RGD Reference Report - The heterozygous disproportionate micromelia (dmm) mouse: morphological changes in fetal cartilage precede postnatal dwarfism and compared with lethal homozygotes can explain the mild phenotype. - Rat Genome Database

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The heterozygous disproportionate micromelia (dmm) mouse: morphological changes in fetal cartilage precede postnatal dwarfism and compared with lethal homozygotes can explain the mild phenotype.

Authors: Seegmiller, RE  Bomsta, BD  Bridgewater, LC  Niederhauser, CM  Montano, C  Sudweeks, S  Eyre, DR  Fernandes, RJ 
Citation: Seegmiller RE, etal., J Histochem Cytochem. 2008 Nov;56(11):1003-11. doi: 10.1369/jhc.2008.951673. Epub 2008 Aug 4.
RGD ID: 11570531
Pubmed: PMID:18678883   (View Abstract at PubMed)
PMCID: PMC2569899   (View Article at PubMed Central)
DOI: DOI:10.1369/jhc.2008.951673   (Journal Full-text)

The disproportionate micromelia (Dmm) mouse has a mutation in the C-propeptide coding region of the Col2a1 gene that causes lethal dwarfism when homozygous (Dmm/Dmm) but causes only mild dwarfism observable approximately 1-week postpartum when heterozygous (Dmm/+). The purpose of this study was 2-fold: first, to analyze and quantify morphological changes that precede the expression of mild dwarfism in Dmm/+ animals, and second, to compare morphological alterations between Dmm/+ and Dmm/Dmm fetal cartilage that may correlate with the marked skeletal differences between mild and lethal dwarfism. Light and electron transmission microscopy were used to visualize structure of chondrocytes and extracellular matrix (ECM) of fetal rib cartilage. Both Dmm/+ and Dmm/Dmm fetal rib cartilage had significantly larger chondrocytes, greater cell density, and less ECM per unit area than +/+ littermates. Quantitative RT-PCR showed a decrease in aggrecan mRNA in Dmm/+ vs +/+ cartilage. Furthermore, the cytoplasm of chondrocytes in Dmm/+ and Dmm/Dmm cartilage was occupied by significantly more distended rough endoplasmic reticulum (RER) compared with wild-type chondrocytes. Fibril diameters and packing densities of +/+ and Dmm/+ cartilage were similar, but Dmm/Dmm cartilage showed thinner, sparsely distributed fibrils. These findings support the prevailing hypothesis that a C-propeptide mutation could interrupt the normal assembly and secretion of Type II procollagen trimers, resulting in a buildup of proalpha1(II) chains in the RER and a reduced rate of matrix synthesis. Thus, intracellular entrapment of proalpha1(II) seems to be primarily responsible for the dominant-negative effect of the Dmm mutation in the expression of dwarfism.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Dwarfism  ISOAcan (Mus musculus)11570531; 11570531mRNA:decreased expression:costal cartilageRGD 
Dwarfism  IEP 11570531mRNA:decreased expression:costal cartilageRGD 
Dwarfism  ISOCol2a1 (Mus musculus)11570531; 11570531DNA:deletion:cds:p.KT206 and 207N(mouse)RGD 
Dwarfism  IAGP 11570531DNA:deletion:cds:p.KT206 and 207N(mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Acan  (aggrecan)
Col2a1  (collagen type II alpha 1 chain)

Genes (Mus musculus)
Acan  (aggrecan)
Col2a1  (collagen, type II, alpha 1)

Genes (Homo sapiens)
ACAN  (aggrecan)
COL2A1  (collagen type II alpha 1 chain)


Additional Information