Novel compound heterozygous mutations in AMN cause Imerslund-Gräsbeck syndrome in two half-sisters: a case report

BMC Med Genet. 2015 Jun 4;16:35. doi: 10.1186/s12881-015-0181-2.

Emma Montgomery ¹, John A Sayer ² ³, Laura A Baines ⁴, Ann Marie Hynes ⁵, Virginia Vega-Warner ⁶, Sally Johnson ⁷, Judith A Goodship ⁸, Edgar A Otto ⁹

Affiliations

1 Renal Services Centre, Freeman Hospital, Newcastle upon Tyne NHS Hospitals Foundation Trust Newcastle upon Tyne, Newcastle upon Tyne, NE7 7DN, UK. [email protected].
2 Renal Services Centre, Freeman Hospital, Newcastle upon Tyne NHS Hospitals Foundation Trust Newcastle upon Tyne, Newcastle upon Tyne, NE7 7DN, UK. [email protected].
3 Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne, UK. [email protected].
4 Renal Services Centre, Freeman Hospital, Newcastle upon Tyne NHS Hospitals Foundation Trust Newcastle upon Tyne, Newcastle upon Tyne, NE7 7DN, UK. [email protected].
5 Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne, UK. [email protected].
6 Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA. [email protected].
7 Paediatric Nephrology, Royal Victoria Infirmary, Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle upon Tyne, N1 4LP, UK. [email protected].
8 Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne, UK. [email protected].
9 Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA. [email protected].

PMID: 26040326 DOI: 10.1186/s12881-015-0181-2

Abstract

Background: Imerslund-Gräsbeck Syndrome (IGS) is a rare autosomal recessive disease characterized by intestinal vitamin B12 malabsorption. Clinical features include megaloblastic anemia, recurrent infections, failure to thrive, and proteinuria. Recessive mutations in cubilin (CUBN) and in amnionless (AMN) have been shown to cause IGS. To date, there are only about 300 cases described worldwide with only 37 different mutations found in CUBN and 30 different in the AMN gene.

Case presentation: We collected pedigree structure, clinical data, and DNA samples from 2 Caucasian English half-sisters with IGS. Molecular diagnostics was performed by direct Sanger Sequencing of all 62 exons of the CUBN gene and 12 exons of the AMN gene. Because of lack of parental DNA, cloning, and Sequencing of multiple plasmid clones was performed to assess the allele of identified mutations. Genetic characterization revealed 2 novel compound heterozygous AMN mutations in both half-sisters with IGS. Trans-configuration of the mutations was confirmed.

Conclusion: We have identified novel compound heterozygous mutations in AMN in a family from the United Kingdom with clinical features of Imerslund-Gräsbeck Syndrome.

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