Hung-Chun Yu, Jennifer L

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An X-Linked Cobalamin Disorder Caused by Mutations in Transcriptional Coregulator HCFC1 Hung-Chun Yu, Jennifer L. Sloan, Gunter Scharer, Alison Brebner, Anita M. Quintana, Nathan P. Achilly, Irini Manoli, Curtis R. Coughlin, Elizabeth A. Geiger, Una Schneck, David Watkins, Terttu Suormala, Johan L.K. Van Hove, Brian Fowler, Matthias R. Baumgartner, David S. Rosenblatt, Charles P. Venditti, Tamim H. Shaikh The American Journal of Human Genetics Volume 93, Issue 3, Pages 506-514 (September 2013) DOI: 10.1016/j.ajhg.2013.07.022 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Metabolite Measurements in cblX Subjects Compared to Treated, Early-Onset cblC Subjects Plasma total homocysteine (tHcy) and serum and urine methylmalonic acid (MMA) were measured in cblX subjects (single measurements) and 23 subjects with early-onset cblC deficiency (1–13 measurements per subject). In cases where multiple measurements were available for the same subject, the mean of all readings was used. n = the total number of subjects in each group. (A) There was no statically significant difference in plasma tHcy measurements between cblC subjects and cblX subjects (cblC, 60.63 ± 4.88 μM; cblX, 64.25 ± 18.30 μM [mean ± SEM]). Normal levels of plasma tHcy are <13 μM. Triangles indicate two subjects with reportedly normal tHcy (no concentration was provided to the referring diagnostic laboratory). (B) There was no significant difference in serum MMA measurements between cblC subjects and cblX subjects (cblC, 11.57 ± 2.99 μM; cblX, 15.00 ± 3.43 μM [mean ± SEM]). Normal levels of serum MMA are <0.4 μM. (C) cblX subjects had higher urine MMA (t test p < 0.001) than did cblC subjects (cblC, 96.52 ± 23.89 mmol/mol creatinine; cblX, 354.20 ± 93.70 mmol/mol creatinine [mean ± SEM]). Normal levels of urine MMA are <4 mmol/mol creatinine. The American Journal of Human Genetics 2013 93, 506-514DOI: (10.1016/j.ajhg.2013.07.022) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Pathogenic Variants of HCFC1 in cblX (A) The top panel shows the 26 exons of HCFC1 as gray boxes. The bottom panel shows the predicted HCFC1 domains, including the kelch domain (kelch motifs K1–K5), Fn3 (fibronectin type 3), the basic domain, HCF-proteolysis repeats (HCF-pro; represented as triangles), the acidic domain, and NLS (nuclear localization signal) domains (adapted from Wilson et al.24). The HCFC1 mutations are clustered within exon 2 and 3 of the cDNA, corresponding to the first (K1) and second (K2) kelch motifs, respectively, in HCFC1. (B) Comparative analysis of HCFC1 from multiple species demonstrated that Gln68, Ala73, and Ala115 (highlighted in red) are evolutionarily conserved throughout vertebrates. The American Journal of Human Genetics 2013 93, 506-514DOI: (10.1016/j.ajhg.2013.07.022) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 Expression Analysis (A) qPCR analysis of mRNA expression. MMACHC expression was either completely lost or reduced by ∼76% in fibroblasts derived from subjects 1 and 11, respectively (asterisks indicate statistical significance). Error bars represent the SEM of relative expression levels. The two control samples used were from healthy individuals with no known biochemical or neurological phenotypes. (B) Immunoblot analysis of MMACHC. Fibroblast lysates from a reference (control) sample (human dermal fibroblast C-013-5C, Life Technologies), two individuals with cblX, and one with cblC were analyzed. The cblX (lanes 2 and 3) and cblC (lane 4) lines show only trace amounts of MMACHC (top panel). (C) Immunoblot analysis of HCFC1. Fibroblast lysates from the same control used in (B) and two cblX cell lines were analyzed. HCFC1 levels in all the samples remained unchanged. β-actin was used as a loading control in all immunoblots (in the bottom of B and C). The American Journal of Human Genetics 2013 93, 506-514DOI: (10.1016/j.ajhg.2013.07.022) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 4 siRNA Knockdown of HCFC1 HEK293 cells were transfected with HCFC1-specific siRNA or scrambled siRNA (control), and the relative expression of HCFC1 and MMACHC was assayed by qPCR using ACTB (β-actin) as an endogenous control. Compared to control cells (average expression levels were fixed at 1), siRNA-treated cells had significantly reduced HCFC1 (0.275) and MMACHC (0.424) expression levels, but the MMADHC expression level remain unchanged. Error bars represent the SEM of relative expression levels. The American Journal of Human Genetics 2013 93, 506-514DOI: (10.1016/j.ajhg.2013.07.022) Copyright © 2013 The American Society of Human Genetics Terms and Conditions