Amnionless (AMN) mutations in Imerslund–Gräsbeck syndrome may be associated with disturbed vitamin B12 transport into the CNS
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Familial selective vitamin B12 (cobalamin, Cbl) malabsorption (Imerslund–Gräsbeck syndrome, IGS, OMIM 261100) is a group of autosomal recessive disorders characterized by selective malabsorption of Cbl from the terminal ileum in the presence of normal histology. Mutations in the amnionless (AMN) and cubilin (CUBN) genes are known to be causes of IGS. Their gene products combine to form a receptor complex (cubam), which is instrumental in the binding and transport of Cbl in the gut. As opposed to Cbl transport in the terminal ileum, normal transport of Cbl into the CNS is poorly understood and little is known regarding its molecular basis. Studies in adults with neuropsychiatric disease have suggested the presence of an active transport mechanism into the central nervous system constituting a blood–brain barrier (BBB) for Cbl. A child with IGS, compound heterozygous for a missense and a nonsense mutation in the amnionless (AMN) protein gene, was noted to have a high daily cobalamin (Cbl) requirement for neuropsychiatric, but not for systemic metabolic and haematological, remission. Measurements of CSF Cbl revealed evidence that the transport of Cbl into the central nervous system was impaired, and a standard Schilling test was consistent with a dose response of cobalamin transport across the terminal ileum. Amnionless protein is known to be expressed in the fetal and postnatal central nervous system, and is known to be involved in Cbl transport in other tissues such as kidney as well as the gut. It is possible that an active Cbl transport mechanism at the BBB exists, and that the amnionless (AMN) protein may be part of this mechanism, as it is in cobalamin transport in the terminal ileum.
central nervous system
We thank Zhongyuan Li for technical assistance. This research was supported by National Cancer Institute (USA) grant CA16058 to the Comprehensive Cancer Center of The Ohio State University.
- Altay C, Cetin M, Gumruk F, et al (1995) Familial selective vitamin B12 malabsorption (Imerslund–Gräsbeck syndrome) in a pool of Turkish patients. Pediatr Hematol Oncol 12: 19–28.Google Scholar
- Aminoff M, Carter JE, Chadwick RB, et al (1999) Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet 21: 309–313.Google Scholar
- Eaton DM, Livingston JH, Seetharam B, et al (1998) Overexpression of an unstable intrinsic factor-cobalamin receptor in Imerslund–Gräsbeck syndrome. Gastroenterology 115: 173.Google Scholar
- Frenkel EP, McCall MS, White JD (1971) An isotopic measurement of vitamin B12 in cerebrospinal fluid. Am J Clin Pathol 55: 58–64.Google Scholar
- Gene Cards (2007) GeneCard for protein-coding AMN.GC14P102458 http://www.genecards.org/cgi-bin/carddisp.pl?gene=AMN&search=amnionless&suff=txt (Accessed May 2007).
- Gräsbeck R (2006) Imerslund–Gräsbeck syndrome (selective vitamin b12 malabsorption with proteinuria). Orphanet J Rare Dis 1: 1750–1772. http://www.OJRD.com/content/1/1/17 (Accessed May 2007).
- Gueant JL, Saunier M, Gastin, et al (1995) Decreased activity of intestinal and urinary intrinsic factor receptor in Gräsbeck–Imerslund disease. Gastroenterology 108: 1622.Google Scholar
- Human Protein Atlas (2007) AMN expression profiles. http://www.proteinatlas.org/tissue_profile.php?antibody_id=0817 (Accessed May 2007).
- Ikeda T, Funikawa Y, Mashimoto T, et al (1990) Vitamin B12 levels in serum and CSF of people with Alzheimer disease. Acta Psychiatr Scand 87: 327–329.Google Scholar
- Karatekin G, Sezgin B, Kayaoglu S, et al (1999) Imerslund–Gräsbeck syndrome. Indian Pediatr 36: 1262–1264.Google Scholar
- Kristiansen M, Aminoff M, Jacobsen C, et al (2000) Cubilin P1279L mutation associated with hereditary megaloblastic anaemia causes impaired recognition of intrinsic factor-vitamin B12 by cubilin. Blood 96: 405.Google Scholar
- Larsson M (2006) Megalin an endocytotic receptor with signaling potential. Acta Universtitatis Upsaliensis (Digital comprehensive summaries of Uppsala dissertations form the faculty of medicine) 2006;60–116 Uppsala ISBN 91–554–6483–1.Google Scholar
- Nijst TQ, Wevers RA, Schoonderwaldt HC, et al (1990) Vitamin B12 and folate concentrations in serum and cerebrospinal fluid of neurological patients with special reference to multiple sclerosis and dementia. J Neurol Neurosurg Psychiatry 53: 951–954.Google Scholar
- Obeid R, Kostopoulos P, Knapp J-P, et al (2007) Biomarkers of folate and vitamin B12 are related in blood and cerebrospinal fluid. Clin Chem 53: 326–333.Google Scholar
- Papageorgiou C, Mavrikakis M, Kesse-Elias M, et al (1983) Radioisotopic determination of cerebrospinal fluid (CSF) folic acid and vitamin B12 in neurological disorders. Cell Mol Life Sci 39: 432–433.Google Scholar
- Rassmussen SA, Fernhoff PM, Scanlon KS (2001) Vitamin B12 deficiency in children and adolescents. J Pediatr 138: 10–17.Google Scholar
- Regland B, Abrahamsson L, Blennow K, et al (1992) Vitamin B12 in CSF: reduced CSF/serum B12 ratio in demented men. Acta Neurol Scand 85: 276–281.Google Scholar
- Reynolds EH, Carney MW, Toone BK (1984) Methylation and mood. Lancet 2: 196–198.Google Scholar
- Sandoval C, Bolten P, Franco I, et al (2000) Recurrent urinary tract infections and genitourinary tract abnormalities in the Imerslund–Gräsbeck syndrome. Pediatr Hematol Oncol 17: 331–334.Google Scholar
- Stabler SP, Allen RH, Dolce ET, Johnson MA (2006) Elevated serum S-adenosylhomocysteine in cobalamin-deficient elderly and response to treatment. Am J Clin Nutr 84: 1422–1429.Google Scholar
- Tanner SM, Aminoff M, Wright FA, et al (2003) Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anaemia. Nat Genet 33: 426–429.Google Scholar
- Tanner SM, Li Z, Bisson R, et al (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.Google Scholar