Deletions and Point Mutations of LRRC50 Cause Primary Ciliary Dyskinesia Due to Dynein Arm Defects Niki Tomas Loges, Heike Olbrich, Anita Becker-Heck,

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Deletions and Point Mutations of LRRC50 Cause Primary Ciliary Dyskinesia Due to Dynein Arm Defects Niki Tomas Loges, Heike Olbrich, Anita Becker-Heck, Karsten Häffner, Angelina Heer, Christina Reinhard, Miriam Schmidts, Andreas Kispert, Maimoona A. Zariwala, Margaret W. Leigh, Michael R. Knowles, Hanswalter Zentgraf, Horst Seithe, Gudrun Nürnberg, Peter Nürnberg, Richard Reinhardt, Heymut Omran The American Journal of Human Genetics Volume 85, Issue 6, Pages 883-889 (December 2009) DOI: 10.1016/j.ajhg.2009.10.018 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Chromosomal Array and Mutations of LRRC50 (A) LRRC50 is located on 16q24.1. (B) Chromosomes of four individuals carrying deletions involving LRRC50 are shown. The gray bars mark the deletions. (C–E) Array of the genes located in the genomic interval of interest; genomic structure of HSDL1 and LRRC50 (C). The arrows indicate the position of the detected point mutations shown in (D) (mutation of UNC65) and (E) (mutation of OP250-II1). The American Journal of Human Genetics 2009 85, 883-889DOI: (10.1016/j.ajhg.2009.10.018) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Deletions on the Alleles of Family OP473 and Patient UNC65 (A) Results of quantitative SNP analysis from the parents of the affected child with PCD (OP473-II1). The graphs indicate log2ratio and copy-number state as a function of genomic position. The father (OP473-I1) carries a large (∼640 kb) deletion on one allele (marked by a yellow arrow), and the mother (OP473-I2) carries a small (11 kb) deletion on one allele (marked by a red arrow) within the region of HSDL1 and LRRC50. The affected son inherited both deleted alleles. The mother's deleted block contained six SNPs and two copy-number variants. Lower panel: The positions of the first 5′ base of primers used for quantitative PCR are given. The breakpoints of the larger deletion are located between primers Rx and Ra (distance: 1488 bp) on 16q23.3 and primers F4a4 and F4a3 (distance: 2816 bp) on 16q24.1. We were unable to narrow this region further because of repetitive Alu elements present within these regions. (B) Patient UNC65 carries a ∼220 kb deletion on one allele (marked by a blue arrow). On the other allele, a point mutation (Figure 1D) was identified. The American Journal of Human Genetics 2009 85, 883-889DOI: (10.1016/j.ajhg.2009.10.018) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 Expression of Mouse Lrrc50 and Randomization of Left-Right Body Asymmetry in Patients with LRRC50 Mutations (A–D) Whole-mount in situ hybridization analysis of mouse Lrrc50 in early gastrulation-stage embryos. Lrrc50 expression is restricted to the node in embryos at 7.75–8.0 dpc (B and C; arrow). (E and F) Lrrc50 expression (arrow) in ciliated cells of the upper airways in 16.5 dpc mouse embryonic sections. (E). Midline sagittal section; arrow depicts nasopharynx. (F) Parasagittal section; arrow depicts respiratory epithelium of the nasal cavity. The identical probe is used in all in situ hybridization panels. (G) Patient OP250-II1 has situs inversus totalis and patient OP473-II1 has situs solitus. (H) The hearts are marked by arrows. Thus, mutations of LRRC50 cause randomization of left-right body asymmetry. The American Journal of Human Genetics 2009 85, 883-889DOI: (10.1016/j.ajhg.2009.10.018) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 4 Axonemal Defects of the IDA and ODA in PCD Patients with LRRC50 Mutations (A) Transmission electron micrographs of cross-sections from respiratory cilia from patients OP250-II1, UNC65, and OP473-II1. Please note ODA and IDA defects as compared to an electron micrograph from a healthy control. (B–E) High-resolution immunofluorescence microscopy of respiratory cells from a healthy control and patient OP250-II1 with the use of specific antibodies directed against ODA chains DNAH5 (B), DNAH9 (C), DNAI2 (D), and IDA component DNALI1 (E). Acetylated α-tubulin and α/β-tubulin were stained as control for ciliary axonemes. In LRRC50 mutant respiratory cells, outer dynein chains DNAH5 (B), DNAH9 (C), and DNAI2 (D) are completely absent from the axonemes of mutant respiratory cells. The inner dynein chain DNALI1 is also completely absent from mutant ciliary axonemes (E). Nuclei were stained with Hoechst 33342 (blue). Black scale bars (A) represent 0.1 μm and white scale bars (B–E) represent 10 μm. The American Journal of Human Genetics 2009 85, 883-889DOI: (10.1016/j.ajhg.2009.10.018) Copyright © 2009 The American Society of Human Genetics Terms and Conditions