RGD Reference Report - The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification.

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The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification.
Authors:	Van Wesenbeeck, L Odgren, PR MacKay, CA D'Angelo, M Safadi, FF Popoff, SN Van Hul, W Marks SC, JR
Citation:	Van Wesenbeeck L, etal., Proc Natl Acad Sci U S A 2002 Oct 29;99(22):14303-8.
RGD ID:	628338
Pubmed:	PMID:12379742 (View Abstract at PubMed)
PMCID:	PMC137879 (View Article at PubMed Central)
DOI:	DOI:10.1073/pnas.202332999 (Journal Full-text)
The toothless (tl) mutation in the rat is a naturally occurring, autosomal recessive mutation resulting in a profound deficiency of bone-resorbing osteoclasts and peritoneal macrophages. The failure to resorb bone produces severe, unrelenting osteopetrosis, with a highly sclerotic skeleton, lack of marrow spaces, failure of tooth eruption, and other pathologies. Injections of CSF-1 improve some, but not all, of these. In this report we have used polymorphism mapping, sequencing, and expression studies to identify the genetic lesion in the tl rat. We found a 10-base insertion near the beginning of the open reading of the Csf1 gene that yields a truncated, nonfunctional protein and an early stop codon, thus rendering the tl rat CSF-1(null). All mutants were homozygous for the mutation and all carriers were heterozygous. No CSF-1 transcripts were identified in rat mRNA that would avoid the mutation via alternative splicing. The biology and actions of CSF-1 have been elucidated by many studies that use another naturally occurring mutation, the op mouse, in which a single base insertion also disrupts the reading frame. The op mouse has milder osteoclastopenia and osteopetrosis than the tl rat and recovers spontaneously over the first few months of life. Thus, the tl rat provides a second model in which the functions of CSF-1 can be studied. Understanding the similarities and differences in the phenotypes of these two models will be important to advancing our knowledge of the many actions of CSF-1.

Annotation Click to see Annotation Detail View

Disease Annotations

Edentulous Mouth (IAGP,ISO)

osteopetrosis (IAGP,ISO)

Gene Ontology Annotations

Biological Process

macrophage differentiation (IEP)

ossification (IMP)

osteoclast differentiation (IMP)

Phenotype Annotations

Mammalian Phenotype

abnormal bone marrow cavity morphology (IAGP)

abnormal long bone morphology (IAGP)

absent teeth (IAGP)

increased bone mineral density (IAGP)

Objects Annotated

Genes (Rattus norvegicus)

Csf1 (colony stimulating factor 1)

Csf1^tl (colony stimulating factor 1; tooth less mutant)

Genes (Mus musculus)

Csf1 (colony stimulating factor 1 (macrophage))

Genes (Homo sapiens)

CSF1 (colony stimulating factor 1)

Strains

F344^tl (toothless (tl))

Additional Information

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The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification.

Mammalian Phenotype