A Novel Locus Harbouring a Functional Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment

English version České info

It is known that hearing impairment running in families can be caused by mutations in more than eighty different genes. However, there are still families where the responsible gene is unknown. By studying a large Danish family with dominant inherited hearing impairment, we found that the disorder cosegregates with genetic markers on chromosome 6, suggesting that the responsible mutation lies within this chromosomal region. By sequencing this genetic locus, we discovered a mutation in the CD164 gene that is passed on to all the affected individuals. In the mouse ear, we demonstrated that the CD164 protein is expressed in hair cells and other sites known to be important for correct hearing. The identified mutation is predicted to result in shortening of the protein, leading to loss of an evolutionary conserved sequence important for cellular trafficking of CD164. Using cell lines, we show that the truncated protein is trapped on the cell surface while the normal protein is internalized. This finding is important because it implicates for the first time a role for CD164 in the complex physiological processes of hearing and suggests that failed endocytosis may be a possible disease mechanism for some types of hearing impairment.

Vyšlo v časopise: A Novel Locus Harbouring a Functional Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005386
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005386

Souhrn

Zdroje

1. Hoefsloot LH, Feenstra I, Kunst HP, Kremer H (2014) Genotype phenotype correlations for hearing impairment: approaches to management. Clin Genet 85: 514–523. doi: 10.1111/cge.12339 24547994

2. Dror AA, Avraham KB (2009) Hearing loss: mechanisms revealed by genetics and cell biology. Annu Rev Genet 43: 411–437. doi: 10.1146/annurev-genet-102108-134135 19694516

3. Brownstein Z, Bhonker Y, Avraham KB (2012) High-throughput sequencing to decipher the genetic heterogeneity of deafness. Genome Biol 13: 245. doi: 10.1186/gb-2012-13-5-245 22647651

4. Rabbani B, Tekin M, Mahdieh N (2014) The promise of whole-exome sequencing in medical genetics. J Hum Genet 59: 5–15. doi: 10.1038/jhg.2013.114 24196381

5. Lenz DR, Avraham KB (2011) Hereditary hearing loss: from human mutation to mechanism. Hear Res 281: 3–10. doi: 10.1016/j.heares.2011.05.021 21664957

6. Wayne S, Robertson NG, DeClau F, Chen N, Verhoeven K, et al. (2001) Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet 10: 195–200. 11159937

7. Chen Z, Montcouquiol M, Calderon R, Jenkins NA, Copeland NG, et al. (2008) Jxc1/Sobp, encoding a nuclear zinc finger protein, is critical for cochlear growth, cell fate, and patterning of the organ of corti. J Neurosci 28: 6633–6641. doi: 10.1523/JNEUROSCI.1280-08.2008 18579736

8. Gilels F, Paquette ST, Zhang J, Rahman I, White PM (2013) Mutation of Foxo3 causes adult onset auditory neuropathy and alters cochlear synapse architecture in mice. J Neurosci 33: 18409–18424. doi: 10.1523/JNEUROSCI.2529-13.2013 24259566

9. Buetow KH, Edmonson MN, Cassidy AB (1999) Reliable identification of large numbers of candidate SNPs from public EST data. Nat Genet 21: 323–325. 10080189

10. Ihrke G, Kyttala A, Russell MR, Rous BA, Luzio JP (2004) Differential use of two AP-3-mediated pathways by lysosomal membrane proteins. Traffic 5: 946–962. 15522097

11. Consortium GT (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45: 580–585. doi: 10.1038/ng.2653 23715323

12. Braulke T, Bonifacino JS (2009) Sorting of lysosomal proteins. Biochim Biophys Acta 1793: 605–614. doi: 10.1016/j.bbamcr.2008.10.016 19046998

13. Zannettino AC, Buhring HJ, Niutta S, Watt SM, Benton MA, et al. (1998) The sialomucin CD164 (MGC-24v) is an adhesive glycoprotein expressed by human hematopoietic progenitors and bone marrow stromal cells that serves as a potent negative regulator of hematopoiesis. Blood 92: 2613–2628. 9763543

14. Ihrke G, Gray SR, Luzio JP (2000) Endolyn is a mucin-like type I membrane protein targeted to lysosomes by its cytoplasmic tail. Biochem J 345 Pt 2: 287–296. 10620506

15. Potter BA, Weixel KM, Bruns JR, Ihrke G, Weisz OA (2006) N-glycans mediate apical recycling of the sialomucin endolyn in polarized MDCK cells. Traffic 7: 146–154.

16. Khajavi M, Inoue K, Lupski JR (2006) Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet 14: 1074–1081. 16757948

17. Le Hir H, Izaurralde E, Maquat LE, Moore MJ (2000) The spliceosome deposits multiple proteins 20–24 nucleotides upstream of mRNA exon-exon junctions. EMBO J 19: 6860–6869. 11118221

18. Wu C, Orozco C, Boyer J, Leglise M, Goodale J, et al. (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 10: R130. doi: 10.1186/gb-2009-10-11-r130 19919682

19. Robertson NG, Khetarpal U, Gutierrez-Espeleta GA, Bieber FR, Morton CC (1994) Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening. Genomics 23: 42–50. 7829101

20. Skvorak AB, Weng Z, Yee AJ, Robertson NG, Morton CC (1999) Human cochlear expressed sequence tags provide insight into cochlear gene expression and identify candidate genes for deafness. Hum Mol Genet 8: 439–452. 9949203

21. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, et al. (2014) Guidelines for investigating causality of sequence variants in human disease. Nature 508: 469–476. doi: 10.1038/nature13127 24759409

22. Nielsen MS, Madsen P, Christensen EI, Nykjaer A, Gliemann J, et al. (2001) The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein. EMBO J 20: 2180–2190. 11331584

23. Ihrke G, Bruns JR, Luzio JP, Weisz OA (2001) Competing sorting signals guide endolyn along a novel route to lysosomes in MDCK cells. EMBO J 20: 6256–6264. 11707397

24. Bae GU, Gaio U, Yang YJ, Lee HJ, Kang JS, et al. (2008) Regulation of myoblast motility and fusion by the CXCR4-associated sialomucin, CD164. J Biol Chem 283: 8301–8309. doi: 10.1074/jbc.M706730200

25. Mellman I, Nelson WJ (2008) Coordinated protein sorting, targeting and distribution in polarized cells. Nat Rev Mol Cell Biol 9: 833–845. doi: 10.1038/nrm2525 18946473

26. Stein M, Wandinger-Ness A, Roitbak T (2002) Altered trafficking and epithelial cell polarity in disease. Trends Cell Biol 12: 374–381. 12191914

27. Forde S, Tye BJ, Newey SE, Roubelakis M, Smythe J, et al. (2007) Endolyn (CD164) modulates the CXCL12-mediated migration of umbilical cord blood CD133+ cells. Blood 109: 1825–1833. 17077324

28. Zhou GQ, Zhang Y, Ferguson DJ, Chen S, Rasmuson-Lestander A, et al. (2006) The Drosophila ortholog of the endolysosomal membrane protein, endolyn, regulates cell proliferation. J Cell Biochem 99: 1380–1396. 16924678

29. Mo D, Ihrke G, Costa SA, Brilli L, Labilloy A, et al. (2012) Apical targeting and endocytosis of the sialomucin endolyn are essential for establishment of zebrafish pronephric kidney function. J Cell Sci 125: 5546–5554. doi: 10.1242/jcs.111468 22976307

30. Mukhopadhyay N, Almasy L, Schroeder M, Mulvihill WP, Weeks DE (2005) Mega2: data-handling for facilitating genetic linkage and association analyses. Bioinformatics 21: 2556–2557. 15746282

31. Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 58: 1323–1337. 8651310

32. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754–1760. doi: 10.1093/bioinformatics/btp324 19451168

33. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, et al. (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20: 1297–1303. doi: 10.1101/gr.107524.110 20644199

34. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, et al. (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43: 491–498. doi: 10.1038/ng.806 21478889

35. Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26: 841–842. doi: 10.1093/bioinformatics/btq033 20110278

36. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, et al. (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25: 2078–2079. doi: 10.1093/bioinformatics/btp352 19505943

37. Pihlmann M, Askou AL, Aagaard L, Bruun GH, Svalgaard JD, et al. (2012) Adeno-associated virus-delivered polycistronic microRNA-clusters for knockdown of vascular endothelial growth factor in vivo. J Gene Med 14: 328–338. doi: 10.1002/jgm.2623 22438271

38. Klinger SC, Glerup S, Raarup MK, Mari MC, Nyegaard M, et al. (2011) SorLA regulates the activity of lipoprotein lipase by intracellular trafficking. J Cell Sci 124: 1095–1105. doi: 10.1242/jcs.072538 21385844

39. Hauge C, Antal TL, Hirschberg D, Doehn U, Thorup K, et al. (2007) Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation. EMBO J 26: 2251–2261. 17446865