title: Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns.
abstract: BACKGROUND
  Inherited malabsorption of cobalamin (Cbl) causes hematological and neurological abnormalities that can be fatal. Three genes have been implicated in Cbl malabsorption; yet, only about 10% of ~400-500 reported cases have been molecularly studied to date. Recessive mutations in CUBN or AMN cause Imerslund-Gräsbeck Syndrome (IGS), while recessive mutations in GIF cause Intrinsic Factor Deficiency (IFD). IGS and IFD differ in that IGS usually presents with proteinuria, which is not observed in IFD. The genetic heterogeneity and numerous differential diagnoses make clinical assessment difficult.
  
  
  METHODS
  We present a large genetic screening study of 154 families or patients with suspected hereditary Cbl malabsorption. Patients and their families have been accrued over a period spanning >12  years. Systematic genetic testing of the three genes CUBN, AMN, and GIF was accomplished using a combination of single strand conformation polymorphism and DNA and RNA sequencing. In addition, six genes that were contenders for a role in inherited Cbl malabsorption were studied in a subset of these patients.
  
  
  RESULTS
  Our results revealed population-specific mutations, mutational hotspots, and functionally distinct regions in the three causal genes. We identified mutations in 126/154 unrelated cases (82%). Fifty-three of 126 cases (42%) were mutated in CUBN, 45/126 (36%) were mutated in AMN, and 28/126 (22%) had mutations in GIF. We found 26 undescribed mutations in CUBN, 19 in AMN, and 7 in GIF for a total of 52 novel defects described herein. We excluded six other candidate genes as culprits and concluded that additional genes might be involved.
  
  
  CONCLUSIONS
  Cbl malabsorption is found worldwide and genetically complex. However, our results indicate that population-specific founder mutations are quite common. Consequently, targeted genetic testing has become feasible if ethnic ancestry is considered. These results will facilitate clinical and molecular genetic testing of Cbl malabsorption. Early diagnosis improves the lifelong care required by these patients and prevents potential neurological long-term complications. This study provides the first comprehensive overview of the genetics that underlies the inherited Cbl malabsorption phenotype.
authors.affiliation: Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. smtrmn@gmail.com
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Tanner
authors.forename: Amy C
authors.initials: AC
authors.lastname: Sturm
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Baack
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000749:Anemia, Megaloblastic; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D006801:Humans; D007437:Intrinsic Factor / Q000235:genetics* / Q000378:metabolism; D008286:Malabsorption Syndromes / Q000208:ethnology* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D011507:Proteinuria / Q000208:ethnology* / Q000235:genetics; D014805:Vitamin B 12 / Q000378:metabolism*; D014806:Vitamin B 12 Deficiency / Q000208:ethnology* / Q000235:genetics
chemical_list: C484714:AMN protein, human; D008565:Membrane Proteins; D011506:Proteins; D007437:Intrinsic Factor; D014805:Vitamin B 12