Canine Imerslund-Gr�sbeck syndrome maps to a region orthologous to HSA14q

Abstract

Selective malabsorption of cobalamin (vitamin B(12)) 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.

Mouse amnionless, which is required for primitive streak assembly,mediates cell-surface localization and endocytic function of cubilin on visceral endoderm and kidney proximal tubules

“…In addition, studies of a canine model of MGA1 revealed that vitamin B12 malabsorption is not genetically linked to dog Cubn, despite loss of Cubn protein from the apical cell surface (Xu et al, 1999). Thus, proper cellular localization of Cubn in dogs requires the product of a second gene, which has recently been genetically linked to a 5 Mb region that includes canine Amn (He et al, 2003). Our immunohistochemical analyses of Amn-deficient mouse VE (Fig.…”

Cubilin Is Essential for Albumin Reabsorption in the Renal Proximal Tubule

“…The observation that AMN, a 50-kD transmembrane protein, was mutated in BASIC RESEARCH www.jasn.org I-GS patients in whom cubilin was normal 22 led to the conclusion that expression of AMN was indispensable for membrane targeting of cubilin 6,7,23,24 and possibly sufficient in vitro to mediate internalization of IF-B12 complexes. 6 Analysis of mosaic tubules in this study demonstrates not only that AMN is required for the membrane expression of cubilin but also that cubilin in vivo is required for membrane expression of AMN as it is in cell culture studies.…”

The functional cobalamin (vitamin B12)–intrinsic factor receptor is a novel complex of cubilin and amnionless

“…7,20 It was further demonstrated that the defects of cubilin expression were not due to a cubilin mutation, 25 and recent genetic analysis has mapped canine I-GS to the AMN locus. 26 A mechanistic explanation of cubilin endocytic function has been sought ever since transmembrane and cytoplasmic domains were found lacking in the structure of cubilin deduced from cDNA sequence. Previously, it was suggested that megalin, an endocytic receptor of the LDL receptor family, might assist the trafficking of cubilin.…”

“…Very recently, Tanner et al 24 demonstrated that mutations in the amnionless (AMN) gene also cause I-GS, and canine I-GS shows highly significant linkage to the same locus. 26 AMN was initially identified by random mutagenesis 27 as a protein essential for amnion and primitive streak formation in mice. AMN is a transmembrane 45-to 50-kDa protein of polarized epithelia.…”