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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3604-3606
Genetic Evidence of an Accessory Activity Required Specifically for
Cubilin Brush-Border Expression and Intrinsic Factor-Cobalamin
Absorption
By
Danbin Xu,
Renata Kozyraki,
Thomas C. Newman, and
John C. Fyfe
From the Department of Microbiology, College of Veterinary Medicine,
and MSU-DOE Plant Research Laboratory, Michigan State University, East
Lansing, MI; and the Institut National de la Santé et de la
Recherche Médicale, U489, Hôpital Tenon, Paris, France.
 |
ABSTRACT |
Cubilin is a high molecular weight multiligand receptor that
mediates intestinal absorption of intrinsic factor-cobalamin and
selective protein reabsorption in renal tubules. The genetic basis of
selective intestinal cobalamin malabsorption with proteinuria was
investigated in a canine model closely resembling human
Imerslund-Gräsbeck syndrome caused by cubilin mutations. Canine
CUBN cDNA was cloned and sequenced, showing high identity with
human and rat CUBN cDNAs. An intragenic CUBN marker was
identified in the canine family and used to test the hypothesis of
genetic linkage of the disease and CUBN loci. Linkage was
rejected, indicating that the canine disorder resembling
Imerslund-Gräsbeck syndrome is caused by defect of a gene product
other than cubilin. These results imply that there may be locus
heterogeneity among human kindreds with selective intestinal cobalamin
malabsorption and proteinuria and that normal brush-border expression
of cubilin requires the activity of an accessory protein.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
GASTROINTESTINAL cobalamin (vitamin
B12) absorption is a complex and highly specific process
for assimilation of a dietary nutrient essential for normal
hematopoiesis and integrity of the central nervous system.
Imerslund-Gräsbeck syndrome (I-GS) is a rare autosomal recessive
disorder, originally described in Norway1 and
Finland,2 that is characterized by selective cobalamin
malabsorption, leading to juvenile-onset severe megaloblastic anemia,
and proteinuria. The disorder was mapped to a locus on chromosome
10p12.1 (MGA 1) in Finnish, Norwegian, and Saudi Arabian kindreds.3,4 The intrinsic factor-cobalamin (IF-cbl)
receptor is a 460-kD apical brush-border multiligand-binding protein
functioning in distal small intestinal and renal proximal tubule
epithelia5-10 and was an obvious candidate gene for I-GS.
The IF-cbl receptor was recently named cubilin in recognition of its
unique domain structure,7 and the human gene locus
(CUBN) was mapped within the MGA 1 locus.11 Accordingly, 2 disease-specific mutations in
the CUBN locus were recently demonstrated in Finnish
kindreds.4
A canine model of autosomal recessive I-GS has been described in which
immunoelectron microscopy and cell fractionation studies demonstrated
failure of cubilin expression in apical brush border membranes of ileum
and renal cortex, whereas other brush-border proteins were expressed
normally.12,13 Similar to I-GS patients, affected dogs
develop hematologic and metabolic signs of selective cobalamin
deficiency in the early juvenile period and excrete several cubilin
ligands in urine8 (Fyfe et al, unpublished data). Purified normal and affected dog renal cubilin
comigrated during sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE), but affected dog cubilin had abnormal
proteolytic peptide profiles and the asparagine-linked oligosaccharides
were endoglycosidase H-sensitive.13 These findings
suggested that affected dog cubilin did not fold properly and did not
reach the mid-Golgi compartment of the biosynthetic pathway, most
likely being retained in the endoplasmic reticulum (ER). Many such
so-called ER storage diseases that selectively inhibit cell surface
expression of a plasma membrane or secretory protein have been
described.14,15 With the exception of abetalipoproteinemia,
these disorders have been attributed to mutations in the coding
sequence of the exportable protein. Therefore, we cloned canine cubilin
cDNA and used genetic linkage analysis to test the hypothesis that a
cubilin mutation caused inherited selective cobalamin malabsorption
with proteinuria in this family (canine I-GS). The data indicate that
canine I-GS and the canine CUBN locus segregate independently,
thus eliminating the CUBN locus as the genetic basis of the disorder.
| |
MATERIALS AND METHODS |
The parents (members of a breeding colony maintained at Michigan State
University, East Lansing, MI) and 23 offspring, including 13 affected
and 10 clinically normal dogs, of matings between an affected female
and an obligate carrier male were studied. The disease phenotype of
each was determined by monitoring puppies until 12 to 16 weeks of age
without parenteral cobalamin administration for growth and laboratory
abnormalities previously described12 and the same
parameters for 3 to 4 weeks after parenteral cobalamin administration.
Peptide sequence was obtained from canine renal cubilin purified,
separated by SDS-PAGE, and transferred to polyvinylidene difluoride
membrane as described.13 In situ protease digestion and
peptide sequencing were performed by the Protein Chemistry Facility of
the Worcester Foundation for Experimental Biology (Shrewsbury, MA). A
canine renal tubule cDNA library16 was screened with a rat
and canine partial cDNA probes by standard methods.17 Hybridizing clones containing overlapping inserts were sequenced on
both strands by automated dideoxy termination cycle sequencing methods
(ABI 373A Sequencer; Applied Biosystems, Inc, Foster, CA). Position 1 of the canine cubilin cDNA refers to the first nucleotide of the
full-length cDNA; the A residue of the first ATG is nucleotide 74. (Canine CUBN nucleotide sequences reported here have been
submitted to GenBank: full-length cDNA, accession no. AF137068; partial
genomic DNA, accession no. AF137069.)
To locate a segregating canine CUBN variation for genotyping,
the CUBN intron/exon structure was partially determined by
polymerase chain reaction (PCR) and sequencing. Genomic DNA was
isolated from liver or blood samples by standard methods,17
and portions of the CUBN gene were amplified using various
combinations of the primers 838F,
5'-AGCCTGCGTGCTGGACATAGAC-3'; 947F,
5'-GGCTGGCAAGGAAATGGATATAGT-3'; 1150R,
5'-TGGGTGGCAGCCTCCATTATTGA-3'; and 1341R,
5'-CAGCCCAACCTGATTCACACTTA-3' from the cDNA sequence. PCR
reactions of 50 µL contained 1× PCR buffer, 0.4 mmol/L of each
deoxynucleotide, 0.5 µmol/L of each primer, and 500 ng of genomic DNA
template. TaKaRa LA Taq polymerase (2.5 U; PanVera
Corp, Madison, WI) was added after 2 minutes at 94°C, and reactions
were performed for 35 cycles of 98°C for 20 seconds and 68°C
for 20 minutes. Obligate carrier male and affected female DNAs were
amplified with primers 947F and 1150R, the products were cloned (pCR
II; Invitrogen, San Diego, CA), and 6 individual clones from each dog
were sequenced. Southern blots of canine genomic DNA digested with the
restriction endonucleases EcoRI, BamHI,
HindIII, Pst I, Xba I, and Stu I were
prepared and hybridized by standard methods17 to a canine
cubilin cDNA probe (bp 947-1150).
CUBN marker genotyping was by PCR amplification of an
identified intron variation (CIV), a 17-base insertion/deletion
sequence, using primers CIVF,
5'-GATCACAGGCCTACAGCTCCATT-3', and CIVR,
5'-CCAGGCCAACCAGAGATCTTCTA-3', and producing
allele-specific products of 199 and 182 bp that were separable by
electrophoresis on 4% agarose gels. Reactions were 50 µL containing
1× PCR buffer, 0.37 mmol/L each deoxynucleotide, 0.25 µmol/L of
each primer, and 100 ng of DNA template. Taq DNA polymerase
(2.5 U; GIBCO/BRL, Bethesda, MD) was added after 5 minutes at 95°C,
and reactions were performed for 28 cycles of 95°C for 30 seconds,
65°C for 1 minute, and 72°C for 2 minutes.
| |
RESULTS AND DISCUSSION |
Canine cubilin cDNA of 11,282 bp was cloned, showing 73 bp of 5'
and 349 bp of 3' untranslated sequence and a 10,860-bp open reading frame. The 3,620 residue deduced amino acid sequence had 83%
identity with human11 and 70% identity with rat
cubilin.7 The structural features identified in human and
rat cubilin and conserved in the deduced dog protein included a furin
cleavage site after Arg32, an N-terminal amphipathic helical pattern
recently suggested to mediate membrane interactions,10 and
154 Cys residues participating in 77 domain-stabilizing disulfide
bonds. Identity of the cloned sequence was further confirmed by the
presence of internal peptides sequenced from purified canine renal
cubilin (KIKLNEEDLGEXLHQ, IDFQQPRMATERG, KLVDLERK, PFYPNVYPGER,
VTGQSGIIESSGYPT, and VGNADGPLMXR) distributed throughout the deduced
protein sequence.
Partial intron/exon structure of canine CUBN and a segregating
CUBN variation in an intron between bp 1079 and 1080 of the cDNA sequence were identified (Fig 1A).
Sequence of the PCR products demonstrated consensus splice donor and
acceptor sites at the points at which genomic sequences diverged from
cDNA sequence. In the 5' to 3' direction, 4 introns (2.2, 0.9, 2.0, and 0.2 kb) and 3 exons (cDNA sequences 948-1079, 1080-1175, and 1176-1294) were defined. A 17-bp insertion
(5'-CAGAACATTGTTTATGC-3') was found 187 bp 5' of the
3' intron/exon boundary in 3 of 6 clones of the PCR-amplified
0.9-kb intron from a clinically normal, carrier male (F274) and in all
6 clones from an affected female (F284). Single hybridizing bands of 5 to 10 kb, identical in carrier and affected dog DNA, were observed on
Southern blots of canine genomic DNA digested with 6 different
restriction enzymes and hybridized to a probe of CUBN cDNA
sequence between bp 947 and 1150, thus confirming that the identified
17-bp variation was in a unique region of the canine genome (data not
shown).
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| Fig 1.
Independent segregation of canine I-GS and CUBN
loci. (A) Four introns (horizontal lines) and included exons
(vertical boxes) were defined by PCR amplification using CUBN
cDNA primers and sequencing the products. A 17-bp variation (vertical
line) was found in the 0.9-kb intron for which dog F274, an obligate
carrier of canine I-GS, was heterozygous and dog F284, an affected dog,
was homozygous. (B) Solid symbols indicate I-GS affected dogs,
half-solid symbols indicate obligate carriers, squares are males, and
circles are females. DNA from offspring of matings between dogs F274
and F284 was amplified by PCR using primers flanking the 17-bp
variation, producing allele-specific products of 199 and 182 bp.
Results of 10 offspring are shown, with the stars indicating
recombinants.
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Genetic linkage of canine I-GS and CUBN was investigated in 10 clinically normal and 13 affected offspring of matings between dogs
F284 and F274. The disease phenotype of each dog was determined by the
following criteria: affected dogs failed to gain weight after 9 to 13 weeks of age; they had low serum cobalamin concentrations, mild
megaloblastic dyshematopoiesis, methylmalonic aciduria, and proteinuria; and all abnormalities other than proteinuria were reversed
by parenteral cobalamin administration. In this family, canine I-GS is
a fully penetrant, autosomal recessive trait.12 Therefore,
affected offspring from these matings are homozygous and clinically
normal littermates are heterozygous at the I-GS disease locus.
CUBN genotyping was performed by PCR amplification of
allele-specific products using primers flanking the 17-bp CUBN
variation. PCR confirmed that the affected dam, homozygous
at the disease locus, was homozygous for the intronic CUBN
insertion and that the clinically normal sire, heterozygous at the
disease locus, was heterozygous at the CUBN locus (Fig 1B).
However, 13 recombinants were detected among 23 offspring of these
matings, a recombination fraction (0.56) that did not differ from the
recombination fraction (0.5) expected under the hypothesis of
independent segregation of the CUBN and disease loci
( 2 = .39, df = 1, P = .53). A disease trait
locus and a marker locus on a different chromosome, or located far from
the disease locus on the same chromosome, recombine randomly (at a
frequency of 0.5 in large samples) and segregate independently during
meiosis. Thus, in contrast to I-GS reported in some human
kindreds,4 the linkage data above indicate that canine I-GS
in this kindred is not caused by mutation of CUBN or any gene
within 50 recombination units either side of the canine CUBN
locus. (A recombination unit [equal to 1% recombination and called a
centiMorgan] in mammals is equivalent, on average, to ~1 Mb of DNA.)
But still, affected dogs lack apical brush-border expression of cubilin
in ileal and renal epithelia,13 causing selective cobalamin
malabsorption12 and selective proteinuria,8
respectively. Therefore, the absence of genetic linkage of the canine
CUBN marker to canine I-GS indicates there must be some other
gene, distant from CUBN, the product of which is required for
normal cubilin folding, exit from the ER, and/or transport to the
brush-border. Because cellular physiology of humans and dogs is highly
homologous, these findings suggest that human I-GS may exhibit locus
heterogeneity in addition to allelic heterogeneity at the CUBN
locus. Human I-GS remains to be mapped in kindreds of various ethnic backgrounds.
There are at least 2 genes whose products associate with
cubilin5,7 that are not linked to the human MGA 1 locus and defects of which could explain our findings and/or be
implicated in some forms of human I-GS. The endocytic receptor, megalin
(gp330), is postulated to anchor cubilin in the apical membrane and to facilitate endocytosis of cubilin-ligand complexes.7
Receptor-associated protein (RAP) is a molecular escort of the
lipoprotein receptor-related proteins, including megalin, and may also
facilitate proper folding of cubilin within the ER.18
Alternatively, there may be activities of other gene products, yet to
be determined, that are specifically required for ER-export competence
and brush-border expression of cubilin.
| |
ACKNOWLEDGMENT |
The authors thank Pierre Verroust, Søren Moestrup, Donald Patterson,
Paula Henthorn, and Karen Friderici for fruitful discussions; Meg Weil,
Mary Lassaline, and Rebeccah Kurzhals for dog care; and Dr Lloyd Shaw
(Woodstock Veterinary Clinic, Woodstock, IL) for initial
referral of the propositi.
| |
FOOTNOTES |
Submitted May 26, 1999; accepted July 8, 1999.
Supported by funds from National Institutes of Health Grants No.
DK45341 (to J.C.F.) and RR02512. R.K. was supported by Association pour
la Recherche contre le Cancer Grant No. 9914.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to John C. Fyfe, DVM, PhD, Department of
Microbiology, 413 Giltner Hall, Michigan State University, East
Lansing, MI 48824; e-mail: fyfe{at}cvm.msu.edu.
| |
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ABSTRACT
INTRODUCTION