Exome Sequencing Identifies a DYNC1H1 Mutation in a Large Pedigree with Dominant Axonal Charcot-Marie-Tooth Disease Michael N. Weedon, Robert Hastings,

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Exome Sequencing Identifies a DYNC1H1 Mutation in a Large Pedigree with Dominant Axonal Charcot-Marie-Tooth Disease Michael N. Weedon, Robert Hastings, Richard Caswell, Weijia Xie, Konrad Paszkiewicz, Thalia Antoniadi, Maggie Williams, Cath King, Lynn Greenhalgh, Ruth Newbury-Ecob, Sian Ellard The American Journal of Human Genetics Volume 89, Issue 2, Pages 308-312 (August 2011) DOI: 10.1016/j.ajhg.2011.07.002 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Partial Pedigree Showing Mutation Status Open symbols represent unaffected individuals; filled squares represent affected males and filled circles affected females. Individual generations are numbered with roman numerals on the left. Individuals heterozygous for the p.His306Arg mutation are indicated as N/M. For the LOD-score calculation we assumed a rare autosomal-dominant model with a disease-allele frequency of 0.0001 and phenocopy rate of 0. The mutant DYNC1H1 allele is rare (frequency <0.001); because we only tested affected individuals to avoid issues of predictive testing and variable penetrance and because there are 12 meioses separating the nine sequenced individuals, the LOD score for the variant can be approximated as −log10(0.512) = 3.6. The American Journal of Human Genetics 2011 89, 308-312DOI: (10.1016/j.ajhg.2011.07.002) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Schematic Representation of Human DYNC1H1 The N-terminal region of DYNC1H1 is represented by a horizontal black bar, and the stem domain (amino acids 53–1867) is indicated by a bracket above. Residues involved in DYNC1H1 dimerization (300–1140) are shown by a light blue bar; open boxes represent binding regions for intermediate (DYN1I; residues 448–703, solid line) and light-intermediate (DYN1LI; residues 651–802, broken line) chains, respectively. The motor domain (amino acids 1868–4646) is indicated by the orange shaded area; the seven ATPase domains are represented by circles, whereas the horizontal bar indicates the stalk region. The equivalent positions of mutations in three mouse models, Loa, Swl, and Cra1, are shown below the figure along with the p.His306Arg mutation identified in the family reported here. Note that the human protein contains two additional glycine residues at position 7 relative to mouse Dync1h1, that is numbering of equivalent residues in human DYNC1H1 is 2 higher than in mouse models. Phe582 is within a highly conserved domain responsible for binding the dynein intermediate chains as well as homodimerization.4 The 9 bp Swl deletion and Cra p.Tyr1057Cys mutation are outside the dynein intermediate-chain binding region but within the putative homodimerization domain.4 Numbering of amino acids is taken from Tynan et al.16 and the UniProtKB entry for human DYNC1H1 (identifier Q14204). The American Journal of Human Genetics 2011 89, 308-312DOI: (10.1016/j.ajhg.2011.07.002) Copyright © 2011 The American Society of Human Genetics Terms and Conditions