PMC6346677_01
Schematic of FANCD2 protein sequence with pathologic alterations. FANCD2 is a 1,452 amino acid protein composed of 44 exons. Orange annotations represent our patient's genetic mutations (deletion of exons 2-18 and R815Q missense mutation; schematic does not reflect that these changes are on different alleles). Cyan annotations show regions of the protein important for protein-protein interaction with the FA-core complex (FANCE) and repair enzymes (BRCA2). Gray annotations represent various exons for helpful for orientation. NLS, or nuclear localization sequence, is in exon 2. Lysine-561 (K561) is located in exon 19 and is the sole site for ubiquitination and activation of FANCD2. Schematic was generated using Geneious  software v11.1.5. The annotations of interacting domains are based on data available from UniProtKB (ID: Q9BXW9) and BioGrid3.4 (ID:108474).
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F1
She presented with numerous congenital anomalies including mesomelia and radial ray defects (Table S1, Figures S1, S2). Our patient has a c.2444G->A mutation in exon 26 of FANCD2 leading to the missense mutation, R815Q (Figure 1).
Assembly of FANCD2 and details of pathogenic missense mutation. (A) Cartoon drawing showing assembly of FANCD2 (cyan) in complex with FANCI (green) based on available crystal structure data (PDB 3S4W). Red amino acid residue represents location of R812Q on the protein surface; orange residue shows location of K561, which is essential for ubiquitination. (B) Closer look at R812Q on the protein surface relative to loop domains. Molecular models were generated using PyMol Molecular Graphics System (v2.2.0).
fped-06-00390-g0002.jpg
PMC6346677_01_fped-06-00390-g0002.jpg
F2
She presented with numerous congenital anomalies including mesomelia and radial ray defects (Table S1, Figures S1, S2). The R815Q mutation is located in exon 26, residing ~42 A away from K561 and the FANCI-interacting region (Figure 2).
PMC6346677_02