International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F8 The LOBO Gene Generates Extraordinary Long Bones in Transgenic Mice and is a Candidate Gene for Albright Hereditary Osteodystrophy

Andreas Rump1, Jochen Hess2, Thomas Aigner3, Thomas Liehr4, Andre Rosenthal1, Thomas Wirth2. 1Institut fur Molekulare Biotechnologie, Abt. Genomanalyse, Jena, Germany; 2Institut fur Medizinische Strahlenkunde und Zellforschung, Werzburg, Germany; 3Institut fuer Pathologie, Werzburg, Germany; 4Institut fur Humangenetik, Jena, Germany

Bone development is a highly complex process controlled by many different gene products. For both clinical and scientific reasons the identification and characterization of genes regulating bone growth is of fundamental interest.

In the process of generating transgenic mice by random cassette mutagenesis we have identified an insertion mutant with significantly elongated bones. Abnormal bone growth results in progressive body deformation of thesemice. As a consequence, reproduction of affected females is extremely inefficient. The long bone phenotype is a dominant trait. The heterozygous offspring completely exhibits the described phenotype.

We have cloned the insertion locus and could show that the cassette has been inserted into a single copy gene, which we have designated LOBO (for "LOng BOnes"). The gene has been isolated from transgenic as well as from wildtype mice. We have shown by comparative sequencing of the wildtype- and the mutant gene that the mutation is caused by integration of the cassette, used for mutagenesis, into an intron in the middle of the gene. The exons are unaffected. However, the insertion completely abolishes transcription of the affacted allele.

The murine LOBO gene is located on Chromosome 1, Band D. The human LOBO homologue is located on 2q37 which is synthenic to murine 1 band D. We have sequenced both the murine and the human LOBO gene along with the corresponding cDNAs. Both genes have a length of about 250 kb and generate a transcription product which is 3.8 kb long. The LOBO protein is highly conserved from yeast to man. It consists of 870 amino acids and shows high similarity to S.pombe Dis3 gene, which has previously been demonstrated to be part of a heterotrimeric G-Protein, involved in cell cycle control. Albright hereditary osteodystrophy (AHO), mainly characterized by short stature, obesity, round face, and brachydactyly, has previously been mapped by deletions in 2q37 and to a locus on 20q13. The gene on 20q13 causing AHO has shown to be a G-protein. Due to the similarity to Dis3 and its location on human 2q37, the LOBO gene is a strong candidate for Albright hereditary osteodystrophy. Currently, we are in the process of testing this hypothesis by fluorescence in-situ hybridization (FISH) of metaphase chromosomes from Albright patients with microdeletions in 2q37.

 


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