Biomedical subjects

Qianchuan He

Publications and source records attributed to Qianchuan He.

5 recordsLinked to original sources

PubMed2005

Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo.

Amnionless (AMN) and cubilin gene products appear to be essential functional subunits of an endocytic receptor called cubam. Mutation of either gene causes autosomal recessive Imerslund-Gräsbeck syndrome (I-GS, OMIM no. 261100) in humans, a disorder characterized by selective intestinal malabsorption of cobalamin (vitamin B12) and urinary loss of several specific low-molecular-weight proteins. Vital insight into the molecular pathology of I-GS has been obtained from studies of dogs with a similar syndrome. In this work, we show that I-GS segregates in a large canine kindred due to an in-frame deletion of 33 nucleotides in exon 10 of AMN. In a second, unrelated I-GS kindred, affected dogs exhibit a homozygous substitution in the AMN translation initiation codon. Studies in vivo demonstrated that both mutations abrogate AMN expression and block cubilin processing and targeting to the apical membrane. The essential features of AMN dysfunction observed in vivo are recapitulated in a heterologous cell-transfection system, thus validating the system for analysis of AMN-cubilin interactions. Characterization of canine AMN mutations that cause I-GS establishes the canine model as an ortholog of the human disorder well suited to studies of AMN function and coevolution with cubilin.

Animals↗

PubMed2005

Inherited motor neuron disease in domestic cats: a model of spinal muscular atrophy.

Juvenile-onset spinal muscular atrophy was observed in an extended family of purebred domestic cats as a fully penetrant, simple autosomal recessive trait. Affected kittens exhibited tremor, proximal muscle weakness, and muscle atrophy beginning at ~4 mo of age. Apparent loss of function was rapid initially but progressed slowly after 7-8 mo of age, and variably disabled cats lived for at least 8 y. Electromyography and microscopic examination of muscle and nerve biopsies were consistent with denervation atrophy as a result of a central lesion. There was astrogliosis and dramatic loss of motor neurons in ventral but not dorsal horn gray matter of spinal cord and loss of axons in ventral horn nerve roots. These phenotypic findings were similar to mild forms (type III) of spinal muscular atrophy in humans caused by survival of motor neuron mutations, but molecular analysis excluded feline survival of motor neuron as the disease gene in this family. A breeding colony has been established for further investigation of this naturally occurring large-animal model of inherited motor neuron disease.

Age Factors↗

PubMed2003

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

Imerslund-Gräsbeck syndrome (I-GS, megaloblastic anemia 1) is an autosomal recessive disorder characterized by intestinal cobalamin (vitamin B(12)) malabsorption and proteinuria. I-GS-causing mutations are found in either of 2 genes encoding the epithelial proteins: cubilin and amnionless (AMN). Cubilin recognizes intrinsic factor (IF)-cobalamin and various other proteins to be endocytosed in the intestine and kidney, respectively, whereas the function of AMN is unknown. Here we show that cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells and copurify as a tight complex during IF-cobalamin affinity and nondenaturing gel filtration chromatography. In transfected cells expressing either AMN or a truncated IF-cobalamin-binding cubilin construct, neither protein alone conferred ligand endocytosis. In cubilin transfectants, cubilin accumulated in early biosynthetic compartments. However, in cells cotransfected with AMN and the cubilin construct, cubilin trafficked to the cell surface and endosomes, and the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF. These data indicate that cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex, where AMN binds to the amino-terminal third of cubilin and directs subcellular localization and endocytosis of cubilin with its ligand. Therefore, mutations affecting either of the 2 proteins may abrogate function of the cubam complex and cause IG-S.

Amino Acid Sequence↗

PubMed2003

Canine Imerslund-Gräsbeck syndrome maps to a region orthologous to HSA14q.

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.

Anemia, Megaloblastic↗

PubMedDate not supplied

Congenital hypothyroidism with goiter in toy fox terriers.

Congenital hypothyroidism with goiter was observed to segregate as a simple autosomal recessive trait in Toy Fox Terriers (TFTs). Neonatal affected pups exhibited inactivity, abnormal hair coat, stenotic ear canals, and delayed eye opening. Palpable ventrolateral cervical swellings were evident by 1 week of age. Serum thyroid hormone and thyroid-stimulating hormone concentrations were low and high, respectively. Histologic examination of the cervical masses disclosed cuboidal to columnar follicular epithelial cell hyperplasia with widely varying follicular size, shape, and amount of colloid. Oral thyroid hormone replacement therapy restored near-normal growth and development. At 8 weeks of age, radioiodine uptake and perchlorate discharge testing indicated an iodine organification defect. Biochemical analysis of thyroid tissue from affected dogs demonstrated enzymatic iodine oxidation deficiency and lack of sodium dodecyl sulfate-resistant thyroglobulin dimers, suggesting thyroid peroxidase deficiency. A nonsense mutation in the thyroid peroxidase gene of affected dogs was discovered and demonstrated to segregate with the disease. A DNA-based carrier test was developed and currently is used by TFT breeders to prevent this disorder.

Animals↗