) Histopathogical examination of tissues obtained from affected fetuses (B, D, F, and H) and from a normal 19-week-old fetus (C, E, G, and I). Affected 46,XX fetus II-12 displays (B) a normal-looking testis (sex reversal) with coiled seminiferous tubules and numerous Leydig cells throughout the interstitium as compared with the testis of an 46,XY healthy fetus (C); affected fetus II-6 demonstrates both testicular (“T”) and ovarian (“O”) tissues (D) including seminiferous tubules (“ST”), Leydig cells (“LC”), and primordial follicles (“PF”) (E); the kidney of affected fetus II-12 (F) showed a very thin rim of nephrogenic zone, with decreased numbers of mature glomeruli, and very few proximal tubules with immature interstitial tissue resembling undifferentiated mesenchyme of dysplastic kidney as compared with a normal fetal kidney at 19 weeks of gestation (G), where the numerous glomeruli identify the renal cortex; examination of lung tissues of affected fetus II-2 (H) revealed focal marked dilatation of distal airways compared with control fetal lung tissue (I) (magnification, 50× [B and C], 100× [D, F, G, H, and I], 400× [E]). The American Journal of Human Genetics 2008 82, 39-47DOI: (10.1016/j.ajhg.2007.08.005) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 Mutation Analysis (A) Sequence analysis revealed in an affected fetus (II-12) a homozygous transition (c.C341T) (blackened letter, upper panel), resulting in amino acid substitution A114V. The wild-type sequence is given for comparison (lower panel). (B) c.C314T creates a novel recognition site for HpyCH4IV endonuclease. A 699 bp fragment was amplified as described in Material and Methods and digested with HpyCH4IV. The affected fetus displays two fragments, of 172 bp and 527 bp, that are carried in a heterozygous state by all other family members. (C) The amino acid (upper panel) and cDNA (lower panel) sequences of human WNT4 were compared to those of other human WNT proteins and WNT4 orthologs in other species. Note the high degree of conservation of both amino acid A114 (upper panel) and nucleotide C341 (lower panel). The American Journal of Human Genetics 2008 82, 39-47DOI: (10.1016/j.ajhg.2007.08.005) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 Consequences of Mutation c.C341T (A) Western-blot analysis of β-catenin and β-actin expression in OVCAR3 cells transfected with empty vector (EV), wild-type WNT4 cDNA (WT), and c.C341T mutant cDNA (M). (B) Expression of WNT4 and ACTB, coding for β-actin, assessed with RT-PCR in amniocytes obtained from an affected embryo (“A”) as compared with control amniocytes (“UA”). (C) Quantitative real-time PCR analysis for gene expression of WNT4 in amniocytes obtained from an affected embryo (“A”) as compared with control amniocytes (“UA”) (bars represent standard errors). Expression levels are expressed as absolute values normalized relative to ACTB RNA levels. (D) Predicted secondary structures of wild-type (“WT”) and c.C314T mutant WNT4 RNA spanning exon 3. The position of c.C341T and mutations resulting in a similar change in mRNA secondary structure are marked with arrows. (E) Quantitative real-time PCR analysis for gene expression of WNT4 in OVCAR3 cells transfected with empty vector (“EV”), wild-type WNT4 cDNA (“WT”), and c.C341T mutant cDNA (“M”). Expression levels are expressed as absolute values normalized relative to ACTB RNA levels (bars represent standard errors). (F) Chromatograms (GC-MS, SIM mode) of urinary-steroid hormones. In both parents, 5-α/5-β isomer ratios [Androsterone/Etiocholanolone(1,2);11-OH-Androsterone/11-OH-etiocholanolone (3,4); α-tetrahydrocorticosterone (THB)/β-THB (5,6); α-tetrahydrocortisol (THF)/β-THF (7,8)], reveal an excess of activity of the enzyme 5-alpha-reductase. The 5α-isomers are 1, 3, 6, and 8; the 5β-isomers are 2, 4, 5, and 7. The American Journal of Human Genetics 2008 82, 39-47DOI: (10.1016/j.ajhg.2007.08.005) Copyright © 2008 The American Society of Human Genetics Terms and Conditions