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Canine Imerslund-Gräsbeck syndrome maps to a region orthologous to HSA14q

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Abstract

Selective malabsorption of cobalamin (vitamin B12) accompanied by proteinuria, known as Imerslund-Gräsbeck syndrome or megaloblastic anemia 1 (I-GS, MGA1; OMIM 261100), is a rare autosomal recessive disorder. In Finnish kindreds, I-GS is caused by mutations in the cubilin gene (CUBN), located on human Chromosome (Chr) 10. However, not all patients have CUBN mutations, and three distinct mutations in the amnionless gene, AMN, were very recently identified in patients from Norwegian and Israeli families. The present study demonstrates that in a large canine I-GS pedigree, the disease is genetically linked (peak multipoint LOD score 11.74) to a region on dog Chr 8 that exhibits conserved synteny with human Chr 14q. Multipoint analysis indicates that the canine disease gene lies in an interval between the echinoderm microtubule-associated, protein-like 1 (EML1) gene and the telomere. A single critical recombinant further suggests that the disease gene is between markers in EML1 and the G protein-coupled receptor (G2A) gene, defining an I-GS interval in the human genome that contains the AMN gene. Thus, these comparative-mapping data provide evidence that canine I-GS is a homologue of one form of the human disease and will provide a useful system for understanding the molecular mechanisms underlying the disease in humans.

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References

  1. JR Al-Alami MK Tayeh MY Al-Sheyyab HI El-Shanti (2002) ArticleTitleLinkage analysis of a large inbred family with congenital megaloblastic anemia. Saudi Med J 23 1251–1256 Occurrence Handle12436132

    PubMed  Google Scholar 

  2. Ç Altay M Çetin F Gümrük G Irken S Yetgin (1995) ArticleTitleFamilial selective vitamin B12 malabsorption (Imerslund-Gräsbeck syndrome) in a pool of Turkish patients. Pediatr Hematol Oncol 12 19–28 Occurrence Handle1:STN:280:ByqB3MjmvVw%3D Occurrence Handle7703038

    CAS  PubMed  Google Scholar 

  3. M Aminoff E Tahvanainen R Gräsbeck J Weissenbach H Broch et al. (1995) ArticleTitleSelective intestinal malabsorption of vitamin B12 displays recessive mendelian inheritance: assignment of a locus to chromosome 10 by linkage. Am J Hum Genet 57 824–831 Occurrence Handle1:CAS:528:DyaK2MXovF2ls70%3D Occurrence Handle7573042

    CAS  PubMed  Google Scholar 

  4. M Aminoff JE Carter RB Chadwick C Johnson R Gräsbeck et al. (1999) ArticleTitleMutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet 21 309–313 Occurrence Handle1:CAS:528:DyaK1MXitVCitb4%3D Occurrence Handle10080186

    CAS  PubMed  Google Scholar 

  5. V Batuman PJ Verroust GL Navar JH Kaysen FO Goda et al. (1998) ArticleTitleMyeloma light chains are ligands for cubilin (gp280). Am J Physiol 275 F246–F254 Occurrence Handle1:CAS:528:DyaK1cXlsVyjurY%3D Occurrence Handle9691015

    CAS  PubMed  Google Scholar 

  6. A Becker D Geiger AA Schäffer (1998) ArticleTitleAutomatic selection of loop breakers for genetic linkage analysis. Hum Hered 48 49–60 Occurrence Handle1:STN:280:DyaK1c7isV2lsQ%3D%3D Occurrence Handle9463802

    CAS  PubMed  Google Scholar 

  7. I Ben-Bassat A Feinstein B Ramot (1969) ArticleTitleSelective vitamin B12 malabsorption with proteinuria in Israel: clinical and genetic aspects. Isr J Med Sci 5 62–68 Occurrence Handle1:STN:280:CCaB2c%2FktlE%3D Occurrence Handle5796281

    CAS  PubMed  Google Scholar 

  8. H Birn PJ Verroust E Nexo H Hager C Jacobsen et al. (1997) ArticleTitleCharacterization of an epithelial approximately 460-kDa protein that facilitates endocytosis of intrinsic factor-vitamin B12 and binds receptor-associated protein. J Biol Chem 272 26497–26504 Occurrence Handle1:CAS:528:DyaK2sXmvV2isbw%3D Occurrence Handle9334227

    CAS  PubMed  Google Scholar 

  9. H Birn JC Fyfe C Jacobsen F Mounier PJ Verroust et al. (2000) ArticleTitleCubilin is an albumin binding protein important for renal tubular albumin reabsorption. J Clin Invest 105 1353–1361 Occurrence Handle1:CAS:528:DC%2BD3cXjtlOnsL8%3D Occurrence Handle10811843

    CAS  PubMed  Google Scholar 

  10. M Breen R Thomas MM Binns NP Carter CF Langford (1999) ArticleTitleReciprocal chromosome painting reveals detailed regions of conserved synteny between the karyotypes of the domestic dog (Canis familiaris) and human. Genomics 61 145–155 Occurrence Handle10.1006/geno.1999.5947 Occurrence Handle1:CAS:528:DyaK1MXmslyitrk%3D Occurrence Handle10534400

    Article  CAS  PubMed  Google Scholar 

  11. M Breen S Jouquand C Renier CS Mellersh C Hitte et al. (2001) ArticleTitleChromosome-specific single-locus FISH probes allow anchorage of an 1800-marker integrated radiation-hybrid/linkage map of the domestic dog genome to all chromosomes. Genome Res 11 1784–1795 Occurrence Handle10.1101/gr.189401 Occurrence Handle1:CAS:528:DC%2BD3MXnvFCmtbg%3D Occurrence Handle11591656

    Article  CAS  PubMed  Google Scholar 

  12. JF Burman WJ Jenkins JA Walker-Smith AD Phillips NA Sourial et al. (1985) ArticleTitleAbsent ileal uptake of IF-bound vitamin B12 in vivo in the Imerslund-Gräsbeck syndrome (familial vitamin B12 malabsorption with proteinuria). Gut 26 311–314 Occurrence Handle1:STN:280:BiqC38flvFI%3D Occurrence Handle3972280

    CAS  PubMed  Google Scholar 

  13. RW Cottingham Jr RM Idury AA Schäffer (1993) ArticleTitleFaster sequential genetic linkage computations. Am J Hum Genet 53 252–263 Occurrence Handle8317490

    PubMed  Google Scholar 

  14. JD Eudy M Ma-Edmonds SF Yao CB Talmadge PM Kelley et al. (1997) ArticleTitleIsolation of a novel human homologue of the gene coding for echinoderm microtubule-associated protein (EMAP) from the Usher syndrome type 1a locus at 14q32. Genomics 43 104–106 Occurrence Handle10.1006/geno.1997.4779 Occurrence Handle1:CAS:528:DyaK2sXks1aht74%3D Occurrence Handle9226380

    Article  CAS  PubMed  Google Scholar 

  15. JC Fyfe U Giger CA Hall PF Jezyk SA Klumpp et al. (1991a) ArticleTitleInherited selective intestinal cobalamin malabsorption and cobalamin deficiency in dogs. Pediatr Res 29 24–31 Occurrence Handle1:CAS:528:DyaK3MXitVCrt7c%3D

    CAS  Google Scholar 

  16. JC Fyfe KS Ramanujam K Ramaswamy DF Patterson B Seetharam (1991b) ArticleTitleDefective brush-border expression of intrinsic factor-cobalamin receptor in canine inherited intestinal cobalamin malabsorption. J Biol Chem 266 4489–4494 Occurrence Handle1:CAS:528:DyaK3MXhs1Wrt7o%3D

    CAS  Google Scholar 

  17. R Gräsbeck R Gordin I Kantero B Kuhlbäck (1960) ArticleTitleSelective vitamin B12 malabsorption and proteinuria in young people. Acta Med Scand 167 289–296 Occurrence Handle13828999

    PubMed  Google Scholar 

  18. R Guyon TD Lorentzen C Hitte L Kirn E Cadieu et al. (2003) ArticleTitleA 1-Mb resolution radiation hybrid map of the canine genome. Proc Natl Acad Sci USA 100 5296–5301 Occurrence Handle10.1073/pnas.0831002100 Occurrence Handle1:CAS:528:DC%2BD3sXjs1yitrc%3D Occurrence Handle12700351

    Article  CAS  PubMed  Google Scholar 

  19. O Imerslund (1960) ArticleTitleIdiopathic chronic megaloblastic anemia in children. Acta Paediatr Scand 49 1–115

    Google Scholar 

  20. EAR Ismail Q Al Saleh MA Sabry M Al Ghanim M Zaki (1997) ArticleTitleGenotypic/phenotypic heterogeneity of selective vitamin B12 malabsorption (Gräsbeck-Imerslund syndrome) in two Bedouin families. Acta Paediatr 86 424–425 Occurrence Handle1:STN:280:ByiA3MnpsFw%3D Occurrence Handle9174232

    CAS  PubMed  Google Scholar 

  21. S Kalantry S Manning O Haub C Tomihara-Newberger HG Lee et al. (2001) ArticleTitleThe amnionless gene, essential for mouse gastrulation, encodes a visceral-endoderm-specific protein with an extracellular cysteine-rich domain. [comment]. Nat Genet 27 412–416 Occurrence Handle10.1038/86912 Occurrence Handle1:CAS:528:DC%2BD3MXjtFShsL8%3D Occurrence Handle11279523

    Article  CAS  PubMed  Google Scholar 

  22. R Kozyraki M Kristiansen A Silahtaroglu C Hansen C Jacobsen et al. (1998) ArticleTitleThe human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region. Blood 91 3593–3600 Occurrence Handle1:CAS:528:DyaK1cXjtFersrg%3D Occurrence Handle9572993

    CAS  PubMed  Google Scholar 

  23. R Kozyraki J Fyfe M Kristiansen C Gerdes C Jacobsen et al. (1999) ArticleTitleThe intrinsic factor-vitamin B12 receptor, cubilin, is a high-affinity apolipoprotein A-I receptor facilitating endocytosis of high-density lipoprotein. Nat Med 5 656–661 Occurrence Handle10.1038/9504 Occurrence Handle1:CAS:528:DyaK1MXjs1Klsrw%3D Occurrence Handle10371504

    Article  CAS  PubMed  Google Scholar 

  24. R Kozyraki J Fyfe PJ Verroust C Jacobsen A Dautry-Varsat et al. (2001) ArticleTitleMegalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. Proc Natl Acad Sci USA 98 12491–12496 Occurrence Handle10.1073/pnas.211291398 Occurrence Handle1:CAS:528:DC%2BD3MXotFaitLk%3D Occurrence Handle11606717

    Article  CAS  PubMed  Google Scholar 

  25. M Kristiansen M Aminoff C Jacobsen A de La Chapelle R Krahe et al. (2000) ArticleTitleCubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B12 by cubilin. Blood 96 405–409 Occurrence Handle1:CAS:528:DC%2BD3cXltVGhtLw%3D Occurrence Handle10887099

    CAS  PubMed  Google Scholar 

  26. E Lander L Kruglyak (1995) ArticleTitleGenetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11 241–247 Occurrence Handle1:CAS:528:DyaK2MXptlSjs74%3D Occurrence Handle7581446

    CAS  PubMed  Google Scholar 

  27. GM Lathrop JM Lalouel C Julier J Ott (1984) ArticleTitleStrategies for multilocus linkage analysis in humans. Proc Natl Acad Sci USA 81 3443–3446 Occurrence Handle6587361

    PubMed  Google Scholar 

  28. IL Mackenzie RM Donaldson Jr JS Trier VI Mathan (1972) ArticleTitleIleal mucosa in familial selective vitamin B12 malabsorption. N Engl J Med 286 1021–1025 Occurrence Handle1:STN:280:CS2C2MzotlU%3D Occurrence Handle5016373

    CAS  PubMed  Google Scholar 

  29. JA Martina CJ Bonangelino RC Aguilar JS Bonifacino (2001) ArticleTitleStonin 2: an adaptor-like protein that interacts with components of the endocytic machinery. J Cell Biol 153 1111–1120 Occurrence Handle10.1083/jcb.153.5.1111 Occurrence Handle1:CAS:528:DC%2BD3MXktVags7Y%3D Occurrence Handle11381094

    Article  CAS  PubMed  Google Scholar 

  30. CS Mellersh C Hitte M Richman F Vignaux C Priat et al. (2000) ArticleTitleAn integrated linkage-radiation hybrid map of the canine genome. Mamm Genome 11 120–130 Occurrence Handle10.1007/s003350010024 Occurrence Handle1:CAS:528:DC%2BD3cXhtFOkurw%3D Occurrence Handle10656926

    Article  CAS  PubMed  Google Scholar 

  31. A Nykjaer JC Fyfe R Kozyraki J-R Leheste C Jacobsen et al. (2001) ArticleTitleCubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D3. Proc Natl Acad Sci USA 98 13895–13900 Occurrence Handle10.1073/pnas.241516998 Occurrence Handle1:CAS:528:DC%2BD3MXovVyntb0%3D Occurrence Handle11717447

    Article  CAS  PubMed  Google Scholar 

  32. M Richman CS Mellersh C André F Galibert EA Ostrander (2001) ArticleTitleCharacterization of a minimal screening set of 172 microsatellite markers for genome-wide screens of the canine genome. J Biochem Biophys Methods 47 137–149 Occurrence Handle10.1016/S0165-022X(00)00160-3 Occurrence Handle1:CAS:528:DC%2BD3MXhtFeitb0%3D Occurrence Handle11179770

    Article  CAS  PubMed  Google Scholar 

  33. MM Salameh RW Banda AA Mohdi (1991) ArticleTitleReversal of severe neurological abnormalities after vitamin B12 replacement in the Imerslund-Gräsbeck syndrome. J Neurol 238 349–350 Occurrence Handle1:STN:280:By2D2cvmtlw%3D Occurrence Handle1940989

    CAS  PubMed  Google Scholar 

  34. J Sambrook EF Fritsch T Maniatis (1989) Molecular Cloning: A Laboratory Manual, 2nd ed. Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY

    Google Scholar 

  35. DR Sargan F Yang M Squire BS Milne PC O’Brien et al. (2000) ArticleTitleUse of flow-sorted canine chromosomes in the assignment of canine linkage, radiation hybrid, and syntenic groups to chromosomes: refinement and verification of the comparative chromosome map for dog and human. Genomics 69 182–195 Occurrence Handle10.1006/geno.2000.6334 Occurrence Handle1:CAS:528:DC%2BD3cXnt1Wjt7s%3D Occurrence Handle11031101

    Article  CAS  PubMed  Google Scholar 

  36. AA Schäffer SK Gupta K Shriram RW Cottingham Jr (1994) ArticleTitleAvoiding recomputation in linkage analysis. Human Hered 44 225–237

    Google Scholar 

  37. B Seetharam EI Christensen SK Moestrup TG Hammond PJ Verroust (1997) ArticleTitleIdentification of rat yolk sac target protein of teratogenic antibodies, gp280, as intrinsic factor-cobalamin receptor. J Clin Invest 99 2317–2322 Occurrence Handle1:CAS:528:DyaK2sXjsVGqsb8%3D Occurrence Handle9153271

    CAS  PubMed  Google Scholar 

  38. SM Tanner M Aminoff FA Wright S Liyanarachchi M Kuronen et al. (2003) ArticleTitleAmnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat Genet 33 426–429 Occurrence Handle10.1038/ng1098 Occurrence Handle1:CAS:528:DC%2BD3sXhsV2kuro%3D Occurrence Handle12590260

    Article  CAS  PubMed  Google Scholar 

  39. C Tomihara-Newberger O Haub HG Lee V Scares K Manova et al. (1998) ArticleTitleThe amn gene product is required in extraembryonic tissues for the generation of middle primitive streak derivatives. Dev Biol 204 34–54 Occurrence Handle10.1006/dbio.1998.9034 Occurrence Handle1:CAS:528:DyaK1cXotFSjurw%3D Occurrence Handle9851841

    Article  CAS  PubMed  Google Scholar 

  40. JC Venter MD Adams EW Myers PW Li RJ Mural et al. (2001) ArticleTitleThe sequence of the human genome. Science 291 1304–1351 Occurrence Handle1:CAS:528:DC%2BD3MXhtlSgsbo%3D Occurrence Handle11181995

    CAS  PubMed  Google Scholar 

  41. AE Vinogradov (1998) ArticleTitleGenome size and GC-percent in vertebrates as determined by flow cytometry: the triangular relationship. Cytometry 31 100–109 Occurrence Handle10.1002/(SICI)1097-0320(19980201)31:2<100::AID-CYTO5>3.0.CO;2-Q Occurrence Handle1:CAS:528:DyaK1cXhtVCkt7g%3D Occurrence Handle9482279

    Article  CAS  PubMed  Google Scholar 

  42. X Wang EA Bornslaeger O Haub C Tomihara-Newberger N Lonberg et al. (1996) ArticleTitleA candidate gene for the amnionless gastrulation stage mouse mutation encodes a TRAF-related protein. Dev Biol 177 274–290 Occurrence Handle10.1006/dbio.1996.0162 Occurrence Handle1:CAS:528:DyaK28XksVGjsbg%3D Occurrence Handle8660894

    Article  CAS  PubMed  Google Scholar 

  43. Z Weng A-C Fluckiger S Nisitani MI Wahl LQ Le et al. (1998) ArticleTitleA DNA damage and stress inducible G protein-coupled receptor blocks cells in G2/M. Proc Natl Acad Sci USA 95 12334–12339 Occurrence Handle10.1073/pnas.95.21.12334 Occurrence Handle1:CAS:528:DyaK1cXmsl2rtL4%3D Occurrence Handle9770487

    Article  CAS  PubMed  Google Scholar 

  44. P Werner CS Mellersh MG Raducha S DeRose GM Acland et al. (1999) ArticleTitleAnchoring of canine linkage groups with chromosome-specific markers. Mamm Genome 10 814–823 Occurrence Handle1:CAS:528:DyaK1MXkvV2msLk%3D Occurrence Handle10430668

    CAS  PubMed  Google Scholar 

  45. D Xu R Kozyraki TC Newman JC Fyfe (1999) ArticleTitleGenetic evidence of an accessory activity required specifically for cubilin brush-border expression and intrinsic factor-cobalamin absorption. Blood 94 3604–3606 Occurrence Handle1:CAS:528:DyaK1MXnsVansrs%3D Occurrence Handle10552972

    CAS  PubMed  Google Scholar 

  46. D Xu JC Fyfe (2000) ArticleTitleCubilin expression and posttranslational modification in the canine gastrointestinal tract. Am J Gastrointest Liver Physiol 279 G748–G756 Occurrence Handle1:CAS:528:DC%2BD3cXnsFOru7c%3D

    CAS  Google Scholar 

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Acknowledgements

We thank Shana Gilbert-Gregory for excellent technical assistance. This work was supported by National Institutes of Health Grants DK45341, DK064161, and RR02512, the Companion Animal Fund of the MSU College of Veterinary Medicine, and by funds from the Dean’s Office, School of Veterinary Medicine, University of Pennsylvania.

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Authors and Affiliations

  1. Laboratory of Comparative Medical Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA

    Qianchuan He, John C. Fyfe & Adam Kilkenney

  2. National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20894, USA

    Alejandro A. Schäffer

  3. Section of Medical Genetics, University of Pennsylvania School of Veterinary Medicine, 3900 Delancey St., Philadelphia, Pennsylvania 19104-6010, USA

    Petra Werner & Paula S. Henthorn

  4. The Institute for Genomic Research, Rockville, Maryland 20850, USA

    Ewen F. Kirkness

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  1. Qianchuan He
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Correspondence to Paula S. Henthorn.

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He, Q., Fyfe, J.C., Schäffer, A.A. et al. Canine Imerslund-Gräsbeck syndrome maps to a region orthologous to HSA14q . Mamm Genome 14, 758–764 (2003). https://doi.org/10.1007/s00335-003-2280-1

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  • DOI: https://doi.org/10.1007/s00335-003-2280-1

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