Abstract
Megaloblastic anaemia 1 (MGA1) is a rare autosomal recessive condition characterized by selective intestinal vitamin B12 malabsorption and proteinuria. More than 200 MGA1 patients have been identified worldwide, but the disease is relatively prevalent in Finland, Norway and several Eastern Mediterranean regions. MGA1 is genetically heterogeneous and can be caused by mutations in either the cubilin (CUBN) or the amnionless (AMN) gene. In the present study we investigated the molecular defect underlying MGA1 in nine Tunisian patients belonging to six unrelated consanguineous families. Haplotype and linkage analyses, using microsatellite markers surrounding both CUBN and AMN genes, indicated that four out of the six families were likely to be linked to the CUBN gene. Patients from these families were screened for the Finnish, Mediterranean and Arabian mutations already published. None of the screened mutations could be detected in our population. One family showed a linkage to AMN gene. Direct screening of the AMN gene allowed the identification of the c.208-2A>G mutation, previously described in a Jewish Israeli patient of Tunisian origin and in Turkish patients. This suggests that the c.208-2A>G mutation may derive from a single Mediterranean founder ancestor. For the last family, haplotype analysis excluded both CUBN and AMN genes, suggesting the existence of a third locus that may cause MGA1.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Abdelaal MA, Ahmed AF (1991) Imerslund-Grasbeck syndrome in a Saudi family. Acta Paediatr Scand 80:1109–1112
Al-Alami JR, Tayeh MK, Al-Sheyyab MY, El-Shanti HI (2002) Linkage analysis of a large inbred family with congenital megaloblastic anemia. Saudi Med J 23:1251–1256
Altay C, Cetin M, Gumruk F, Irken G, Yetgin S, Laleli Y (1995) Familial selective vitamin B12 malabsorption (Imerslund-Grasbeck syndrome) in a pool of Turkish patients. Pediatr Hematol Oncol 12:19–28
Aminoff M, Tahvanainen E, Grasbeck R, Weissenbach J, Broch H, de la Chapelle A (1995) Selective 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
Aminoff M, Carter JE, Chadwick RB, Johnson C, Grasbeck R, Abdelaal MA, Broch H, Jenner LB, Verroust PJ, Moestrup SK, de la Chapelle A, Krahe R (1999) Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet 21:309–313
Ben-Bassat I, Feinstein A, Ramot B (1969) Selective vitamin B 12 malabsorption with proteinuria in Israel: clinical and genetic aspects. Isr J Med Sci 5:62–68
Ben Meriem C, Pousse H, Bourgeay-Causse M, Amri F, Besbes A, Belkhir A, Sfar MT, Jrad T (1993) [Imerslund-Najman-Grasbeck anemia. A propos of a case]. Pediatrie 48:693–695
Birn H, Verroust PJ, Nexo E, Hager H, Jacobsen C, Christensen EI, Moestrup SK (1997) Characterization 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
Bouchlaka C, Abdelhak S, Amouri A, Ben Abid H, Hadiji S, Frikha M, Ben Othman T, Amri F, Ayadi H, Hachicha M, Rebai A, Saad A, Dellagi K, Tunisian Fanconi Anemia Study Group (2003) Fanconi anemia in Tunisia: high prevalence of group A and identification of new FANCA mutations. J Hum Genet 48:352–361
Broch H, Imerslund O, Monn E, Hovig T, Seip M (1984) Imerslund-Grasbeck anemia. A long-term follow-up study. Acta Paediatr Scand 73:248–253
Burman JF, Jenkins WJ, Walker-Smith JA, Phillips AD, Sourial NA, Williams CB, Mollin DL (1985) Absent ileal uptake of IF-bound vitamin B12 in vivo in the Imerslund-Grasbeck syndrome (familial vitamin B12 malabsorption with proteinuria). Gut 26:311–314
Campbell AN, Inglis J, Paynter AS (1981) Failure to thrive associated with the Imerslund-Grasbeck syndrome. Postgrad Med J 57:509–510
Carmel R, Green R, Rosenblatt DS, Watkins D (2003) Update on cobalamin, folate, and homocysteine. Hematology (Am Soc Hematol Educ Program) 1:62–81
Celep F, Karaguzel A, Aynaci FM, Erduran E (1996) A case report of 46,XX,del(21)(q22) de novo deletion associated with Imerslund-Grasbeck syndrome. Clin Genet 50:248–250
Charfeddine C, Mokni M, Ben Mousli R, Elkares R, Bouchlaka C, Boubaker S, Ghedamsi S, Baccouche D, Ben Osman A Dellagi K, Abdelhak A (2003) A novel missense mutation in the gene encoding SLURP-1 in patients with Mal de Meleda from northern Tunisia. Br J Dermatol 149:1108–1115
Christensen EI, Birn H (2002) Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol 3:256–266
Dib C, Faure S, Fizames C, Samson D, Drouot N, Vignal A, Millasseau P, Marc S, Hazan J, Seboun E, Lathrop M, Gyapay G, Morissette J, Weissenbach J (1996) A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380:152–154
el Bez M, Souid M, Kallel J, Mebazaa R, Ben Dridi MF (1992) [Imerslund-Najman-Grasbeck anemia. A propos of a case] Ann Pediatr (Paris) 39:305–308
Elloumi-Zghal H, Barbouche MR, Chemli J, Bejaoui M, Harbi A, Snoussi N, Abdelhak S, Dellagi K (2002) Clinical and genetic heterogeneity of inherited autosomal recessive susceptibility to disseminated Mycobacterium bovis bacille calmette-guerin infection. J Infect Dis 185:1468–1475
Fitouri Z, Zidi F, Cheour M, Ben Becher S (2001) La maladie d’Imerslund. A propos de 4 observations. Rev Maghr Pédiatr (XI-II) 97–101
Fyfe JC, Madsen M, Hojrup P, Christensen EI, Tanner SM, de la Chapelle A, He Q, Moestrup SK (2004) The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood 103:1573–1579
Gräsbeck R (1972) Familial selective vitamin B 12 malabsorption. N Engl J Med 287:358
Gräsbeck R, Gordin R, Kantero I, Kuhlback B (1960) Selective vitamin B12 malabsorption and proteinuria in young people. Acta Med Scand 167:289–296
Hazan J, Dubay C, Pankowiak MP, Becuwe N, Weissenbach J (1992) A genetic linkage map of human chromosome 20 composed entirely of microsatellite markers. Genomics 12:183–189
Imerslund O (1960) Idiopathic chronic megaloblastic anemia in children. Acta Paediatr 49:1–115
Ismail EA, Al Saleh Q, Sabry MA, Al Ghanim M, Zaki M (1997) Genotypic/phenotypic heterogeneity of selective vitamin B12 malabsorption (Grasbeck-Imerslund syndrome) in two Bedouin families. Acta Paediatr 86:424–425
Kozyraki R, Kristiansen M, Silahtaroglu A, Hansen C, Jacobsen C, Tommerup N, Verroust PJ, Moestrup SK (1998) The 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
Kristiansen M, Kozyraki R, Jacobsen C, Nexo E, Verroust PJ, Moestrup SK (1999) Molecular dissection of the intrinsic factor-vitamin B12 receptor, cubilin, discloses regions important for membrane association and ligand binding. J Biol Chem 274:20540–20544
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363
Mackenzie IL, Donaldson RM, Trier JS, Mathan VI (1972) Ileal mucosa in familial selective vitamin B 12 malabsorption. N Engl J Med 286:1021–1025
Moestrup SK, Kozyraki R, Kristiansen M, Kaysen JH, Rasmussen HH, Brault D, Pontillon F, Goda FO, Christensen EI, Hammond TG, Verroust PJ (1998) The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins. J Biol Chem 273:5235–5242
Salameh MM, Banda RW, Mohdi AA (1991) Reversal of severe neurological abnormalities after vitamin B12 replacement in the Imerslund-Grasbeck syndrome. J Neurol 238:349–350
Sambrook J, Fritsh EF, Maniatis T (1989) Molecular cloning: a laboratory manual. Cold Spring Laboratory Press, Cold spring Harbor
Schilling RF (1953) Intrinsic factor studies II. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B12. J Lab Clin Med 42:860–866
Smith CA (1963) testing for heterogeneity of recombination fraction values in human genetics. Ann Hum Genet 27:175–182
Tanner SM, Aminoff M, Wright FA, Liyanarachchi S, Kuronen M, Saarinen A, Massika O, Mandel H, Broch H, de la Chapelle A (2003) Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat Genet 33:426–429
Tanner SM, Li Z, Bisson R, Acar C, Oner C, Oner R, Cetin M, Abdelaal MA, Ismail EA, Lissens W, Krahe R, Broch H, Grasbeck R, de la Chapelle A (2004) Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East. Hum Mutat 23:327–333
Tanner SM, Li Z, Perko JD, Oner C, Cetin M, Altay C, Yurtsever Z, David KL, Faivre L, Ismail EA, Grasbeck R, de la Chapelle A (2005) Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc Natl Acad Sci USA 102:4130–4133
Wahlstedt-Froberg V, Pettersson T, Aminoff M, Dugue B, Grasbeck R (2003) Proteinuria in cubilin-deficient patients with selective vitamin B12 malabsorption. Pediatr Nephrol 18:417–421
Wulffraat NM, De Schryver J, Bruin M, Pinxteren-Nagler E, van Dijken PJ (1994) Failure to thrive is an early symptom of the imerslund Grasbeck syndrome. Am J Pediatr Hematol Oncol 16:177–180
Yammani RR, Seetharam S, Seetharam B (2001) Identification and characterization of two distinct ligand binding regions of cubilin. J Biol Chem 276:44777–44784
Yetgin S, Ozsoylu S, Zamani VP (1983) Imerslund-Grasbeck syndrome and generalized malabsorption. Turk J Pediatr 25:193–196
Acknowledgements
This work was supported by the Tunisian Ministry of Scientific and Technological Research and Development of Competencies (Research Unit on Molecular Investigation of Genetic Orphan Diseases UR 26/04 and the Laboratory of Immunology, Vaccinology and Molecular Genetics). We are grateful to the families for their cooperation in this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bouchlaka, C., Maktouf, C., Mahjoub, B. et al. Genetic heterogeneity of megaloblastic anaemia type 1 in Tunisian patients. J Hum Genet 52, 262–270 (2007). https://doi.org/10.1007/s10038-007-0110-0
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10038-007-0110-0
Keywords
This article is cited by
-
Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases
Orphanet Journal of Rare Diseases (2023)
-
Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome
BMC Medical Genetics (2013)
-
Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East
Orphanet Journal of Rare Diseases (2012)
-
Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities
Orphanet Journal of Rare Diseases (2011)
-
Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene
Journal of Human Genetics (2011)
