Mutations in FEZF1 Cause Kallmann Syndrome

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Mutations in FEZF1 Cause Kallmann Syndrome L. Damla Kotan, B. Ian Hutchins, Yusuf Ozkan, Fatma Demirel, Hudson Stoner, Paul J. Cheng, Ihsan Esen, Fatih.

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Mutations in FEZF1 Cause Kallmann Syndrome L. Damla Kotan, B. Ian Hutchins, Yusuf Ozkan, Fatma Demirel, Hudson Stoner, Paul J. Cheng, Ihsan Esen, Fatih Gurbuz, Y. Kenan Bicakci, Eda Mengen, Bilgin Yuksel, Susan Wray, A. Kemal Topaloglu The American Journal of Human Genetics Volume 95, Issue 3, Pages 326-331 (September 2014) DOI: 10.1016/j.ajhg.2014.08.006 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree and Olfactory MRI of the Probands (A) Pedigrees of the families; arrows point to probands. Solid symbols indicate affected family members, open symbols indicate unaffected family members, squares indicate male family members, circles indicate female family members, and the double line indicates consanguinity. Under each symbol is the FEZF1 genotype. (B) Brain MRI at T2 coronal sections. The left panel is from a healthy young adult; the arrow indicates normal olfactory bulbs. The middle panel shows the absence of olfactory bulbs (aplasia) in the proband from family 1. The right panel demonstrates the absence of olfactory bulbs (aplasia) in the proband from family 2. The American Journal of Human Genetics 2014 95, 326-331DOI: (10.1016/j.ajhg.2014.08.006) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Functional Analysis of Mutated FEZF1 (A) Predicted 3D model of the zinc-finger domain containing histidine 278. Histidine residues (blue) are shown alongside cysteine (yellow) and bound zinc. (B) Predicted 3D model of the altered FEZF1, in which histidine 278 changed to a tyrosine, from family 1. (C) Analysis of DsRed band optical density (normalized to tubulin) with either no FEZF1, altered FEZF1, or wild-type FEZF1. Histograms show the mean, and error bars represent the SE (∗p < 0.05, repeated-measures one-way ANOVA with the Holm-Sidak posttest). (D) Example of an immunoblot showing Hes5-DsRed levels when cotransfected with no FEZF1 (left), altered FEZF1 (middle), or wild-type FEZF1 (right). Immunoblot analysis was performed according to standard protocols. Protein was extracted 24 hr after transfection. Fifty micrograms of total protein was denatured, subsequently loaded into a 7.5% gel, and then separated. Protein was then transferred to a polyvinylidene fluoride membrane, blocked, and incubated in primary antibody overnight. Then the membranes were washed, subsequently incubated with horseradish-peroxidase-conjugated secondary antibody for 2 hr, and visualized with an enhanced chemiluminescence reaction. Band density was quantified with ImageJ. DsRed band density was normalized to β-tubulin levels. Rabbit anti-human ZNF312B (FEZF1, Abcam, catalog no. ab81251, 1:1,000), anti-DsRed (Clontech, catalog no. 632496, 1:1,000), mouse anti-β-tubulin (Sigma, catalog no. T4026, 1:1,000), anti-rabbit HRP (Cell Signaling, catalog no. 7074, 1:5,000), anti-mouse HRP (Cell Signaling, catalog no. 7076, 1:5,000) antibodies were used in these experiments. Statistical significance was determined with Prism (GraphPad). The American Journal of Human Genetics 2014 95, 326-331DOI: (10.1016/j.ajhg.2014.08.006) Copyright © 2014 The American Society of Human Genetics Terms and Conditions